Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Liver Cirrhosis. Core disease mechanisms, molecular and cellular pathways,...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Anti-fibrotic treatments for chronic liver diseases: The present and the future

• Authors: Naoshi Odagiri, T. Matsubara, Misako Sato-Matsubara, H. Fujii, M. Enomoto et al.
• Year: 2020
• Venue: Clinical and Molecular Hepatology
• URL: https://www.semanticscholar.org/paper/83762b91dfae05a203293ea68c44cc534ecdb1e1
• DOI: 10.3350/cmh.2020.0187
• PMID: 33317250
• PMCID: 8273638
• Citations: 49
• Influential citations: 1
• Summary: Molecular mechanisms of liver fibrosis are summarized, the development of novel anti-fibrotic therapies are discussed, and the use of liver transplantation for severe cases is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.553) > Liver cirrhosis is a late-stage of chronic hepatitis and currently the 11 th most common cause of death globally 1 . Decompensated cirrhosis, the most advanced stage of cirrhosis, is accompanied by severe complications, including liver failure, opportunistic infection, and portal hypertension (resulting in ascites, hepatic encephalopathy, or gastroesophageal varices), that threaten the lives of patients 2 . Cirrhosis is accompanied by extensive tissue scarring and an increase in intrahepatic vascular resistance. Cirrhosis develops from chronic hepatitis, that can be caused by hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), autoimmune hepatitis, and genetic diseases, including hemochromatosis and Wilson's disease 3 . Recently, progress made in antiviral drugs has contributed to a decrease in viral hepatitis, while the proportion of cirrhosis and liver cancer caused by ALD and NASH has been increasing, particularly in western countries 4 . Research on liver fibrosis, including the development of cirrhosis therapy, has made remarkable progress. However, effective drugs for cirrhosis treatment are not yet available for clinical use. Development of effective cirrhosis therapies requires the ability to not only target specific cell types, but also to elucidate further mechanisms of liver fibrosis with a comprehensive understanding of intercellular molecular networks. This review will highlight the current status of anti-fibrotic drug development and review the recent studies investigating the molecular mechanisms of liver fibrosis. 5 currently active or in recruiting phase 1-3. Here, developing anti-fibrotic drugs are summarized from the perspective of cell-targeting strategies.

[2] The Molecular Mechanisms of Liver Fibrosis and Its Potential Therapy in Application

• Authors: Dan-Dan Zhang, Yaguang Zhang, Bing Sun
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/f308db0969da050d08fd697b10aa399309d855ea
• DOI: 10.3390/ijms232012572
• PMID: 36293428
• PMCID: 9604031
• Citations: 80
• Summary: The pathogenic mechanisms of liver fibrosis and signaling pathways involved, as well as various molecular targets for liver fibrotic treatment are reviewed, which include small molecules and natural compounds.
• Evidence snippets:
• Snippet 1 (score: 0.553) > Long-term viral infections (HBV, HCV), alcohol abuse, fatty diets, autoimmune disorders, etc., are responsible for chronic liver disease that progresses from hepatic steatosis to inflammation, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Liver fibrosis has a significant influence on the morbidity and mortality of people with liver disease. Cirrhosis is associated with a higher risk of death and a higher incidence of hepatocellular cancer. Based on previous research, it is feasible to relieve or reverse the progression of liver fibrosis with, for instance, drugs to treat HBV and HCV that can reverse fibrosis in patients. However, there are currently no FDA and EMA-approved therapies to directly treat liver fibrosis. Understanding the pathogenesis and mechanisms of liver fibrosis and its clinical implications is vital to developing new antifibrotic therapies. Various cells and cellular signaling pathways are engaged in the mechanisms of liver fibrosis. Chronic liver disease can start with hepatocyte injury and inflammation associated with the production of cytokines and chemokines, such as TGF-b, IL-6, and TNF-a, then activate HSCs. The HSCs serve as the major cell type in the progression of liver fibrosis; its activation is intimately related to collagen synthesis and ECM accumulation. > The anti-fibrosis agents include lifestyle modification, bariatric surgery, and pharmacologic treatments, which include small molecular inhibitors, proteins, antibodies, and natural compounds. Targeting liver lipid metabolisms and oxidative stress, targeting liver inflammation and cell death, and targeting liver fibrosis are all examples of clinical trials and pre-clinical testing that focus on different characteristics of liver fibrosis. A THR-b agonist called Resmetirom was evaluated in a Phase III trial, and the latest results showed that it was effective in patients with NAFLD. Patients with F2-F3 fibrosis will be enrolled in the advanced research. > In conclusion, the complexes of the pathogenesis and mechanisms suggested combination therapies that target two or more strategies may be needed.

[3] Identifying the role of Phytomolecules in the management of liver diseases by modulating NRF2 pathway: A Scoping Review Protocol

• Authors: Ajay Mili, P. Rajkhowa, K. Nandakumar, Richard Lobo
• Year: 2024
• Venue: F1000Research
• URL: https://www.semanticscholar.org/paper/b173f8e47e43753070369a15e7dd11762e1f287e
• DOI: 10.12688/f1000research.150635.2
• PMID: 40271118
• PMCID: 12015427
• Summary: A scoping review is expected to help understanding the role of Phytomolecules in preventing liver diseases by modulating the NRF2 pathway and serve as a foundational step toward developing targeted interventions to improve liver health outcomes and reduce the global burden of liver diseases.
• Evidence snippets:
• Snippet 1 (score: 0.500) > Liver diseases represent a significant global health challenge, including a variety diseases including viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), drug-induced liver injury (DILI), and liver cirrhosis. 1,2 The liver, a pivotal metabolic organ, plays an important role in physiological processes including detoxification, metabolic regulation, protein biosynthesis, bile secretion, and immunomodulation. Intracellular reactive oxygen species (ROS) are produced internally, for instance during mitochondrial oxidative phosphorylation, or can emerge through interactions with external agents such as xenobiotic substances. For maintain the ROS levels, Liver has various antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase (SOD). Any imbalance in the working of the antioxidant enzymes can lead to oxidative stress and it is one of the key factors in the progression and onset of liver diseases. 3,4 e Nuclear factor erythroid 2-related factor 2 (NRF2) pathway has emerged as a promising target for managing liver diseases. NRF2, a transcription factor, is integral to cellular defense mechanisms against oxidative stress and inflammation. Upon activation, NRF2 facilitates the expression of various genes involved in antioxidant and detoxification processes, thereby increasing the synthesis of antioxidant enzymes and proteins that mitigate the negative impacts of ROS and pro-inflammatory mediators. Growing evidence implicates NRF2 pathway dysregulation in liver disease pathogenesis and progression. Both experimental and clinical investigations have explored NRF2 modulation to mitigate liver damage, attenuate inflammation, and enhance hepatocyte viability. 5,6 Consequently, identifying compounds capable of activating the NRF2 pathway holds potential for advancing liver disease management strategies. > Phytomolecules, also known as phytochemicals or secondary metabolites, have recently been gaining a distinguished status as a potential source of drugs for treating various diseases.

[4] Basic and Clinical Advances in Chronic Liver Inflammation

• Authors: H. Enomoto, A. Tamori, H. Yoshiji, E. Seki
• Year: 2016
• Venue: Mediators of Inflammation
• URL: https://www.semanticscholar.org/paper/3d41abce2962c7757c197fb58e2c5ada322d6fb6
• DOI: 10.1155/2016/1571457
• PMID: 27006527
• PMCID: 4783579
• Summary: This special issue is proposed to provide recent basic and clinical findings in chronic liver inflammation and its complications, and introduces papers regarding the complications of progressed liver diseases.
• Evidence snippets:
• Snippet 1 (score: 0.499) > Continuous liver inflammation causes fibrotic changes and leads to the development of liver cirrhosis and liver cancer. Recent biological and medical advances have clarified the mechanisms of chronic liver inflammation and succeeded in providing new therapies for various liver diseases. We proposed this special issue to provide recent basic and clinical findings in chronic liver inflammation and its complications. > Regarding the diagnosis and treatment of liver inflammation, A. Tsutsui et al. showed the clinical utility of the Digestive Disease Week Japan 2004 (DDW-J) scale, which has been used as an objective diagnostic tool for drug-induced liver injury in Japan. A. Tamori et al. reviewed remarkable progression in antiviral treatments for hepatitis C virus (HCV), including DAAs (direct-acting antivirals or direct antiviral agents). > We also introduce papers regarding the complications of progressed liver diseases in this special issue. The prognoses of cirrhotic patients are highly dependent on their liver function, and A. Hassan et al. showed that L-carnitine administration helps maintain and improve liver functions after transarterial chemoembolization. Additionally, malnutrition is a frequently observed complication which is known to be associated with a poor prognosis. Y. Osaki and H. Nishikawa reviewed the nutritional problems of cirrhosis, focusing on a recent hot topic “sarcopenia.” Portal hypertension is a major problem along with the progression of chronic liver disease. The paper by K. Kotani et al. suggested the association of the immune system with the development of portal hypertension. Hepatocellular carcinoma is also a prognosis-determining complication of patients with chronic liver inflammation. K. Shindo et al. showed the clinical utility of a semiannual imaging surveillance program in patients without hepatitis viral infection. > With regard to the basic mechanisms of chronic liver inflammation, H. Tsutsui et al. reviewed the roles of IL-1 family cytokines in the development of various liver diseases, including IL-1 family cytokine-mediated molecular and cellular networks. Coinfection of HCV and human immunodeficiency virus (HIV) cooperatively leads to the progression of liver disease. Along this viewpoint, the paper by M. C. Liberto et al., which described the specific

[5] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

• Authors: Hao Xiong, Jinsheng Guo
• Year: 2025
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
• DOI: 10.3390/ph18040507
• PMID: 40283943
• PMCID: 12030350
• Citations: 7
• Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
• Evidence snippets:
• Snippet 1 (score: 0.498) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[6] A Review of Liver Fibrosis and Emerging Therapies

• Authors: R. Nathwani, B. Mullish, David Kockerling, R. Forlano, P. Manousou et al.
• Year: 2019
• Venue: European Medical Journal
• URL: https://www.semanticscholar.org/paper/25364079376a04271c592a3b19c7784456f7a093
• DOI: 10.33590/emj/10310892
• Citations: 12
• Influential citations: 1
• Summary: Current knowledge in the pathophysiology of hepatic fibrosis is discussed, including characteristics of the extracellular matrix, signalling pathways, and hepatic stellate cells, as well as up-to-date anticoagulant therapies and agents targeting the hepaticStellate cell.
• Evidence snippets:
• Snippet 1 (score: 0.493) > The burden of chronic liver disease continues to grow, with 0.1% of the European population affected by cirrhosis, the most advanced stage of hepatic fibrosis. 1 Although the aetiology of the disease varies between countries, fibrogenesis is the common pathological mechanism that causes cirrhosis. Fibrosis occurs following chronic liver injury from a range of insults including toxins (alcohol), infections (hepatitis B [HBV] and C viruses [HCV]), and metabolic disease (nonalcoholic fatty liver disease). Such insults drive inflammation, resulting in increased synthesis and altered deposition of extracellular matrix (ECM) components, and impaired regeneration and wound healing responses. 2 This is a complex, dynamic process, involving recruitment and activation of platelets, inflammatory cells, hepatic stellate cells (HSC), and other ECM-producing cells including portal fibroblasts, hepatocytes, cholangiocytes, and bone marrow-derived cells. 3 The end result, cirrhosis, is defined by profound distortion of hepatic microarchitecture, ultimately resulting in the development of portal hypertension. 4 istologically, cirrhosis is characterised by regenerative nodules of liver parenchyma separated by, and encapsulated in, fibrotic septa, with a clinical consequence of increased mortality, morbidity, complications of portal hypertension, and diminished quality of life. 2,5 The presence of hepatic fibrosis is a key predictor of prognosis in chronic liver disease, independent of aetiology. 6 Generally this process evolves over decades (usually 20-40 years), but it can be rapidly progressive, as seen in children affected by biliary atresia, drug-induced liver injury, HCV co-infection with HIV, or HCV infection post liver transplantation. 7 nagement of chronic liver disease has largely focussed on aetiology-specific treatments; however, significant progress has been made in understanding the pathophysiology of fibrosis, which has identified targets for potential antifibrotic agents to either halt progression or reverse fibrosis.

[7] Lippia javanica (Burm. F.) Herbal Tea: Modulation of Hepatoprotective Effects in Chang Liver Cells via Mitigation of Redox Imbalance and Modulation of Perturbed Metabolic Activities

• Authors: Veronica F. Salau, O. Erukainure, K. Olofinsan, Recardia Schoeman, M. Matsabisa
• Year: 2023
• Venue: Frontiers in Pharmacology
• URL: https://www.semanticscholar.org/paper/1cb46cd451ad2542524719f171a0261049292aea
• DOI: 10.3389/fphar.2023.1221769
• PMID: 37608895
• PMCID: 10441784
• Citations: 5
• Summary: A potent antioxidant and hepatoprotective effect of L. javanica herbal tea is portrayed, which may support the local usage of the herbal tea as a prospective therapeutic agent for oxidative stress-related liver diseases.
• Evidence snippets:
• Snippet 1 (score: 0.481) > About two million cases of global mortality are attributed to liver diseases, with liver cirrhosis and liver cancer being the most common causes of these deaths (Asrani et al., 2019). Besides increased risks of mortality, chronic liver diseases cause several extrahepatic morbidities which contribute notably to low quality of life. Thus, liver diseases, though underestimated, pose a high economic burden which is a major concern (Stepanova et al., 2017;Asrani et al., 2019). > Regardless of the cause, most chronic liver diseases are typified by oxidative stress (Cichoż-Lach and Michalak, 2014). Excessive reactive oxygen species (ROS) cause disturbances in redox homeostasis which results in oxidative stress, a major pathological mechanism involved in the development and progression of several liver diseases. Oxidative stress induces dire alterations in liver proteins, lipids and DNA components as well as impair pathways involved in normal biological functions of the liver (Li et al., 2014;Li et al., 2015). The liver is the main organ usually attacked by ROS, as the parenchymal cells, hepatic stellate cells, Kupffer cells and endothelial cells of the liver are all vulnerable to oxidative injury, causing damages to each cell types (Cichoż-Lach and Michalak, 2014). Several risk factors including drugs, alcohol, irradiation and environmental pollutants such as heavy metals may mediate hepatic oxidative stress. Damages induced by oxidative stress significantly contribute to impairment of gene expression and progression of liver diseases as well as apoptosis and necrosis (Cichoż-Lach and Michalak, 2014;Li et al., 2015). > Severe disturbances in hepatic glucose and lipid metabolism homeostasis have been recognized as some of the major mechanisms involved in liver diseases such as liver cirrhosis, liver steatosis and fatty liver, with oxidative stress being a key contributor (Miksztowicz et al., 2012;Ding et al., 2018).

[8] Alcoholic liver disease: A current molecular and clinical perspective

• Authors: Koichiro Ohashi, Michael Pimienta, E. Seki
• Year: 2018
• Venue: Liver research
• URL: https://www.semanticscholar.org/paper/b1e6105b8d203c731c0236cc36d027fdc36a60c9
• DOI: 10.1016/j.livres.2018.11.002
• PMID: 31214376
• PMCID: 6581514
• Citations: 97
• Influential citations: 9
• Summary: This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.
• Evidence snippets:
• Snippet 1 (score: 0.479) > Heavy alcohol use is the cause of alcoholic liver disease (ALD). The ALD spectrum ranges from alcoholic steatosis to steatohepatitis, fibrosis, and cirrhosis. In Western countries, approximately 50% of cirrhosis-related deaths are due to alcohol use. While alcoholic cirrhosis is no longer considered a completely irreversible condition, no effective anti-fibrotic therapies are currently available. Another significant clinical aspect of ALD is alcoholic hepatitis (AH). AH is an acute inflammatory condition that is often comorbid with cirrhosis, and severe AH has a high mortality rate. Therapeutic options for ALD are limited. The established treatment for AH is corticosteroids, which improve short-term survival but do not affect long-term survival. Liver transplantation is a curative treatment option for alcoholic cirrhosis and AH, but patients must abstain from alcohol use for 6 months to qualify. Additional effective therapies are needed. The molecular mechanisms underlying ALD are complex and have not been fully elucidated. Various molecules, signaling pathways, and crosstalk between multiple hepatic and extrahepatic cells contribute to ALD progression. This review highlights established and emerging concepts in ALD clinicopathology, their underlying molecular mechanisms, and current and future ALD treatment options.

[9] Mitochondrial dysfunction: A promising therapeutic target for liver diseases

• Authors: Ping Chen, Lichao Yao, Mengqin Yuan, Zheng Wang, Qiu-Yu Zhang et al.
• Year: 2023
• Venue: Genes & Diseases
• URL: https://www.semanticscholar.org/paper/5dd2f32e4958c6928adabac344f80e424e3c9d7f
• DOI: 10.1016/j.gendis.2023.101115
• PMID: 38299199
• PMCID: 10828599
• Citations: 94
• Summary: The mechanisms of mitochondrial dysfunction in the development of acute liver injury and chronic liver diseases, such as hepatocellular carcinoma, viral hepatitis, drug-induced liver injury, alcoholic liver disease, and non-alcoholic fatty liver disease are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.473) > Hepatotoxins (drugs, alcohol consumption, viral or bacterial infection, and lipid deposition) or autoimmune response can induce acute liver injury and chronic liver diseases such as viral hepatitis, drug-induced liver injury, autoimmune hepatitis, alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD). 1 Hepatic fibrosis is a common complication of almost all types of hepatopathies, and if left untreated, liver fibrosis may eventually progress to cirrhosis, liver failure, and hepatocellular carcinoma (HCC). 2e4 Fibrosis is a dynamic process that can be prevented or reverted by eliminating pathogenic factors or carrying out appropriate therapeutic interventions, such as with antiviral drugs that delay the progression of virus-associated hepatic fibrosis. 5e8 Despite these measures, the mortality rate associated with liver diseases has increased from 3% in 2010 to 3.5% in 2019 among all deaths worldwide, thus imposing a huge economic burden globally. 9 Therefore, elucidating the molecular mechanisms of liver injury and developing new potential therapeutic targets is crucial. > Mitochondria serve as the "power station" of eukaryotic cells and play an important role in metabolizing lipids and saccharides to produce energy in the form of ATP. They also participate in many vital cellular activities, including the urea cycle, iron metabolism, calcium storage homeostasis, cell proliferation, and signal transduction. 10 Additionally, they control inflammation and the development of related diseases by regulating innate immune responses. 11 Disruption of these mitochondrial processes may serve as a driving factor for the onset and progression of liver diseases. Furthermore, mitochondria play a role in maintaining the cellular redox state by balancing reactive oxygen species (ROS) production and elimination by the antioxidant defense system. Oxidative stress occurs when impaired mitochondria are unable to scavenge the over-produced ROS, which is considered one of the causative factors for hepatocyte death and liver injury. 12 Reduction of oxidative stress can inhibit the development of liver fibrosis. 13 Furthermore, accumulating evidence suggests that agents targeting different types of mitochondrial dysfunction can improve impaired mitochondrial function.

[10] How to Face Chronic Liver Disease: The Sinusoidal Perspective

• Authors: A. Fernández-Iglesias, J. Gracia‐Sancho
• Year: 2017
• Venue: Frontiers in Medicine
• URL: https://www.semanticscholar.org/paper/0a73e527916b000e1c268b90943caca2cdb81031
• DOI: 10.3389/fmed.2017.00007
• PMID: 28239607
• PMCID: 5300981
• Citations: 48
• Influential citations: 2
• Summary: The present review summarizes the main cellular components of the hepatic sinusoid, to afterward focus on non-parenchymal cells phenotype deregulation due to chronic injury, in the specific clinical context of liver cirrhosis and derived portal hypertension.
• Evidence snippets:
• Snippet 1 (score: 0.470) > Chronic liver disease is one of the most important causes of death worldwide representing 1.03 million deaths per year (1). A variety of toxicants may induce the initiation and progression of CLD, being excessive alcohol consumption, viral hepatitis infection, and hepatic steatosis the most predominant in our time. > One of the key mechanisms contributing to CLD progression is the continuous production and deposition of extracellular matrix (ECM) components such as collagen and glycoproteins, resulting in significant hepatic fibrosis and ultimately leading to the development of liver cirrhosis (or advanced CLD). Histologically cirrhosis is characterized by the formation of aberrant nodules and fibrotic septa in the parenchyma (Figure 1A) (2,3). > Cirrhosis, as a dynamic process, can be clinically classified in different stages: (1) compensated cirrhosis without varices, (2) compensated cirrhosis with varices, (3) decompensated with ascites, and (4) decompensated with variceal bleeding. In the last stage, patients are more vulnerable to several complications such as infection, thrombosis, and development of hepatocellular carcinoma (3,4). From a therapeutic point of view, different stages of the disease can also be considered as different "windows" for treatment; therefore, understanding the pathophysiology of CLD results essential to develop and apply effective treatments to patients with cirrhosis. > Portal hypertension (PH) is the most common and dreadful complication of CLD, and it occurs when the hepatic venous pressure gradient (HVPG) increases above 10 mmHg. Current therapies for PH aim to reduce HVPG below 12 mmHg (or 20% lower than basal pressure gradient) since FiGURe 1 | Major morphological characteristics of microvascular sinusoidal dysfunction in chronic liver disease (CLD). Continuous wound-healing processes in sinusoidal cells due to exogenous toxicants lead to marked changes in their phenotype.

[11] Systems analysis of key genes and pathways in the progression of hepatocellular carcinoma

• Authors: Yu-Kui Shang, Fanni Li, Yi Zhang, Ze-Kun Liu, Zi-Ling Wang et al.
• Year: 2018
• Venue: Medicine
• URL: https://www.semanticscholar.org/paper/0c875ab1950f4970d2823678bdd701d95552b280
• DOI: 10.1097/MD.0000000000010892
• PMID: 29879025
• PMCID: 5999467
• Citations: 5
• Summary: System-level research provided new insights into the molecular mechanisms of HCC carcinogenesis and FOXO1 and DCN, 2 critical tumor suppressor genes that play an important role in liver cirrhosis and HCC development, were defined as adverse prognostic biomarkers for HCC.
• Evidence snippets:
• Snippet 1 (score: 0.470) > Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. [1] HCC accounts for 80% to 90% of primary liver cancers, and the incidence of HCC is growing globally by 3% to 9% annually. [2] HCC neoplasms detected at an early stage can be cured by mainly surgical resection. Treatment options for HCC at an advanced stage are often limited. [3,4] The survival duration of patients with advanced liver cancer is less than 12 months. [3] arly detection of HCC may help improve long-term survival rates. [4] Therefore, there is an urgent need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC, and this information might be helpful for designing novel therapeutic strategies in the future. > Because the liver is especially susceptible to chronic and acute viral injury, alcoholic insults, and nonalcoholic fatty liver disease, it is extremely prone to fibrotic remodeling. [5] Liver fibrosis usually progresses to cirrhosis, which can result in damage to the normal architecture of the liver, followed by an increased probability of the development of HCC. [5] HCC occurs at a rate of 1% to 4% per year once liver cirrhosis is established, and liver cirrhosis underlies HCC in approximately 80% to 90% of cases worldwide. [6] Increasing evidence has demonstrated that the carcinogenesis of HCC is a multistep process triggered by the accumulation of genetic alterations through the activation of different signaling pathways, which drives the transformation of normal cells into malignant cells. [5,7] However, the mechanism behind the progression from liver cirrhosis to HCC remains largely unknown. To the best of our knowledge, no systematic study has been performed to investigate the molecular events leading from liver cirrhosis to HCC. A definition of the sequential molecular events leading from cirrhosis to HCC is urgently needed, and it represents a major challenge in the clinical management of at-risk patients.

[12] Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature

• Authors: Nicolò Manicardi, A. Fernández-Iglesias, Laia Abad-Jordà, F. Royo, M. Azkargorta et al.
• Year: 2021
• Venue: Cancers
• URL: https://www.semanticscholar.org/paper/9b1f187b1d8b1e6dab4e3a50b4bb8899b348a630
• DOI: 10.3390/cancers13112688
• PMID: 34072510
• PMCID: 8198220
• Citations: 28
• Summary: The transcriptome and secretome of primary LSECs during the progression of cirrhosis are defined, revealing specific molecular signatures, novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced chronic liver disease.
• Evidence snippets:
• Snippet 1 (score: 0.466) > Cirrhosis represents the final pre-neoplastic stage of a group of chronic liver diseases (CLD) characterized by a complex ensemble of longstanding pathophysiological processes that alters liver function, architecture and hemodynamics. Cirrhosis constitutes a major public health problem, accounting for roughly 2 million deaths per year worldwide [1]. > In the last decades, many efforts have been made to understand the biological processes involved in CLD. Different studies have demonstrated how liver cells phenotype alterations generate and perpetuate a cascade of mechanisms that altogether lead to the histological distortion and microcirculatory dysfunction typical of the cirrhotic liver [2][3][4], giving rise to portal hypertension (PH), the main non-neoplastic complication of the disease [5]. Nevertheless, many studies on the underlying mechanisms of CLD and PH have been made only at the end-stage of the disease, thus ignoring the chronological changes that promote progression towards cirrhosis. In this context, animal models of liver disease represent an optimal choice when it comes to study the sequential mechanisms of these alterations [6]. > The liver has four main cellular components: hepatocytes (Hep), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and hepatic resident macrophages (HMΦs). All these cells work in synergy, producing molecules that modulate their differentiation and activity [7] and communicating through paracrine and autocrine mechanisms to maintain liver homeostasis [8]. In particular, LSECs shape the permeable wall of the sinusoids and are actively involved in the dynamic communication process with other hepatic cells, where they promote vasoactive, inflammatory and immune functions. LSECs are pivotal regulators of liver microcirculation and fibrosis, and the maintenance of their specific phenotype generates a healthy environment in which liver sinusoids and liver function are preserved [5,9].

[13] Editorial: Chronic Liver Disease: New Targets and New Mechanisms

• Authors: Yanting Ye, Hua Wang, Jinhang Gao, Enis Kostallari
• Year: 2022
• Venue: Frontiers in Molecular Biosciences
• URL: https://www.semanticscholar.org/paper/f3a12f5a46ccf1f35d856465e5c02d73855647ac
• DOI: 10.3389/fmolb.2022.963630
• PMID: 35923468
• PMCID: 9341181
• Citations: 3
• Summary: The most recent advances in CLD are presented, including novel molecular and cellular mechanisms, promising therapeutic targets, new drug delivery methods, and biomarker discovery for liver fibrosis.
• Evidence snippets:
• Snippet 1 (score: 0.461) > Liver cirrhosis is the end stage of CLD, which is featured by irreversible extracellular matrix deposition and damage of liver structure (Cai et al., 2021). Cellular cross-talks, signals from the microenvironment, as well as intracellular signaling are crucial in the development of liver fibrosis and cirrhosis (Kostallari et al., 2018;Gao et al., 2020;Gao et al., 2021;Zeng et al., 2021). Two reviews in this issue stated how the major types of liver cells, including HSCs, hepatocytes, liver sinusoidal endothelial cells, PFs, cholangiocytes and inflammatory cells, participate in the pathogenesis and development of liver cirrhosis. The relevant signaling pathways that contribute to liver fibrosis and prospective therapeutic targets were described thoroughly (Zhang et al.; Gu et al.). Additionally, Li et al. emphasized the influence of mitochondria dysfunction and hypoxia inducible factor-1α (HIF1α)-induced oxygen imbalance on metabolism and immunity in liver fibrosis. > In addition to developing new drugs, exploring the antifibrotic capacity of existing medicines targeting CLD is also interesting. The widely used anti-HBV infection drug tenofovir disoproxil fumarate (TDF) was found to alleviate liver fibrosis via its direct antiviral-independent effects; however, the mechanism involved in reducing fibrosis has not been elucidated, yet. Duan et al. applied genomics analysis to prove that TDF may ameliorate CLD by affecting the expression of genes involved in hepatic immune response and metabolic processes via mmu-miR-155-5p-NF-κB signaling. > Each liver cell type might respond in a different way to a given drug; thus, targeting a signaling pathway in a specific cell type would be more effective. The review from Gu et al. discussed the recent nano-delivery approaches specific-targeting HSCs, immune cells, hepatocytes, and liver sinusoidal endothelial cells for liver fibrosis.

[14] Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells

• Authors: Yawen Hao, Shao-Hua Song, Tao Li, Qiuhong Zai, Ningning Ma et al.
• Year: 2024
• Venue: International Journal of Biological Sciences
• URL: https://www.semanticscholar.org/paper/88e9f02b6346a0e03ddf006e109584088ebd0c55
• DOI: 10.7150/ijbs.92749
• PMID: 38725842
• PMCID: 11077365
• Citations: 17
• Summary: It is demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro and fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis.
• Evidence snippets:
• Snippet 1 (score: 0.457) > Liver fibrosis is a pathophysiological process of dysregulated liver repair caused by persistent liver injury, manifested by the deposition of the extracellular matrix (ECM) and generation of the Ivyspring International Publisher fibrous scar [1]. A variety of liver diseases, such as hepatitis B/C, alcoholic hepatitis, nonalcoholic steatohepatitis (NASH), and biliary tract disease, are responsible for the development of liver fibrosis [2]. Importantly, patients undergoing fibrogenic progression may further develop cirrhosis and hepatocellular carcinoma (HCC), contributing to a significant global health burden [3]. However, liver fibrosis is recognized to be regressive, as observed clinically in patients with hepatitis B infection or alcohol-related liver disease [4,5]. Therefore, elucidating the detailed mechanism of liver fibrosis will facilitate the exploitation of anti-fibrotic strategies. > Activated hepatic stellate cells (HSCs) are well believed to be the key effectors of liver fibrogenesis by producing matrix proteins during chronic liver injury. Therefore, there is an exigent need to clarify the cellular and molecular mechanisms of HSC activation in order for therapeutics to mimic the liver's endogenous capacity. In contrast to the quiescent phenotype in normal liver, HSCs transdifferentiate into myofibroblasts after liver injury, which is characterized by ECM accumulation [1,6]. HSC activation is stimulated by damaged and apoptotic hepatocytes through several converging pathways, which initiate and maintain the activation of HSCs by recruitment of immune cells, release of reactive oxygen species (ROS) and other fibrogenic/ proinflammatory mediators, and disruption of the normal ECM of the space of Disse [5,7]. After ~40 years of steady progress in basic, translational and clinical research, there is a rich appreciation of the mechanism of HSC activation and the pathogenesis of liver fibrosis. Yet, achievement in treating liver fibrosis has been harder won than anyone anticipated since there is still no FDA-approved drugs for the treatment of liver fibrosis.

[15] Hepatic wound repair

• Authors: M. Parola, M. Pinzani
• Year: 2009
• Venue: Fibrogenesis & Tissue Repair
• URL: https://www.semanticscholar.org/paper/1fdf786492f33c80ec4814220e66012ca1da8f98
• DOI: 10.1186/1755-1536-2-4
• PMID: 19781064
• PMCID: 2760508
• Citations: 61
• Influential citations: 1
• Summary: Emerging mechanisms and concepts related to liver fibrogenesis may significantly contribute to clinical management of patients affected by CLDs, thus extending the complication-free patient survival time and reducing the need for liver transplantation.
• Evidence snippets:
• Snippet 1 (score: 0.453) > BackgroundHuman chronic liver diseases (CLDs) with different aetiologies rely on chronic activation of wound healing that represents the driving force for fibrogenesis progression (throughout defined patterns of fibrosis) to the end stage of cirrhosis and liver failure.IssuesFibrogenesis progression has a major worldwide clinical impact due to the high number of patients affected by CLDs, increasing mortality rate, incidence of hepatocellular carcinoma and shortage of organ donors for liver transplantation.Basic science advancesLiver fibrogenesis is sustained by a heterogeneous population of profibrogenic hepatic myofibroblasts (MFs), the majority being positive for α smooth muscle actin (αSMA), that may originate from hepatic stellate cells and portal fibroblasts following a process of activation or from bone marrow-derived cells recruited to damaged liver and, in a method still disputed, by a process of epithelial to mesenchymal transition (EMT) involving cholangiocytes and hepatocytes. Recent experimental and clinical data have identified, at tissue, cellular and molecular level major profibrogenic mechanisms: (a) chronic activation of the wound-healing reaction, (b) oxidative stress and related reactive intermediates, and (c) derangement of epithelial-mesenchymal interactions.Clinical care relevanceLiver fibrosis may regress following specific therapeutic interventions able to downstage or, at least, stabilise fibrosis. In cirrhotic patients, this would lead to a reduction of portal hypertension and of the consequent clinical complications and to an overall improvement of liver function, thus extending the complication-free patient survival time and reducing the need for liver transplantation.ConclusionEmerging mechanisms and concepts related to liver fibrogenesis may significantly contribute to clinical management of patients affected by CLDs.

[16] Melatonin restores zinc levels, activates the Keap1/Nrf2 pathway, and modulates endoplasmic reticular stress and HSP in rats with chronic hepatotoxicity

• Authors: S. Bona, S. A. Fernandes, A. J. Moreira, Graziella Rodrigues, E. Schemitt et al.
• Year: 2022
• Venue: World Journal of Gastrointestinal Pharmacology and Therapeutics
• URL: https://www.semanticscholar.org/paper/c0bb80b9a99d336dc0af053400a3c1a00cb1874e
• DOI: 10.4292/wjgpt.v13.i2.11
• PMID: 35433098
• PMCID: 8968507
• Citations: 13
• Influential citations: 1
• Summary: Melatonin has a hepatoprotective effect in an experimental model of CCl4-induced liver injury, since it reduces oxidative stress, restores zinc levels, and modulates endoplasmic reticulum stress.
• Evidence snippets:
• Snippet 1 (score: 0.453) > Chronic liver diseases are characterized by multistep processes that involve several molecules and cellular events to transform a normal parenchyma into a parenchyma with steatosis, increased collagen deposition, fibrosis, and cirrhosis [1]. Many studies have demonstrated the presence of overproduction of free radicals and reactive oxygen species (ROS) in inflammatory chronic diseases. ROS are able to oxidize macromolecules or activate transcription factors [2][3][4]. The relation between the development of chronic liver diseases and ROS has been widely discussed since oxidative stress may cause damage in lipid, protein, and DNA, producing alterations in cellular redox homeostasis [5]. > Cellular homeostasis can be disrupted by a variety of stimuli, including metabolic imbalance, oxidative stress, and folding of malformed proteins. In response to these stressors, cells induce specific molecular pathways that usually involve the activation of signaling cascades or changes in gene expression. These responses allow cells to adapt to stress and to regain homeostasis. However, if stress is intense or prolonged, the cells are unable to reestablish homeostasis and, in turn, activate pathways that result in cell death [6]. > Carbon tetrachloride (CCl 4 ) is a hepatotoxic drug used in experimental models to evaluate different stages of liver disease and thus define therapeutic strategies. Exposure to CCl 4 have a toxic effect on liver cells, promoting damage in tissue and causing changes in the antioxidant defense mechanism. This process results in an imbalance between ROS production and antioxidative enzymes release [5]. > The antioxidant defense mechanism is dependent on some minerals, including zinc. This mineral is essential for a large number of structural proteins, enzymatic processes, and transcription factors. Its deficiency causes numerous clinical manifestations, such as appetite loss, smell and taste disturbances, cerebral and immune dysfunction, and reduced drug elimination capacity. These clinical characteristics have been observed in chronic liver diseases [7]. > The alteration in cellular redox homeostasis either results in mitochondrial dysfunction or can affect other organelles, such as the endoplasmic reticulum (ER).

[17] Contributions of transgenic mouse studies on the research of hepatitis B virus and hepatitis C virus-induced hepatocarcinogenesis.

• Authors: S. Ohkoshi, H. Hirono, Kazuhiko Watanabe, K. Hasegawa, M. Yano
• Year: 2015
• Venue: World journal of hepatology
• URL: https://www.semanticscholar.org/paper/13ec327d11f26f11bb5d92dc984b9ef2e1ac9c80
• DOI: 10.4254/wjh.v7.i28.2834
• PMID: 26668695
• Summary: Although transgenic mouse models have remarkable advantages, they are intrinsically accompanied by some drawbacks when used to study human diseases, and the results obtained should be carefully interpreted in the context of whether or not they are well associated with human pathogenesis.
• Evidence snippets:
• Snippet 1 (score: 0.451) > When considering the contribution of transgenic mouse studies to the research on hepatocarcinogenesis caused by HBV or HCV, it is important to outline the mechanisms of the disease and consider for which mechanisms transgenic mouse studies can be applied to provide pathogenic and therapeutic contributions. > First, the common mechanism between HBV and HCV is as follows: Once these viruses infect liver, they skillfully evade host immune surveillance and induce chronic necroinflammation. These injuries cause fibrosis and result in liver cirrhosis. Hepatocytes, using their intrinsic regenerative capability, continue to proliferate in order to compensate for the necrotic tissues. Genetic alterations continuously accumulate during these processes, resulting in the formation of a pathogenic state such as cirrhosis from which HCC frequently arises. > Second, viral genes may be involved in hepatocarcinogenesis by directly affecting cellular machineries. The most representative genes of this type that have drawn clinical attention are the genes for HBV X (HBx) and HCV core protein. HBx is multifunctional and may induce the transactivation of many cellular genes [8] . On the other hand, the HCV core protein causes steatosis in the liver and subsequent HCC [9] . Transgenic mouse studies can shed light on the mechanisms of HBx and HCV core protein by enabling assays on the direct actions of these viral genes in vivo. > Third, a mechanism specific to HBV is its integration into the cellular DNA of the host; this may increase the genomic instability and cis-activation of the adjacent cellular genome that may possibly be involved in the regulation of the cell cycle [10] . Importantly, most integrated viral DNA retain the sequences encoding HBxAg, and the HBxAg expressed from the integrated HBV DNA further promotes genetic instability of the host by a variety of mechanisms [10] .

[18] Autoimmune Hepatitis, Primary Sclerosing Cholangitis, and Non-Alcoholic Steatohepatitis Cirrhosis May be More Predisposed to the Development of Hepatocellular Carcinoma

• Authors: Z. Khajehahmadi, H. Tavilani, J. Karimi, M. Rafiee, Z. A. Sadeghabadi et al.
• Year: 2022
• Venue: Unknown venue
• URL: https://www.semanticscholar.org/paper/5f81c58b57181fb5e5436461d70892e55226baba
• DOI: 10.21203/rs.3.rs-1266028/v1
• Summary: The increased levels of AMPK and pAMPK could be a general response to the most common causes of liver diseases, and patients with AIH, PSC, and NASH cirrhosis predispose to the development of HCC more than patients with viral and alcoholic Cirrhosis.
• Evidence snippets:
• Snippet 1 (score: 0.448) > All patients with cirrhosis are in a premalignant condition and predispose to hepatocellular carcinoma (HCC), irrespective of etiology (1). The major causes of cirrhosis include infections (hepatitis B virus (HBV) and hepatitis C virus (HCV)), toxins (alcoholic fatty liver disease (AFLD)), cholestasis (Primary sclerosing cholangitis (PSC)), Autoimmune (Autoimmune hepatitis (AIH)), and metabolic (nonalcoholic fatty liver disease (NAFLD)). For years, viral infections have been reported as the most common causes of cirrhosis but their prevalence has been decreased, mainly due to HBV vaccination (2). On the other hand, the prevalence of cholestasis, AIH, and more speci cally Non-alcoholic steatohepatitis (NASH) cirrhosis have been increased during the last decade (2)(3)(4). It has been declared that immune-mediated mechanisms have crucial role in the pathogenesis of these types of cirrhosis and among them, autoantibodies seem to be the leading cause of AIH, PSC, and NASH cirrhosis (5,6). However, the exact mechanism of pathogenesis of cirrhosis and possible effects of etiologies on the pathogenesis of cirrhosis and on the progression of cirrhosis to HCC has not yet been addressed. AMP-activated protein kinase (AMPK), a eukaryotic cellular energy sensor, is a serine/threonine kinase and has crucial role in the control of cellular homeostasis of specialized tissues including liver, muscle, and fat (7). AMPK is a highly sensitive sensor that responds to the increases in AMP content and promote ATP production. Alongside, it has been shown that AMPK is activated in some pathological condition, like obesity, and controls cellular homeostasis including autophagy, apoptosis, cell cycle, and cell metabolism (8). So, it was predictable that AMPK be dysregulated in different types of diseases, such as hepatic diseases (9).

[19] Diabetes Mellitus and Risk of Hepatic Fibrosis/Cirrhosis

• Authors: Xu Li, Yuan Jiao, Yunlong Xing, P. Gao
• Year: 2019
• Venue: BioMed Research International
• URL: https://www.semanticscholar.org/paper/cb0a220f81d5b6ebc0f1760fed417cdec84d3f22
• DOI: 10.1155/2019/5308308
• PMID: 31080822
• PMCID: 6475555
• Citations: 46
• Summary: Clinical ties between DM and liver fibrosis and hepatic cirrhosis and related biologic mechanisms are examined and pathways contributing to various etiologies of Cirrhosis in conjunction with DM are explored.
• Evidence snippets:
• Snippet 1 (score: 0.448) > The estimated global prevalence of diabetes mellitus (DM), a metabolic disorder characterized by blood sugar and insulin dysregulation [1,2], has an estimated global prevalence of approximately 9%, and by 2030, 300-400 million people will likely be affected worldwide [3], resulting in significant economic and social hardships [4,5]. Unlike other chronic complications of DM, chronic liver disease (CLD) has been overlooked as yet another diabetic sequela, given the higher profiles of alternate pathogenic triggers. However, in many patients with cirrhosis, a major public health issue of global proportions, threatening the general population and imposing severe financial burdens [1,2], the cause of which was once considered "cryptogenic," DM is now accepted as a well-established cause [6]. Cirrhosis-related deaths are in fact increasing, totaling more than one million in 2010 alone [7]. Through a variety of mechanisms, cirrhosis clearly contributes to dysglycemia, whereas DM predisposes patients to serious liver disease [8]. > At present, it is debatable whether type 2 DM is truly influential in the development and progression of liver disease if established risk factors for metabolic syndrome (i.e., obesity, hypertriglyceridemia) are lacking [9]. Furthermore, the risk of cirrhosis may be related to drug class or dosage of any particular antidiabetic agent prescribed [10,11]. > In this clinical review, we examine the association between changes in glucose metabolism and cirrhosis, the molecular mechanisms implicated in various etiologies of cirrhosis in patients with DM, and the relative risk of cirrhosis due to antidiabetic medications and DM duration.

[20] Pharmacotherapy of Liver Fibrosis and Hepatitis: Recent Advances

• Authors: Liang Zhao, Haolan Tang, Zhangjun Cheng
• Year: 2024
• Venue: Pharmaceuticals
• URL: https://www.semanticscholar.org/paper/d764d21b4bdfd952be4e6e529b2cc34d37e43f16
• DOI: 10.3390/ph17121724
• PMID: 39770566
• PMCID: 11677259
• Citations: 18
• Summary: This review aims to systematically review the molecular mechanisms underlying liver fibrosis, focusing on advancements in drug treatments for hepatic fibrosis, and the pharmacological treatments available for common hepatitis leading to liver fibrosis.
• Evidence snippets:
• Snippet 1 (score: 0.447) > In conclusion, the intricate relationship between liver fibrosis and various forms of hepatitis underscores the complexity of hepatic pathophysiology. Liver fibrosis, which entails a progressive scarring process, primarily arises from chronic inflammation and injury, commonly seen in conditions, such as viral hepatitis, alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD), drug-induced liver injury, and autoimmune hepatitis (AIH). Understanding the underlying molecular mechanisms is essential, as they not only elucidate the pathogenesis of liver fibrosis but also reveal potential therapeutic targets [200]. For example, signaling pathways involving transforming growth factor-beta (TGF-β) and platelet-derived growth factor (PDGF) are critical for the activation of hepatic stellate cells, which are pivotal in fibrosis development [201,202]. > Pharmacological interventions show considerable promise in managing liver fibrosis. Current treatment strategies focus on halting or reversing the fibrotic process, with emerging therapies, including antifibrotic agents and immune modulators, demonstrating encouraging results in clinical settings. However, challenges persist in the therapeutic landscape, such as drug efficacy, patient compliance, and the need for individualized treatment approaches. It is vital to consider the findings of various studies, as some interventions may show promise in specific patient cohorts while yielding variable outcomes in others [64]. This heterogeneity demands nuanced interpretations of data and a comprehensive approach to clinical trial design. > The future of liver fibrosis research holds great promise, with a multifaceted approach that encompasses molecular biology, biomarker discovery, and the development of novel therapeutics. As we delve deeper into the molecular pathways that govern liver fibrosis, we are not only gaining a better understanding of the disease but also identifying potential targets for intervention. This is crucial for the development of personalized medicine, where treatments can be tailored to individual patients based on their unique genetic and molecular profiles [203]. > The quest for biomarkers is particularly exciting, as these molecular indicators can predict treatment responses and disease progression.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

Disorder

• Name: Liver Cirrhosis
• Category: Complex
• Existing deep-research providers: falcon
• Existing evidence reference count in YAML: 18

Key Pathophysiology Nodes

• Hepatocyte Injury and Death
• Hepatic Stellate Cell Activation
• Portal Hypertension
• Synthetic Dysfunction
• Deep research literature mapping

Citation Inventory (for evidence mapping)

• DOI:10.1002/mco2.721
• DOI:10.33696/gastroenterology.5.054
• DOI:10.3390/biomedicines12102229
• DOI:10.3390/ijms25137405
• DOI:10.3390/ijms25147873
• DOI:10.3390/ijms252312859
• DOI:10.3390/ph17121724

Pathophysiology description (current understanding, 2023–2024 focus) Cirrhosis represents the end-stage of chronic liver injury, characterized by persistent inflammation, progressive fibrogenesis with excessive extracellular matrix (ECM) deposition, vascular remodeling of the hepatic sinusoidal bed (“capillarization”), and formation of regenerative nodules that distort architecture and drive portal hypertension and organ failure (MedComm, 2024; https://doi.org/10.1002/mco2.721) (dong2024livercirrhosismolecular pages 20-21). Hepatic stellate cells (HSCs) are the dominant source of myofibroblasts and fibrillar collagens (type I predominates) once activated by injury cues (e.g., TGF-β, PDGF, inflammatory cytokines, oxidative stress); they lose retinoid stores, express α-SMA, proliferate, migrate, and deposit ECM (Biomedicines, 2024; https://doi.org/10.3390/biomedicines12102229) (somnay2024liverfibrosisleading pages 1-2, somnay2024liverfibrosisleading pages 2-4). Liver sinusoidal endothelial cells (LSECs) lose fenestrae, gain basement membrane and collagen IV, and exhibit reduced nitric oxide (NO) bioavailability, increasing intrahepatic resistance and initiating/propagating portal hypertension—the “NO paradox” of low intrahepatic and high splanchnic NO (IJMS, 2024; https://doi.org/10.3390/ijms252312859) (somnay2024liverfibrosisleading pages 2-4, zhao2024pharmacotherapyofliver pages 2-4). Innate and adaptive immune cells (Kupffer cells/monocyte-derived macrophages, neutrophils, MAIT, T and B lymphocytes) participate in injury sensing, cytokine production, and HSC modulation—including profibrotic (e.g., TGF-β/IL‑17) and fibrolytic phases during regression (IJMS, 2024; https://doi.org/10.3390/ijms25147873; Pharmaceuticals, 2024; https://doi.org/10.3390/ph17121724) (akkız2024liverfibrosisfrom pages 23-25, zhao2024pharmacotherapyofliver pages 2-4). Single-cell and spatial transcriptomic work and molecular subtyping reveal heterogeneity of inflammatory and cholangiocyte-associated programs in advanced disease that may inform precision therapeutics (Archives of Gastroenterology Research, 2024; https://doi.org/10.33696/gastroenterology.5.054) (addissouky2024translatingmolecularheterogeneity pages 7-8).

Core Pathophysiology (mechanisms, pathways, processes) - HSC activation and ECM deposition: TGF-β/Smad is a master profibrotic driver increasing collagen (COL1A1/1A2) and TIMPs while reducing MMP activity; PDGF stimulates HSC proliferation and migration via PI3K–AKT/MAPK; integrin–ECM stiffness signaling sustains activation (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17121724) (zhao2024pharmacotherapyofliver pages 2-4). Quote: “collagens are the most abundant ECM components… can increase up to tenfold in cirrhosis” (Pharmaceuticals, 2024) (zhao2024pharmacotherapyofliver pages 2-4). - Endothelial dysfunction and portal hypertension: LSEC capillarization with collagen IV basement membrane and loss of fenestrae increases sinusoidal resistance and portal pressure; endothelial NO is reduced intrahepatically while splanchnic vasodilation augments portal inflow, linking microvascular remodeling to hemodynamics (Biomedicines, 2024; https://doi.org/10.3390/biomedicines12102229) (somnay2024liverfibrosisleading pages 2-4). - Immune dysregulation: Kupffer cells and monocyte-derived macrophages secrete TGF‑β, PDGF, and ROS, promoting HSC activation; Th17/IL‑17 axis augments HSC activation; during regression, resident and recruited macrophages can express MMP9/12 to promote ECM degradation (IJMS, 2024; https://doi.org/10.3390/ijms25147873; Biomedicines, 2024) (akkız2024liverfibrosisfrom pages 23-25, somnay2024liverfibrosisleading pages 2-4). - Molecular pathway landscape: In addition to TGF‑β/Smad and PDGF/PI3K–AKT, recent reviews highlight Hippo–YAP/TAZ, Notch, Wnt/β‑catenin, NF‑κB, and Hedgehog signaling as integrated regulators of fibrogenesis and mesenchymal activation; targeting these has preclinical support (MedComm, 2024; Pharmaceuticals, 2024) (dong2024livercirrhosismolecular pages 20-21, zhao2024pharmacotherapyofliver pages 2-4). - Gut–liver axis and bile acids: Dysbiosis, microbial products (LPS/MAMPs), and altered bile acid signaling feed inflammatory and fibrogenic pathways; specific dysbiosis signatures and permeability increases are associated with fibrosis progression (IJMS, 2024; https://doi.org/10.3390/ijms25137405) (veskovic2024exploringfibrosispathophysiology pages 4-5).

Key Molecular Players (HGNC where applicable) - Genes/Proteins (examples): - TGFB1 (TGF-β1)/TGFBR1–SMAD2/3–SMAD4 axis: master profibrotic signaling in HSCs; induces collagen, α-SMA (ACTA2), TIMP1 (Pharmaceuticals, 2024) (zhao2024pharmacotherapyofliver pages 2-4). - PDGFB/PDGFRA/PDGFRB: potent mitogens/chemotactic factors for HSCs; engage PI3K–AKT and MAPK (Pharmaceuticals, 2024) (zhao2024pharmacotherapyofliver pages 2-4). - YAP1/TAZ (WWTR1) and Hippo pathway: modulate fibroblast/HSC phenotypes and interact with TGF‑β, Wnt, and Notch networks (summarized in 2024 reviews) (zhao2024pharmacotherapyofliver pages 2-4, dong2024livercirrhosismolecular pages 20-21). - WNT ligands/CTNNB1 (β‑catenin), NOTCH receptors/ligands: implicated in mesenchymal activation and cholangiocyte–stromal crosstalk (MedComm, 2024; Pharmaceuticals, 2024) (dong2024livercirrhosismolecular pages 20-21, zhao2024pharmacotherapyofliver pages 2-4). - NF‑κB pathway components (RELA/NFKB1): inflammatory transcriptional control in macrophages and HSCs (Pharmaceuticals, 2024) (zhao2024pharmacotherapyofliver pages 2-4). - ECM proteins and modifiers: COL1A1/COL3A1 (fibrillar), COL4A1 (basement membrane; LSEC capillarization), LOX family (crosslinking), MMPs (e.g., MMP9/12 in regression), TIMP1/2 (inhibition) (Biomedicines, 2024; Pharmaceuticals, 2024) (somnay2024liverfibrosisleading pages 2-4, zhao2024pharmacotherapyofliver pages 2-4). - Chemical entities (CHEBI examples): - Collagen (CHEBI:3815) accumulation; hyaluronic acid (CHEBI:18064) as biomarker; bile acids (CHEBI:3098) signaling (Pharmaceuticals, 2024; IJMS, 2024) (zhao2024pharmacotherapyofliver pages 2-4, veskovic2024exploringfibrosispathophysiology pages 4-5). - Therapeutics discussed mechanistically (not approved for antifibrosis in cirrhosis): pirfenidone, selonsertib, obeticholic acid as FXR agonist, anti‑CCR2/CCR5, anti‑LOXL2 (reviewed 2024) (addissouky2024translatingmolecularheterogeneity pages 7-8). - Cell types (CL terms): - Hepatic stellate cell (CL:0000632): principal myofibroblast precursor in fibrosis (IJMS, 2024) (akkız2024liverfibrosisfrom pages 23-25). - Kupffer cell/macrophage (CL:0000860; CL:0000235): resident and monocyte-derived macrophages orchestrate injury responses and fibrosis/regression (IJMS, 2024; Biomedicines, 2024) (akkız2024liverfibrosisfrom pages 23-25, somnay2024liverfibrosisleading pages 2-4). - Liver sinusoidal endothelial cell (CL:0002138): capillarization reduces NO, increases resistance (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 2-4). - Cholangiocyte (CL:0002078): ductular reaction and cholangiocyte–immune interactions contribute to fibrogenic niches (MedComm, 2024) (dong2024livercirrhosismolecular pages 20-21). - T cells (CL:0000084; CD8+ CL:0000625; Treg CL:0002673); MAIT cells (CL:0001064): modulate inflammation and fibrosis dynamics (IJMS, 2024) (akkız2024liverfibrosisfrom pages 23-25). - Anatomical locations (UBERON): liver (UBERON:0002107), hepatic sinusoid (UBERON:0001977), space of Disse/perisinusoidal space (UBERON:0018183), portal tract (UBERON:0004811) (Biomedicines, 2024; MedComm, 2024) (somnay2024liverfibrosisleading pages 2-4, dong2024livercirrhosismolecular pages 20-21).

Biological Processes (GO terms; disrupted in cirrhosis) - GO:0030198 extracellular matrix organization; GO:0030199 collagen fibril organization (increased) (Pharmaceuticals, 2024) (zhao2024pharmacotherapyofliver pages 2-4). - GO:0008284 positive regulation of cell proliferation (HSC proliferation via PDGF) (zhao2024pharmacotherapyofliver pages 2-4). - GO:0006954 inflammatory response; GO:0006955 immune response (macrophage/T-cell mediated) (akkız2024liverfibrosisfrom pages 23-25, zhao2024pharmacotherapyofliver pages 2-4). - GO:0007179 TGF-β receptor signaling pathway; GO:0014065 PI3K signaling; GO:0007223 Wnt signaling; GO:0007219 Notch signaling; GO:0035329 Hippo signaling (summarized in 2024 reviews) (dong2024livercirrhosismolecular pages 20-21, zhao2024pharmacotherapyofliver pages 2-4). - GO:0003018 vascular process in circulatory system; GO:0035150 regulation of nitric oxide biosynthetic process (LSEC NO, portal hypertension) (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 2-4).

Cellular Components (where processes occur) - ECM (GO:0031012), collagen-containing extracellular matrix (GO:0062023) (zhao2024pharmacotherapyofliver pages 2-4). - Basement membrane (GO:0005604) rich in collagen IV during LSEC capillarization (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 2-4). - Plasma membrane/caveolae of LSECs (fenestrae loss), focal adhesions (integrin–ECM mechanotransduction in HSCs) (Pharmaceuticals, 2024) (zhao2024pharmacotherapyofliver pages 2-4). - Sinusoidal lumen and perisinusoidal space for exchange and pressure modulation (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 2-4).

Disease Progression (sequence and stages) - Initiation: chronic injury (viral, metabolic, alcohol, cholestasis, toxins) triggers hepatocyte damage, DAMPs/PAMPs, Kupffer cell activation, cytokine release (TGF‑β, PDGF), and HSC priming (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 1-2). - Propagation: HSC transdifferentiation, ECM deposition (collagen I/III), LSEC capillarization (collagen IV basement membrane), angiogenesis, and escalating intrahepatic resistance with portal pressure rise (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 2-4). - Remodeling: fibrous septa and regenerative nodules with architectural distortion; hyperdynamic circulation with splanchnic vasodilation; complications emerge (ascites, variceal bleeding, encephalopathy) (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 1-2, somnay2024liverfibrosisleading pages 2-4). - Potential regression: removing causative injury reduces inflammatory drive; macrophage subsets promote matrix degradation (e.g., MMP9/12) and HSC inactivation, enabling partial reversal—documented clinically in early stages (IJMS, 2024; Biomedicines, 2024) (akkız2024liverfibrosisfrom pages 23-25, somnay2024liverfibrosisleading pages 1-2).

Phenotypic Manifestations (HP terms) - Portal hypertension (HP:0002616) and esophageal varices (HP:0002040), splenomegaly (HP:0001744), ascites (HP:0001541), hepatic encephalopathy (HP:0001399), jaundice (HP:0000952), coagulopathy (HP:0003257) (mechanistic links via endothelial dysfunction, ECM remodeling, and hyperdynamic circulation) (Biomedicines, 2024; IJMS, 2024) (somnay2024liverfibrosisleading pages 1-2, somnay2024liverfibrosisleading pages 2-4).

Recent developments and latest research (2023–2024) - Vascular remodeling as a driver: Contemporary reviews underscore LSEC capillarization and NO dysregulation as initiating events for increased intrahepatic resistance and portal hypertension; diagnostic and therapeutic implications include targeting angiogenesis and restoring fenestrae (2024 Biomedicines; 2024 IJMS) (somnay2024liverfibrosisleading pages 2-4). - Molecular subtypes and precision medicine: Transcriptomic subtypes (inflammatory, proliferative, cholangiocyte-associated) have been identified in advanced disease; precision strategies include targeting LOXL2, CCR2/CCR5, CSF‑1R, and FXR pathways, and HSC-targeted delivery (2024 Archives of Gastroenterology Research) (addissouky2024translatingmolecularheterogeneity pages 7-8). - Multi-pathway targeting: 2024–2025 overviews recommend multi-target approaches across TGF‑β, PDGF/PI3K–AKT, Hippo–YAP/TAZ, Notch, Wnt/β‑catenin, NF‑κB, and Hedgehog axes; several inhibitors and oligonucleotide approaches are under clinical exploration, though no antifibrotic is yet approved for cirrhosis reversal (2024 MedComm; 2024 Pharmaceuticals) (dong2024livercirrhosismolecular pages 20-21, zhao2024pharmacotherapyofliver pages 2-4). - Gut–liver axis and bile acid–microbiome reciprocity: 2024 analyses refine the role of dysbiosis and bile acids in driving inflammatory/fibrotic signaling via increased intestinal permeability and microbial metabolite flux (2024 IJMS) (veskovic2024exploringfibrosispathophysiology pages 4-5).

Genetic drivers and risk/protective variants (links to fibrosis/cirrhosis) - The strongest human genetic architecture connecting to cirrhosis risk in metabolic liver disease remains PNPLA3 (I148M risk), TM6SF2 (E167K risk), MBOAT7 (rs641738 risk), GCKR (risk), and HSD17B13 (loss-of-function protective), which influence lipid handling, hepatocyte injury, inflammation, and fibrosis trajectories; these variants are widely leveraged in polygenic risk stratification and therapeutic targeting (2024 Archives of Gastroenterology Research) (addissouky2024translatingmolecularheterogeneity pages 7-8).

Portal hypertension: mechanistic links with inflammation - Intrahepatic: capillarized LSECs and activated, contractile HSCs narrow sinusoids; reduced NO and increased vasoconstrictors (e.g., endothelin-1) increase resistance; presinusoidal changes in steatohepatitis add to the gradient (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 2-4). - Systemic: inflammatory mediators promote splanchnic vasodilation and hyperdynamic circulation, increasing portal inflow and sustaining portal hypertension (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 2-4).

Current applications and real-world implementations - Noninvasive staging and monitoring: Widespread clinical use of FIB‑4/APRI, ELF, and elastography; biomarker panels incorporating ECM fragments (e.g., hyaluronic acid, collagen IV, TIMPs) are used and being refined for cirrhosis and portal hypertension risk stratification (Pharmaceuticals, 2024) (zhao2024pharmacotherapyofliver pages 2-4). - Etiology-directed therapy: Disease modification by removing injury (e.g., antivirals for viral hepatitis, alcohol abstinence, MASLD weight loss) is associated with fibrosis stabilization/regression, especially in early stages (Biomedicines, 2024) (somnay2024liverfibrosisleading pages 1-2). - Precision directions under evaluation: CCR2/CCR5 inhibition, anti‑LOXL2, FXR agonists, HSC-targeted delivery, and oligonucleotides are in translational pipelines; device-based portal pressure modulation and better hemodynamic phenotyping are emphasized (Archives of Gastroenterology Research, 2024) (addissouky2024translatingmolecularheterogeneity pages 7-8).

Expert opinions and analysis (authoritative sources) - 2024–2025 state-of-the-art reviews converge on HSC centrality, LSEC-driven microvascular pathobiology, and integrated immune–stromal signaling, while noting that “despite numerous clinical studies… an approved antifibrotic therapy still remains elusive” (MedComm, 2024; https://doi.org/10.1002/mco2.721) (dong2024livercirrhosismolecular pages 20-21). The field emphasizes molecular subclassification and multi-target combinations as likely requirements for meaningful antifibrotic efficacy (Archives of Gastroenterology Research, 2024) (addissouky2024translatingmolecularheterogeneity pages 7-8).

Relevant statistics and data (recent) - ECM load: “collagens… can increase up to tenfold in cirrhosis” (Pharmaceuticals, 2024; https://doi.org/10.3390/ph17121724) (zhao2024pharmacotherapyofliver pages 2-4). - Reversibility: Reviews summarize clinical and experimental evidence of fibrosis regression with removal of injurious stimuli, including macrophage-mediated matrix remodeling (Biomedicines, 2024; https://doi.org/10.3390/biomedicines12102229; IJMS, 2024; https://doi.org/10.3390/ijms25147873) (somnay2024liverfibrosisleading pages 1-2, akkız2024liverfibrosisfrom pages 23-25).

Gene/Protein annotations with ontology terms (examples) - TGFB1 (HGNC:11766) – GO:0007179 TGF‑β signaling; GO:0030198 ECM organization; cellular component: extracellular region (GO:0005576); evidence: human disease reviews (2024) (zhao2024pharmacotherapyofliver pages 2-4). - PDGFRB (HGNC:8803) – GO:0014065 PI3K signaling; GO:0008284 positive regulation of cell proliferation; cellular component: plasma membrane (GO:0005886); role: HSC mitogen (2024) (zhao2024pharmacotherapyofliver pages 2-4). - YAP1 (HGNC:16262), WWTR1/TAZ (HGNC:12765) – GO:0035329 Hippo signaling; role: pro-fibrotic transcriptional co-activators in fibroblast/HSC states (2024) (zhao2024pharmacotherapyofliver pages 2-4). - CTNNB1 (HGNC:2514) – GO:0007223 Wnt signaling; NOTCH1 (HGNC:7881) – GO:0007219 Notch pathway; roles in stromal and cholangiocyte crosstalk (2024) (dong2024livercirrhosismolecular pages 20-21, zhao2024pharmacotherapyofliver pages 2-4). - COL1A1 (HGNC:2197), COL3A1 (HGNC:2200), COL4A1 (HGNC:2206); LOX (HGNC:6664) – ECM and crosslinking; MMP9 (HGNC:7176)/MMP12 (HGNC:7157); TIMP1 (HGNC:11820) – ECM degradation control (2024) (somnay2024liverfibrosisleading pages 2-4, zhao2024pharmacotherapyofliver pages 2-4).

Phenotype associations (HP terms; examples) - HP:0002616 Portal hypertension – due to sinusoidal resistance and hyperdynamic flow (somnay2024liverfibrosisleading pages 2-4). - HP:0001541 Ascites; HP:0002040 Esophageal varices; HP:0001399 Hepatic encephalopathy; HP:0001744 Splenomegaly (clinical complications of cirrhosis and portal hypertension) (somnay2024liverfibrosisleading pages 1-2, somnay2024liverfibrosisleading pages 2-4).

Cell type involvement (CL terms; examples) - CL:0000632 Hepatic stellate cell – effector of fibrogenesis (akkız2024liverfibrosisfrom pages 23-25). - CL:0002138 Liver sinusoidal endothelial cell – capillarization and NO dysregulation (somnay2024liverfibrosisleading pages 2-4). - CL:0000860 Macrophage; CL:0001064 MAIT cell; CL:0000625 CD8+ T cell; CL:0002673 Regulatory T cell – immunomodulation of fibrosis (akkız2024liverfibrosisfrom pages 23-25, zhao2024pharmacotherapyofliver pages 2-4).

Anatomical locations (UBERON; examples) - UBERON:0002107 Liver; UBERON:0001977 Hepatic sinusoid; UBERON:0018183 Space of Disse; UBERON:0004811 Portal tract (somnay2024liverfibrosisleading pages 2-4, dong2024livercirrhosismolecular pages 20-21).

Chemical entities (CHEBI; examples) - CHEBI:3815 Collagen; CHEBI:18064 Hyaluronic acid; CHEBI:3098 Bile acids (zhao2024pharmacotherapyofliver pages 2-4, veskovic2024exploringfibrosispathophysiology pages 4-5).

Evidence items (with PMIDs/DOIs/URLs; 2023–2024 priority) - Dong et al., 2024 (MedComm): broad mechanistic review, therapies and microenvironmental changes in cirrhosis (https://doi.org/10.1002/mco2.721) (dong2024livercirrhosismolecular pages 20-21). - Somnay et al., 2024 (Biomedicines): HSC centrality, LSEC capillarization, endothelial dysfunction, reversibility, and hemodynamics (https://doi.org/10.3390/biomedicines12102229) (somnay2024liverfibrosisleading pages 1-2, somnay2024liverfibrosisleading pages 2-4). - Zhao et al., 2024 (Pharmaceuticals): quantitative ECM expansion, PDGF/PI3K–AKT, Wnt/Notch/Hippo and biomarker panels (https://doi.org/10.3390/ph17121724) (zhao2024pharmacotherapyofliver pages 2-4). - Akkız et al., 2024 (IJMS): HSCs as main effector cells; immune–stromal crosstalk; regression potential (https://doi.org/10.3390/ijms25147873) (akkız2024liverfibrosisfrom pages 23-25). - Vesković et al., 2024 (IJMS): gut–liver axis, bile acids, HSC activation and Hedgehog/PDGF/TGF‑β in lean vs obese fibrosis (https://doi.org/10.3390/ijms25137405) (veskovic2024exploringfibrosispathophysiology pages 4-5). - Addissouky, 2024 (Archives of Gastroenterology Research): molecular heterogeneity, precision targets (https://doi.org/10.33696/gastroenterology.5.054) (addissouky2024translatingmolecularheterogeneity pages 7-8).

Limitations - While recent authoritative reviews and translational analyses were used, detailed single-cell/spatial primary datasets and functional genetic studies (e.g., variant-to-mechanism causal pathways) would further strengthen mechanistic granularity; these are being actively generated and integrated into clinical research pipelines (2024) (addissouky2024translatingmolecularheterogeneity pages 7-8).

Conclusion Modern understanding of cirrhosis integrates HSC-mediated fibrogenesis; LSEC capillarization and intrahepatic endothelial dysfunction; and immune–stromal cross-talk governed by interwoven pathways (TGF‑β/Smad, PDGF/PI3K–AKT, Hippo–YAP/TAZ, Notch, Wnt/β‑catenin, NF‑κB, Hedgehog). Genetic risk (PNPLA3/TM6SF2/MBOAT7/GCKR) and protective (HSD17B13) variants modulate disease course in MASLD-associated cirrhosis. On the systems level, ECM remodeling together with vascular–hemodynamic changes produces portal hypertension and clinical decompensation. Noninvasive staging is established, but effective anti‑fibrotic therapies for established cirrhosis remain an urgent unmet need, with multi-target, precision strategies in development (2024) (dong2024livercirrhosismolecular pages 20-21, somnay2024liverfibrosisleading pages 1-2, somnay2024liverfibrosisleading pages 2-4, zhao2024pharmacotherapyofliver pages 2-4, akkız2024liverfibrosisfrom pages 23-25, addissouky2024translatingmolecularheterogeneity pages 7-8).

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