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Beta Thalassemia

Disease Pathophysiology Research Template

2026-02-15
Falcon MONDO:0019402 Model: Edison Scientific Literature 34 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Beta Thalassemia
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Beta Thalassemia. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Beta thalassemia (β-thalassemia): pathophysiology research report (molecular/cellular focus)

Target disease and identifiers

  • Disease: β-thalassemia (Mendelian hemoglobinopathy; β-globin quantitative defect). Core molecular defect is reduced/absent β-globin production, typically due to HBB variants (HGNC:HBB). (liang2023elevatedcdkn1a(p21) pages 1-2, daniels2023humancellularmodel pages 1-2)
  • Disease subtypes (pathophysiology relevant): transfusion-dependent thalassemia (TDT) vs non-transfusion-dependent thalassemia (NTDT), reflecting severity of ineffective erythropoiesis and anemia. (basu2023understandingtheintricacies pages 1-2, traegersynodinos2024impactofαglobin pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Core definition: globin chain imbalance → ineffective erythropoiesis

β-thalassemia is defined by reduced (β+) or absent (β0) β-globin chain synthesis, producing α/non-α globin chain imbalance and impaired hemoglobin A (HbA; α2β2) formation. (liang2023elevatedcdkn1a(p21) pages 1-2, daniels2023humancellularmodel pages 1-2)

A central mechanistic concept is that reduced β-globin causes excess free α-globin, which forms insoluble aggregates and undergoes auto-oxidation, generating ROS and triggering intracellular injury that culminates in ineffective erythropoiesis (IE) (intramedullary death of erythroid precursors) and peripheral hemolysis. Nature Communications describes this as: “Reduction in β-globin results in excess α-globin, forming insoluble aggregates which undergo auto-oxidation leading to increased reactive oxygen species (ROS) and a range of intracellular downstream events that result in ineffective erythropoiesis (IE), the hallmark and primary cause of β-thalassemia disease pathophysiology.” (daniels2023humancellularmodel pages 1-2)

Traeger‑Synodinos et al. emphasize the specific toxicity of α-globin excess: “Free α-globin chains cannot form homo-tetramers, as they are highly unstable and tend to aggregate, forming insoluble precipitates in the cell. The reactive oxygen species (ROS) formed as a result, underlie red cell membrane damage, ultimately causing premature cell death, observed as ineffective erythropoiesis.” (traegersynodinos2024impactofαglobin pages 1-2)

1.2 Distinguishing pathophysiologic modules

The modern mechanistic view is modular: 1. Erythroid module: globin imbalance → oxidative injury → apoptosis/eryptosis → maturation block and IE. (daniels2023humancellularmodel pages 1-2, liang2023elevatedcdkn1a(p21) pages 1-2) 2. Iron homeostasis module: IE and anemia-driven erythropoietic stress suppress hepcidin, increasing intestinal iron absorption and mobilization of iron from stores, predisposing to iron overload (particularly with transfusion). (wake2024ahumanantimatriptase2 pages 9-10, guerra2023novelpotentialtherapeutics pages 1-3) 3. End-organ damage module: iron excess → NTBI, ROS, mitochondrial dysfunction → liver/cardiac/endocrine toxicity. (narahari2024exploringtheimpact pages 1-2)

2) Core pathophysiology (mechanisms, pathways, cellular processes)

2.1 Primary pathophysiologic mechanisms

(A) α-globin precipitation and oxidative damage

In β-thalassemia, “excess unpaired alpha chains precipitate as hemochromes, leading to the premature death of erythroid precursor cells and impaired erythropoiesis.” (narahari2024exploringtheimpact pages 1-2)

(B) Ineffective erythropoiesis and maturation arrest

IE features expansion of erythroid progenitors but failure to produce mature RBCs. Daniels et al. specify a stage: IE “is manifest as increased expansion of erythroid progenitors… but with a maturation block at the polychromatic stage of differentiation… with increased apoptosis.” (daniels2023humancellularmodel pages 1-2)

(C) Apoptosis networks in erythroid precursors (FOXO3–P21 axis)

A 2023 Blood Advances study frames β-thalassemia as a disorder where “Premature death of β-thalassemic erythroid precursors results in ineffective erythroid maturation, increased production of erythropoietin (EPO), expansion of erythroid progenitor compartment, extramedullary erythropoiesis, and splenomegaly.” (liang2023elevatedcdkn1a(p21) pages 1-2)

Mechanistically, Liang et al. describe globin imbalance→redox injury→aggregates: “The accumulation of excessive unpaired α-globin chains in erythroblasts triggers redox-mediated reactions, leading to the generation of toxic aggregates… [resulting in] premature death, ineffective erythroid maturation, and hemolytic anemia.” (liang2023elevatedcdkn1a(p21) pages 1-2)

They also provide experimental support that FOXO3 and its target CDKN1A/p21 regulate apoptosis in β-thalassemic erythroid cells, showing reduced apoptosis in genetic knockouts while IE may persist. (liang2023elevatedcdkn1a(p21) pages 1-2, liang2023elevatedcdkn1a(p21) pages 6-7)

2.2 Dysregulated iron homeostasis pathways (hepcidin/ferroportin axis)

(A) Hepcidin as the systemic “master regulator”

Guerra et al. summarize the canonical axis: hepcidin (HAMP) from liver binds/inhibits ferroportin (SLC40A1) to limit iron export from enterocytes, macrophages, and hepatocytes; high hepcidin → iron-restricted erythropoiesis/anemia, low hepcidin → iron overload. (guerra2023novelpotentialtherapeutics pages 1-3)

(B) Hepatic BMP–SMAD control of hepcidin and its negative regulation by TMPRSS6

Hepcidin transcription is driven by a hepatic BMP–SMAD pathway. Guerra et al. state that “Hepcidin transcription in hepatocytes is driven by a BMP–SMAD pathway” involving BMP ligands and SMAD1/5/8 activation. (guerra2023novelpotentialtherapeutics pages 1-3)

Silvestri et al. describe TMPRSS6 as a key inhibitor: “the main hepcidin inhibitor is type II transmembrane serine protease 6 (TMPRSS6 or matriptase-2).” (silvestri2023managingthedual pages 9-11)

Wake et al. integrate this with β-thalassemia, noting IE is associated with “down-regulation of hepcidin and up-regulation of ferroportin,” increasing iron absorption. (wake2024ahumanantimatriptase2 pages 9-10)

(C) EPO–EPOR–JAK2–ERFE axis: erythroid-to-liver signaling

Guerra et al. connect erythropoietic drive to iron regulation: “EPO acts via EPOR → JAK2 phosphorylation to activate downstream genes including erythroferrone (ERFE),” which links erythroid stress to hepcidin suppression. (guerra2023novelpotentialtherapeutics pages 1-3)

(D) Cellular iron distribution and iron overload compartments

Iron loading results in transferrin saturation and NTBI deposition. Narahari et al. state: “Inefficient iron utilization… results in transferrin saturation and eventually the accumulation of NTBI in secondary sites such as the liver, cardiac tissue, and endocrine glands.” (narahari2024exploringtheimpact pages 1-2)

2.3 Oxidative stress, mitochondrial dysfunction, ferroptosis

(A) ROS and mitochondrial injury

Narahari et al. highlight mitochondrial mechanisms: “iron overload can impair the electron transport chain, reduce adenosine tri phosphate synthesis, and increase the generation of reactive oxygen species.” (narahari2024exploringtheimpact pages 1-2)

(B) Ferroptosis and its coupling to ineffective erythropoiesis

Lin et al. review ferroptosis as “an iron-dependent lipid peroxidation” and position it as mechanistically intertwined with IE via shared dependencies on iron and ROS homeostasis. (lin2024theinteractionsbetween pages 1-2)

They also cite an estimate of intramedullary precursor loss: “around 65% of nucleated erythrocytes perish before maturation.” (lin2024theinteractionsbetween pages 1-2)

3) Key molecular players (genes/proteins, chemicals, cells, anatomy)

3.1 Genes/proteins (HGNC-style list with roles)

Causal / primary: - HBB (β-globin): mutations cause reduced/absent β-globin; initiates globin imbalance. (liang2023elevatedcdkn1a(p21) pages 1-2, daniels2023humancellularmodel pages 1-2) - HBA1/HBA2 (α-globin): excess free α-globin is the proximate toxic species; aggregates drive ROS and IE. (traegersynodinos2024impactofαglobin pages 1-2)

Erythroid injury / apoptosis: - FOXO3, CDKN1A (p21), TP53: implicated in regulation of erythroid apoptosis in β-thalassemia models. (liang2023elevatedcdkn1a(p21) pages 1-2)

Iron regulation network: - HAMP (hepcidin): master systemic regulator. (guerra2023novelpotentialtherapeutics pages 1-3) - SLC40A1 (ferroportin/FPN1): iron exporter inhibited by hepcidin. (guerra2023novelpotentialtherapeutics pages 1-3, silvestri2023managingthedual pages 9-11) - TMPRSS6 (matriptase-2): “main hepcidin inhibitor”; therapeutic target to raise hepcidin. (silvestri2023managingthedual pages 9-11, wake2024ahumanantimatriptase2 pages 1-2) - ERFE (erythroferrone): erythroid-derived hepcidin suppressor induced downstream of EPO signaling. (guerra2023novelpotentialtherapeutics pages 1-3, settakorn2024arandomizedplacebo−controlled pages 1-2) - BMP6/BMP2, SMAD1/5/8 (hepcidin induction), and SMAD2/3 (TGF-β superfamily signaling targeted by luspatercept-like ligands). (guerra2023novelpotentialtherapeutics pages 1-3, wake2024ahumanantimatriptase2 pages 1-2) - HFE, TFR1, TFR2, HJV: hepatic iron-sensing/BMP coregulation components. (guerra2023novelpotentialtherapeutics pages 1-3, silvestri2023managingthedual pages 9-11)

Proteostasis/autophagy modifiers: - AHSP (α-hemoglobin stabilizing protein): candidate buffer against α-globin toxicity. (traegersynodinos2024impactofαglobin pages 1-2, gambari2024therapeuticrelevanceof pages 1-3) - ULK1, PI3K/AKT/mTOR axis: autophagy regulation proposed to reduce α-globin excess/aggregates. (gambari2024therapeuticrelevanceof pages 1-3)

3.2 Chemical entities (CHEBI-style)

3.3 Cell types (CL-style)

3.4 Anatomical locations (UBERON-style)

4) Biological processes (GO-style) disrupted

Supported by the above evidence, disrupted processes include: - Hemoglobin biosynthetic process / hemoglobin complex assembly (globin imbalance as initiating lesion). (liang2023elevatedcdkn1a(p21) pages 1-2, daniels2023humancellularmodel pages 1-2) - Erythrocyte differentiation with a polychromatic-stage maturation block and increased apoptosis. (daniels2023humancellularmodel pages 1-2) - Erythroblast apoptotic process / response to oxidative stress (α-globin auto-oxidation → ROS → apoptosis). (daniels2023humancellularmodel pages 1-2, liang2023elevatedcdkn1a(p21) pages 1-2) - Iron ion homeostasis / iron ion transport governed by hepcidin–ferroportin. (guerra2023novelpotentialtherapeutics pages 1-3, silvestri2023managingthedual pages 9-11) - Regulation of hepcidin production via BMP–SMAD and negative regulation by TMPRSS6. (guerra2023novelpotentialtherapeutics pages 1-3, silvestri2023managingthedual pages 9-11) - Autophagy as an adaptive process to clear α-globin aggregates; regulated by ULK1 and PI3K/AKT/mTOR. (gambari2024therapeuticrelevanceof pages 1-3) - Lipid peroxidation / ferroptosis as iron-dependent oxidative death pathway interacting with IE. (lin2024theinteractionsbetween pages 1-2)

5) Cellular components (GO-CC-style) implicated

6) Disease progression: sequence of events (trigger → clinical manifestations)

6.1 Initiation (genotype to molecular lesion)

HBB mutations reduce β-globin synthesis and cause α/β imbalance. (liang2023elevatedcdkn1a(p21) pages 1-2, daniels2023humancellularmodel pages 1-2)

6.2 Early cellular pathophysiology (erythroid compartment)

Excess α-globin aggregates, ROS, and apoptosis drive IE; Daniels et al. describe a polychromatic-stage block. (daniels2023humancellularmodel pages 1-2)

6.3 Systemic compensation and hematopoietic remodeling

Anemia increases EPO, expanding erythroid progenitors, promoting extramedullary erythropoiesis and splenomegaly. (liang2023elevatedcdkn1a(p21) pages 1-2)

6.4 Iron overload development

Iron overload arises from both: - Erythropoiesis-driven hepcidin suppression (↑ ferroportin, ↑ intestinal absorption). (wake2024ahumanantimatriptase2 pages 9-10, guerra2023novelpotentialtherapeutics pages 1-3) - Transfusional iron loading in TDT. (narahari2024exploringtheimpact pages 1-2, settakorn2024arandomizedplacebo−controlled pages 1-2)

6.5 End-organ toxicity

With transferrin saturation, NTBI deposits in liver/heart/endocrine organs. (narahari2024exploringtheimpact pages 1-2)

7) Phenotypic manifestations (HP-style) linked to mechanisms

  • Hemolytic anemia / chronic anemia (HP: anemia) from IE and hemolysis. (liang2023elevatedcdkn1a(p21) pages 1-2, daniels2023humancellularmodel pages 1-2)
  • Splenomegaly due to extramedullary erythropoiesis and RBC clearance. (liang2023elevatedcdkn1a(p21) pages 1-2)
  • Iron overload (HP: iron overload) with liver/cardiac/endocrine deposition and oxidative tissue damage. (narahari2024exploringtheimpact pages 1-2)

8) Recent developments and latest research (prioritizing 2023–2024)

8.1 Human cellular models enabling mechanistic profiling and target discovery (2023)

Daniels et al. (Nature Communications; accepted 26 Sep 2023; published Oct 2023 per citation metadata) developed gene-edited BEL-A erythroid lines that “accurately recapitulate the phenotype of patient erythroid cells” and enable “extensive analysis of the altered molecular mechanisms” via proteomics and a “high throughput compatible fluorometric-based assay” to quantify IE severity. (daniels2023humancellularmodel pages 1-2)

Their mechanistic framing reiterates globin imbalance→ROS as primary cause (quote in §1.1). (daniels2023humancellularmodel pages 1-2)

8.2 Ferroptosis as an emerging mechanistic layer (2024)

Lin et al. (Frontiers in Physiology; Feb 2024) synthesize evidence that ferroptosis (iron-dependent lipid peroxidation) may interact with IE through shared iron/ROS dysregulation, proposing ferroptosis as a therapeutic concept for β-thalassemia. (lin2024theinteractionsbetween pages 1-2)

8.3 TMPRSS6 (matriptase-2) as a therapeutic lever to correct iron overload and improve erythropoiesis (2024)

Wake et al. (Blood Advances; Apr 2024; DOI 10.1182/bloodadvances.2023012010) report that a human anti-matriptase-2 antibody can raise hepcidin and “limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice,” supporting TMPRSS6 inhibition as a strategy to restore the hepcidin–ferroportin brake on iron loading. (wake2024ahumanantimatriptase2 pages 9-10)

Wake et al. also cite mechanistic linkage between matriptase-2, hepatic BMP–SMAD signaling, and hepcidin regulation: “Limiting hepatic Bmp-Smad signaling by matriptase-2 is required for erythropoietin-mediated hepcidin suppression in mice.” (wake2024ahumanantimatriptase2 pages 9-10)

8.4 Autophagy induction to reduce α-globin toxicity (2024)

Gambari & Finotti (Cells; May 2024) position autophagy as an approach to lower excess free α-globin chains and aggregates; autophagy is “regulated by the Unc-51-like kinase 1 (Ulk1) gene” and interacts with the “PI3K/Akt/TOR pathway” and AHSP/microRNA regulation. (gambari2024therapeuticrelevanceof pages 1-3)

Traeger‑Synodinos et al. (IJMS; Mar 2024) similarly identify AHSP and autophagy as modifiers to counteract α-globin excess. (traegersynodinos2024impactofαglobin pages 1-2)

8.5 Clinical modulation of erythropoiesis regulators and oxidative stress with EGCG (2024 trial)

Settakorn et al. (Frontiers in Molecular Biosciences; published 24 Jan 2024; DOI 10.3389/fmolb.2023.1248742) conducted a “randomized placebo−controlled clinical trial” in “Twenty−seven TDT patients… for 60 days,” reporting that GTE tablets “lowered plasma levels of erythroferrone (p < 0.05)” alongside signals consistent with improved hemolysis/erythropoiesis modulation. (settakorn2024arandomizedplacebo−controlled pages 1-2)

9) Current applications and real-world implementations (mechanism-linked)

9.1 Standard-of-care implementations

  • Regular blood transfusions in TDT to maintain hemoglobin and suppress extreme erythropoietic stress, but with iron loading risk. (settakorn2024arandomizedplacebo−controlled pages 1-2, daniels2023humancellularmodel pages 1-2)
  • Iron chelation therapy to mitigate organ iron deposition/toxicity, often lifelong in transfused patients. (settakorn2024arandomizedplacebo−controlled pages 1-2)

9.2 Mechanism-based newer/adjunct approaches

  • TGF-β superfamily ligand trapping to improve late-stage erythroid maturation (luspatercept class): Wake et al. describe RAP-536L (murine analog) that “sequesters ligands of the TGF-β superfamily… particularly GDF8 and GDF11” inhibiting SMAD2/3 to promote erythroid differentiation; combination with TMPRSS6 antibody improved multiple disease axes in mice. (wake2024ahumanantimatriptase2 pages 1-2)
  • Restoring hepcidin signaling / limiting ferroportin-mediated iron entry via TMPRSS6 targeting (preclinical in 2024). (wake2024ahumanantimatriptase2 pages 9-10, silvestri2023managingthedual pages 9-11)
  • Antioxidant/iron-chelation nutraceutical adjuncts (EGCG/GTE): small randomized trial indicates ERFE modulation (p<0.05). (settakorn2024arandomizedplacebo−controlled pages 1-2)

10) Expert opinions / authoritative synthesis (from reviews)

10.1 Hepcidin regulation is multi-signal, multi-cell-type, and still mechanistically incomplete

Silvestri et al. emphasize that hepcidin regulation integrates iron and erythropoiesis and involves intraorgan crosstalk (hepatocytes ↔ liver sinusoidal endothelial cells). They also highlight unresolved details (e.g., how iron regulates BMP6 and how HFE/TFR2 signal through BMP–SMAD). (silvestri2023managingthedual pages 9-11)

10.2 Therapeutics that improve erythropoiesis can secondarily improve iron metabolism (and vice versa)

Guerra et al. synthesize that “improvements in red blood cell production also ameliorate iron metabolism and vice versa” (review theme), framing a coupled axis as central to next-generation therapeutics in β-thalassemia. (guerra2023novelpotentialtherapeutics pages 1-3)

11) Recent statistics and quantitative data (from included sources)

11.1 Epidemiology / burden

  • Global burden estimates in a 2023 source: “80–90 million carriers (~1.5% global)” and “~60,000 symptomatic births/year” are reported in Zahed 2023. (zahed2023effectiveutilizationof pages 58-61)
  • Basu 2023 reports “~56,000 infants born with severe thalassemia annually worldwide” and India-specific estimates (e.g., ~10,000–12,000 thalassemia major births/year; ~42 million carriers; prevalence ~3–4%). (basu2023understandingtheintricacies pages 1-2)

11.2 Quantification of ineffective erythropoiesis

11.3 Clinical trial numeric elements (2024)

  • Settakorn 2024: n=27 TDT randomized to placebo vs GTE tablets (50 or 100 mg EGCG equivalent) for 60 days; reported lowering of plasma ERFE with p < 0.05. (settakorn2024arandomizedplacebo−controlled pages 1-2)

12) Knowledge-base style annotations (entities and ontology mappings)

12.1 Pathophysiology description (knowledge-base narrative)

β-thalassemia is caused by HBB variants that reduce β-globin synthesis, producing α/β-globin imbalance. Excess free α-globin forms insoluble aggregates and undergoes auto-oxidation, driving ROS generation and oxidative membrane/cellular injury in erythroid precursors, leading to apoptosis, a polychromatic-stage maturation block, and ineffective erythropoiesis; peripheral hemolysis contributes further to anemia. Anemia elevates EPO signaling, expanding erythroid progenitors and promoting extramedullary erythropoiesis and splenomegaly. Ineffective erythropoiesis and erythroid signaling (ERFE) suppress hepatic hepcidin, increasing ferroportin-mediated iron export and intestinal absorption; transfusion therapy adds exogenous iron. Progressive transferrin saturation leads to NTBI and iron deposition in liver, heart, and endocrine tissues, causing ROS/mitochondrial dysfunction and organ toxicity. (daniels2023humancellularmodel pages 1-2, liang2023elevatedcdkn1a(p21) pages 1-2, guerra2023novelpotentialtherapeutics pages 1-3, narahari2024exploringtheimpact pages 1-2)

12.2 Gene/protein annotations (HGNC; with mechanistic evidence)

12.3 GO biological process candidates (non-exhaustive)

12.4 GO cellular component candidates

12.5 Phenotype associations (HP-style)

  • Anemia; hemolytic anemia; ineffective erythropoiesis; splenomegaly; iron overload; liver iron deposition; cardiomyopathy/heart involvement; endocrine dysfunction. (liang2023elevatedcdkn1a(p21) pages 1-2, narahari2024exploringtheimpact pages 1-2)

12.6 Cell type involvement (CL-style)

12.7 Anatomical locations (UBERON-style)

12.8 Chemical entities (CHEBI-style)

  • Iron; heme; NTBI; ROS; EGCG; iron chelators (DFO/DFP/DFX). (settakorn2024arandomizedplacebo−controlled pages 1-2)

13) Evidence items (PMID/DOI/URL/date)

Note: The provided full texts include DOIs and dates; PMIDs were not present in the retrieved excerpts for several items.

1) Daniels DE et al. Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype. Nature Communications. Accepted 26 Sep 2023 (as shown in article header). DOI: 10.1038/s41467-023-41961-9. URL: https://doi.org/10.1038/s41467-023-41961-9 (daniels2023humancellularmodel pages 1-2, daniels2023humancellularmodel pages 9-10)

2) Liang R et al. Elevated CDKN1A (P21) mediates β-thalassemia erythroid apoptosis… Blood Advances. Prepublished online 6 Sep 2023; volume date 28 Nov 2023 (as shown). DOI: 10.1182/bloodadvances.2022007655. URL: https://doi.org/10.1182/bloodadvances.2022007655 (liang2023elevatedcdkn1a(p21) pages 1-2, liang2023elevatedcdkn1a(p21) pages 6-7)

3) Wake M et al. A human anti-matriptase-2 antibody limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice. Blood Advances. Apr 2024. DOI: 10.1182/bloodadvances.2023012010. URL: https://doi.org/10.1182/bloodadvances.2023012010 (wake2024ahumanantimatriptase2 pages 9-10, wake2024ahumanantimatriptase2 pages 1-2)

4) Lin S et al. The interactions between ineffective erythropoiesis and ferroptosis in β-thalassemia. Frontiers in Physiology. Feb 2024. DOI: 10.3389/fphys.2024.1346173. URL: https://doi.org/10.3389/fphys.2024.1346173 (lin2024theinteractionsbetween pages 1-2)

5) Settakorn K et al. A randomized placebo-controlled clinical trial of oral green tea EGCG on erythropoiesis and oxidative stress in TDT β-thalassemia patients. Frontiers in Molecular Biosciences. Published 24 Jan 2024. DOI: 10.3389/fmolb.2023.1248742. URL: https://doi.org/10.3389/fmolb.2023.1248742 (settakorn2024arandomizedplacebo−controlled pages 1-2, settakorn2024arandomizedplacebo−controlled pages 6-7)

6) Traeger‑Synodinos J et al. Impact of α-globin gene expression and α-globin modifiers on β-thalassemia phenotype. International Journal of Molecular Sciences. Published 17 Mar 2024. DOI: 10.3390/ijms25063400. URL: https://doi.org/10.3390/ijms25063400 (traegersynodinos2024impactofαglobin pages 1-2)

7) Gambari R, Finotti A. Therapeutic relevance of inducing autophagy in β-thalassemia. Cells. May 2024. DOI: 10.3390/cells13110918. URL: https://doi.org/10.3390/cells13110918 (gambari2024therapeuticrelevanceof pages 1-3)

8) Guerra A et al. Novel potential therapeutics to modify iron metabolism and red cell synthesis… Haematologica. Jun 2023. DOI: 10.3324/haematol.2023.283057. URL: https://doi.org/10.3324/haematol.2023.283057 (guerra2023novelpotentialtherapeutics pages 1-3)

9) Silvestri L et al. Managing the dual nature of iron to preserve health. International Journal of Molecular Sciences. Feb 2023. DOI: 10.3390/ijms24043995. URL: https://doi.org/10.3390/ijms24043995 (silvestri2023managingthedual pages 9-11)

10) Narahari JM et al. Exploring the impact of iron overload on mitochondrial DNA in β-thalassemia. Gene Expression. Apr 2024. DOI: 10.14218/ge.2023.00128. URL: https://doi.org/10.14218/ge.2023.00128 (narahari2024exploringtheimpact pages 1-2)

11) Basu S et al. Understanding the intricacies of iron overload associated with β-thalassemia. Thalassemia Reports. Jul 2023. DOI: 10.3390/thalassrep13030017. URL: https://doi.org/10.3390/thalassrep13030017 (basu2023understandingtheintricacies pages 1-2)

Limitations of this report

  • Several mechanistic claims in the included reviews cite foundational primary literature (often pre-2023). Where those underlying primary papers would be needed for strict “PMID for all mechanistic claims,” the current tool session did not retrieve those specific primary full texts/PMIDs; therefore, DOIs and direct quotes from the available 2023–2024/2023 sources were used wherever possible. (sadiq2024thalassemiapathophysiologydiagnosis pages 17-18)

References

  1. (liang2023elevatedcdkn1a(p21) pages 1-2): Raymond Liang, Miao Lin, Vijay Menon, Jiajing Qiu, Anagha Menon, Laura Breda, Tasleem Arif, Stefano Rivella, and Saghi Ghaffari. Elevated cdkn1a (p21) mediates β-thalassemia erythroid apoptosis, but its loss does not improve β-thalassemic erythropoiesis. Blood Advances, 7:6873-6885, Nov 2023. URL: https://doi.org/10.1182/bloodadvances.2022007655, doi:10.1182/bloodadvances.2022007655. This article has 5 citations and is from a peer-reviewed journal.

  2. (daniels2023humancellularmodel pages 1-2): Deborah E. Daniels, Ivan Ferrer-Vicens, Joseph Hawksworth, Tatyana N. Andrienko, Elizabeth M. Finnie, Natalie S. Bretherton, Daniel C. J. Ferguson, A. Sofia. F. Oliveira, Jenn-Yeu A. Szeto, Marieangela C. Wilson, John N. Brewin, and Jan Frayne. Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype. Nature Communications, Oct 2023. URL: https://doi.org/10.1038/s41467-023-41961-9, doi:10.1038/s41467-023-41961-9. This article has 8 citations and is from a highest quality peer-reviewed journal.

  3. (basu2023understandingtheintricacies pages 1-2): Subhangi Basu, Motiur Rahaman, Tuphan Kanti Dolai, Praphulla Chandra Shukla, and Nishant Chakravorty. Understanding the intricacies of iron overload associated with β-thalassemia: a comprehensive review. Thalassemia Reports, Jul 2023. URL: https://doi.org/10.3390/thalassrep13030017, doi:10.3390/thalassrep13030017. This article has 23 citations.

  4. (traegersynodinos2024impactofαglobin pages 1-2): Joanne Traeger-Synodinos, Christina Vrettou, Christalena Sofocleous, Matteo Zurlo, Alessia Finotti, and Roberto Gambari. Impact of α-globin gene expression and α-globin modifiers on the phenotype of β-thalassemia and other hemoglobinopathies: implications for patient management. International Journal of Molecular Sciences, 25(6):3400, Mar 2024. URL: https://doi.org/10.3390/ijms25063400, doi:10.3390/ijms25063400. This article has 14 citations.

  5. (wake2024ahumanantimatriptase2 pages 9-10): Matthew Wake, Anaïs Palin, Audrey Belot, Mathieu Berger, Megane Lorgouilloux, Margot Bichon, Jonathan Papworth, Luke Bayliss, Benjamin Grimshaw, Natalie Rynkiewicz, Jemima Paterson, Alicia Poindron, Erin Spearing, Emily Carter, Robyne Hudson, Millie Campbell, Verena Petzer, Céline Besson-Fournier, Chloé Latour, Amélie Largounez, Ophélie Gourbeyre, Alexis Fay, Hélène Coppin, Marie-Paule Roth, Igor Theurl, Volker Germaschewski, and Delphine Meynard. A human anti-matriptase-2 antibody limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice. Blood Advances, 8:1898-1907, Apr 2024. URL: https://doi.org/10.1182/bloodadvances.2023012010, doi:10.1182/bloodadvances.2023012010. This article has 7 citations and is from a peer-reviewed journal.

  6. (guerra2023novelpotentialtherapeutics pages 1-3): Amaliris Guerra, Hamideh Parhiz, and Stefano Rivella. Novel potential therapeutics to modify iron metabolism and red cell synthesis in diseases associated with defective erythropoiesis. Haematologica, 108:2582-2593, Jun 2023. URL: https://doi.org/10.3324/haematol.2023.283057, doi:10.3324/haematol.2023.283057. This article has 20 citations.

  7. (narahari2024exploringtheimpact pages 1-2): Jyothi M. Narahari, Prajwal Guruswamy, Navyashree M. Jagadeesha, Kusuma K. Shivashakar, Divya P. Kumar, Prashanth S. Narayana, Prashant M. Vishwanath, and Akila Prashant. Exploring the impact of iron overload on mitochondrial dna in β-thalassemia: a comprehensive review. Gene Expression, 000:000-000, Apr 2024. URL: https://doi.org/10.14218/ge.2023.00128, doi:10.14218/ge.2023.00128. This article has 9 citations and is from a peer-reviewed journal.

  8. (liang2023elevatedcdkn1a(p21) pages 6-7): Raymond Liang, Miao Lin, Vijay Menon, Jiajing Qiu, Anagha Menon, Laura Breda, Tasleem Arif, Stefano Rivella, and Saghi Ghaffari. Elevated cdkn1a (p21) mediates β-thalassemia erythroid apoptosis, but its loss does not improve β-thalassemic erythropoiesis. Blood Advances, 7:6873-6885, Nov 2023. URL: https://doi.org/10.1182/bloodadvances.2022007655, doi:10.1182/bloodadvances.2022007655. This article has 5 citations and is from a peer-reviewed journal.

  9. (silvestri2023managingthedual pages 9-11): Laura Silvestri, Mariateresa Pettinato, Valeria Furiosi, Letizia Bavuso Volpe, Antonella Nai, and Alessia Pagani. Managing the dual nature of iron to preserve health. International Journal of Molecular Sciences, 24:3995, Feb 2023. URL: https://doi.org/10.3390/ijms24043995, doi:10.3390/ijms24043995. This article has 43 citations.

  10. (lin2024theinteractionsbetween pages 1-2): Siyang Lin, Yanping Zheng, Meihuan Chen, Liangpu Xu, and Hailong Huang. The interactions between ineffective erythropoiesis and ferroptosis in β-thalassemia. Frontiers in Physiology, Feb 2024. URL: https://doi.org/10.3389/fphys.2024.1346173, doi:10.3389/fphys.2024.1346173. This article has 17 citations.

  11. (wake2024ahumanantimatriptase2 pages 1-2): Matthew Wake, Anaïs Palin, Audrey Belot, Mathieu Berger, Megane Lorgouilloux, Margot Bichon, Jonathan Papworth, Luke Bayliss, Benjamin Grimshaw, Natalie Rynkiewicz, Jemima Paterson, Alicia Poindron, Erin Spearing, Emily Carter, Robyne Hudson, Millie Campbell, Verena Petzer, Céline Besson-Fournier, Chloé Latour, Amélie Largounez, Ophélie Gourbeyre, Alexis Fay, Hélène Coppin, Marie-Paule Roth, Igor Theurl, Volker Germaschewski, and Delphine Meynard. A human anti-matriptase-2 antibody limits iron overload, α-globin aggregates, and splenomegaly in β-thalassemic mice. Blood Advances, 8:1898-1907, Apr 2024. URL: https://doi.org/10.1182/bloodadvances.2023012010, doi:10.1182/bloodadvances.2023012010. This article has 7 citations and is from a peer-reviewed journal.

  12. (settakorn2024arandomizedplacebo−controlled pages 1-2): Kornvipa Settakorn, Sasinee Hantrakool, Touchwin Petiwathayakorn, Nuntouchaporn Hutachok, Adisak Tantiworawit, Pimlak Charoenkwan, Nopphadol Chalortham, Anchan Chompupoung, Narisara Paradee, Pimpisid Koonyosying, and Somdet Srichairatanakool. A randomized placebo−controlled clinical trial of oral green tea epigallocatechin 3−gallate on erythropoiesis and oxidative stress in transfusion−dependent β−thalassemia patients. Frontiers in Molecular Biosciences, Jan 2024. URL: https://doi.org/10.3389/fmolb.2023.1248742, doi:10.3389/fmolb.2023.1248742. This article has 7 citations.

  13. (gambari2024therapeuticrelevanceof pages 1-3): Roberto Gambari and Alessia Finotti. Therapeutic relevance of inducing autophagy in β-thalassemia. Cells, 13:918, May 2024. URL: https://doi.org/10.3390/cells13110918, doi:10.3390/cells13110918. This article has 1 citations.

  14. (zahed2023effectiveutilizationof pages 58-61): R Zahed. Effective utilization of molecular genetic screening of patients with sickle cell disease and beta thalassemia major in saudi arabia. Unknown journal, 2023.

  15. (daniels2023humancellularmodel pages 9-10): Deborah E. Daniels, Ivan Ferrer-Vicens, Joseph Hawksworth, Tatyana N. Andrienko, Elizabeth M. Finnie, Natalie S. Bretherton, Daniel C. J. Ferguson, A. Sofia. F. Oliveira, Jenn-Yeu A. Szeto, Marieangela C. Wilson, John N. Brewin, and Jan Frayne. Human cellular model systems of β-thalassemia enable in-depth analysis of disease phenotype. Nature Communications, Oct 2023. URL: https://doi.org/10.1038/s41467-023-41961-9, doi:10.1038/s41467-023-41961-9. This article has 8 citations and is from a highest quality peer-reviewed journal.

  16. (settakorn2024arandomizedplacebo−controlled pages 6-7): Kornvipa Settakorn, Sasinee Hantrakool, Touchwin Petiwathayakorn, Nuntouchaporn Hutachok, Adisak Tantiworawit, Pimlak Charoenkwan, Nopphadol Chalortham, Anchan Chompupoung, Narisara Paradee, Pimpisid Koonyosying, and Somdet Srichairatanakool. A randomized placebo−controlled clinical trial of oral green tea epigallocatechin 3−gallate on erythropoiesis and oxidative stress in transfusion−dependent β−thalassemia patients. Frontiers in Molecular Biosciences, Jan 2024. URL: https://doi.org/10.3389/fmolb.2023.1248742, doi:10.3389/fmolb.2023.1248742. This article has 7 citations.

  17. (sadiq2024thalassemiapathophysiologydiagnosis pages 17-18): Idris Zubairu Sadiq, Fatima Sadiq Abubakar, Hauwa Salisu Usman, Aliyu Dantani Abdullahi, Bashiru Ibrahim, Babangida Sanusi Kastayal, Maryam Ibrahim, and Hassan Aliyu Hassan. Thalassemia: pathophysiology, diagnosis, and advances in treatment. Thalassemia Reports, 14:81-102, Oct 2024. URL: https://doi.org/10.3390/thalassrep14040010, doi:10.3390/thalassrep14040010. This article has 48 citations.