| Pathway Name | Key Components/Mediators | Role in MI Pathophysiology | Cellular Process Affected | Therapeutic Implications |
|---|---|---|---|---|
| MAPK (p38, JNK, ERK1/2) | p38 MAPK, JNK, ERK1/2, ADAM17, ACE2, Bim | Activated during ischemia/reperfusion and post-MI remodeling; promotes inflammatory signaling, apoptosis, mitochondrial dysfunction, ferroptosis, and adverse remodeling/fibrosis. p38/JNK are generally injury-amplifying; ERK can be context-dependent with survival and remodeling effects. (pqac-00000022, pqac-00000028) | Apoptosis, mitochondrial fission, oxidative stress response, ferroptosis, remodeling | Experimental inhibition of p38/JNK/ERK-axis components can reduce myocardial injury; pathway is a candidate for cardioprotection and anti-remodeling therapies, though translation remains challenging. (pqac-00000022, pqac-00000028) |
| PI3K/AKT/mTOR | PI3K, AKT, mTOR, BAD, Mdm2, PKD1, GLUT4 | Core pro-survival pathway in MI and reperfusion injury; suppresses apoptosis, modulates autophagy, supports metabolic adaptation, and can limit inflammatory injury. Reduced signaling is associated with greater injury. (pqac-00000021, pqac-00000024, pqac-00000025) | Cell survival, glucose uptake, metabolism, autophagy control, anti-apoptotic signaling | Therapies that enhance PI3K/AKT signaling or fine-tune mTOR/autophagy may reduce infarct size and improve reperfusion outcomes; a major cardioprotective target in preclinical studies. (pqac-00000024, pqac-00000025) |
| NF-κB | NF-κB, TLR4, MyD88, IL-1β, TNF-α, IL-6, Beclin-1 | Central inflammatory transcriptional program activated by DAMPs and innate immune receptors after cardiomyocyte necrosis; drives cytokine/chemokine expression, leukocyte recruitment, and can suppress protective autophagy in some contexts. (pqac-00000021, pqac-00000024, pqac-00000025, pqac-00000043) | Inflammation, cytokine production, leukocyte recruitment, autophagy regulation | Anti-inflammatory strategies targeting upstream TLR4/MyD88/NF-κB signaling may attenuate reperfusion injury and maladaptive remodeling; promising but requires timing-specific modulation. (pqac-00000021, pqac-00000024) |
| Wnt/β-catenin | Canonical Wnt/β-catenin, non-canonical Wnt/PCP, Wnt/Ca2+, JNK, CaMKII, PKC, calcineurin | Wnt signaling shows pathway-specific effects in MI/I/R injury: canonical Wnt/β-catenin tends to support recovery and survival, whereas non-canonical Wnt signaling can worsen apoptosis, calcium overload, inflammation, fibrosis, and hypertrophy. (pqac-00000027) | Apoptosis, macrophage polarization, oxidative stress, ECM remodeling, angiogenesis, fibrosis | Selective activation of canonical Wnt or inhibition of damaging non-canonical Wnt branches is a potential precision strategy for limiting reperfusion injury and fibrosis. (pqac-00000027) |
| TGF-β/Smad | TGF-β, TGF-β receptors, Smad proteins, MMP-2, MMP-9 | Master profibrotic pathway after MI; activated during repair/remodeling and drives fibroblast activation, myofibroblast conversion, collagen synthesis, EndoMT, and scar formation. Essential for structural repair but excessive activation promotes pathological fibrosis. (pqac-00000023, pqac-00000043) | Fibroblast activation, collagen deposition, scar formation, fibrosis, EndoMT | Targeted modulation may preserve necessary scar formation while reducing adverse remodeling; attractive for anti-fibrotic therapy after MI. (pqac-00000023, pqac-00000043) |
| NLRP3 inflammasome | NLRP3, ASC, caspase-1, IL-1β, ROS, DAMPs | Activated in macrophages, fibroblasts, and injured myocardium after ischemia/reperfusion; links mitochondrial damage and oxidative stress to IL-1β release and inflammatory amplification, and contributes to pyroptotic cell death. (pqac-00000021, pqac-00000024, pqac-00000032, pqac-00000049) | Inflammasome activation, pyroptosis, sterile inflammation | NLRP3/caspase-1/IL-1 axis inhibitors are promising candidates to reduce infarct inflammation, reperfusion injury, and downstream remodeling. (pqac-00000019, pqac-00000021) |
| TLR4/MyD88 | TLR4, MyD88, DAMPs/alarmins, HMGB1, NF-κB | One of the earliest innate immune sensing systems after MI; recognizes DAMPs released from necrotic cardiomyocytes and triggers downstream inflammatory cascades, endothelial activation, and leukocyte recruitment. (pqac-00000021, pqac-00000043, pqac-00000044) | Innate immune activation, cytokine induction, leukocyte trafficking | TLR4/MyD88 blockade is a mechanistically strong anti-inflammatory strategy for limiting sterile injury and reperfusion damage, but may risk impairing necessary repair if over-suppressed. (pqac-00000021, pqac-00000043) |
| JAK-STAT | JAKs, STATs, IL-6, STAT3 | Implicated in vascular inflammation, smooth muscle cell proliferation/differentiation, and post-MI inflammatory signaling; also participates in reparative cytokine signaling such as IL-10/STAT3-mediated suppression of excessive inflammation. (pqac-00000007, pqac-00000045) | Cytokine signaling, inflammation resolution, vascular remodeling, cell proliferation | JAK inhibition has been proposed as a strategy in atherosclerosis/MI biology, while preserving beneficial STAT3-mediated repair signaling may be important; pathway likely needs selective modulation. (pqac-00000007, pqac-00000045) |
| Apoptosis | Fas, TNF receptors, cytochrome c, caspase-8, caspase-9, executioner caspases, BAX/BAK, Bcl-2 | Major programmed cell-death pathway in ischemia/reperfusion injury; initiated during ischemia and executed during reperfusion via intrinsic mitochondrial and extrinsic death-receptor mechanisms. (pqac-00000021, pqac-00000024, pqac-00000032) | Programmed cell death, cardiomyocyte loss | Anti-apoptotic therapies, mitochondrial stabilizers, and survival-pathway activators may reduce infarct expansion and preserve viable myocardium. (pqac-00000015, pqac-00000021) |
| Necroptosis | RIPK1, RIPK3, MLKL | Regulated necrotic death contributes to cardiomyocyte loss during reperfusion and overlaps with inflammatory amplification because cell lysis releases DAMPs. (pqac-00000025, pqac-00000032) | Regulated necrotic cell death, DAMP release | RIPK/MLKL-targeted inhibition is a potential cardioprotective approach in reperfusion injury. (pqac-00000025) |
| Pyroptosis | Caspase-1, caspase-4/5/11, GSDMD, NLRP3, ASC, calpains | Inflammatory cell death pathway activated by inflammasomes in MIRI; causes membrane pore formation, cytokine release, and propagation of sterile inflammation. (pqac-00000025, pqac-00000026, pqac-00000032) | Inflammatory programmed cell death, cytokine release | Caspase-1, GSDMD, or inflammasome inhibition may reduce inflammatory tissue damage and infarct progression. (pqac-00000019, pqac-00000026) |
| Ferroptosis | Iron-dependent lipid peroxidation machinery, ROS, MAPK/ERK-associated regulators | Emerging reperfusion-related death mechanism characterized by iron-dependent lipid peroxidation; contributes to myocardial injury and interacts with oxidative stress/MAPK signaling. (pqac-00000022, pqac-00000028, pqac-00000033) | Lipid peroxidation-driven cell death, oxidative membrane damage | Ferroptosis inhibitors and antioxidant/lipid-peroxidation-targeting strategies are under investigation as adjunct cardioprotective therapies. (pqac-00000022, pqac-00000033) |
| Autophagy | Beclin-1, mTOR, LAMP2, ATF6, IRE1, PERK, ROS | Context-dependent in MI: basal or adaptive autophagy can be protective, but dysregulated or excessive autophagy during reperfusion may worsen injury. Controlled by PI3K/AKT/mTOR, TLR4/NF-κB, ER stress, and ROS signaling. (pqac-00000024, pqac-00000025, pqac-00000026) | Organelle quality control, stress adaptation, cell survival vs cell death balance | Therapies that restore balanced autophagic flux rather than simple inhibition/activation may improve myocardial salvage and remodeling. (pqac-00000024, pqac-00000025) |


*Table: This table summarizes the major molecular signaling pathways implicated in myocardial infarction pathophysiology, emphasizing their mediators, biological roles, affected cellular processes, and therapeutic relevance. It is useful for linking mechanistic disease biology to candidate intervention points.*