Delaying cardiac aging: potential mechanisms centered on PANoptosis and targeted intervention strategies

Figures

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  Figure 1. Pathophysiological features of cardiac aging at structural, functional, and molecular levels. (A) Key structural alterations: Cardiac hypertrophy, coronary atherosclerosis, myocardial fibrosis, arrhythmia, valve calcification. (B) Systolic/diastolic dysfunction: Reduced myofilament calcium sensitivity impairs systole, fibrosis-induced stiffness impairs diastole, elevating filling pressures. (C) Molecular changes: Mitochondrial dysfunction, epigenetic alterations. (D) Chronic inflammation: SASP from senescent cells releases proinflammatory factors, activating immune cells; inflammasome-mediated IL-1β/IL-18 amplifies inflammation, exacerbating damage.This figure was drawn by Figdraw.

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  Figure 2. Molecular mechanisms and regulatory networks of PANoptosis. (A) Upstream damage sensing. In aging myocardium, mitochondrial dysfunction triggers signals: mtDNA leakage activates cGAS-STING and AIM2 inflammasome; mitochondrial ROS promotes Z-RNA aggregation, bound by ZBP1 to initiate necroptosis. Nuclear stress amplifies sensing: dsDNA activates AIM2; TERRA from inactive telomeres binds ZBP1; SASP releases pro-inflammatory factors for signal transduction. (B) PANoptosome assembly. Signals converge on complex assembly: ZBP1 recruits RIPK3 and FADD via RHIM; AIM2 recognizes dsDNA, forms inflammasome with ASC/caspase-1, and integrates RIPK1/3; NLRP3 forms a similar complex with analogous functions. (C) Downstream cell death. PANoptosome initiates apoptosis (caspase-8/-3/-7/-9 activation), necroptosis (MLKL phosphorylation/membrane pore formation), and pyroptosis (caspase-1-mediated IL-1β/IL-18 release and GSDMD pore formation).This figure was drawn by Figdraw.

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  Figure 3. Targeting PANoptosis: an interventional strategy against cardiac aging. (A) Small molecule inhibitors targeting the Zα2 domain of ZBP1 or RIPK3 kinase activity to block PANoptosis initiation. (B) Blockade of PANoptosome assembly using compounds (e.g., Baicalin) or biomolecules (e.g., VHH antibody against FADD, ASC-targeting agents) to disrupt complex formation and inhibit PANoptosis. (C) Gene knockout of ZBP1 to specifically abrogate PANoptosis signaling in cardiomyocytes. (D) siRNA-mediated knockdown of RIPK3 to suppress expression and prevent myocardial cell death. (E) Combination therapy utilizing PANoptosis inhibitors with senolytics to synergistically inhibit cell death and clear senescent cells. (F) Novel delivery systems (e.g., ligand-modified liposomes, exosomes) for targeted delivery of therapeutics (e.g., RIPK1 inhibitors) to the heart, enhancing efficacy and reducing off-target effects.This figure was drawn by Figdraw.