The role of different types of programmed cell death in myocardial fibrosis: from mechanisms to therapeutics

Figures

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  Figure 1. Apoptosis pathways and their role in cardiac fibrosis. (Left) The extrinsic pathway is activated by TNF-α and caspase-8. The intrinsic pathway is triggered by cell stress, mitochondrial damage (MOMP), cytochrome c release, and caspase-9 activation. Both pathways activate caspase-3, leading to cardiomyocyte apoptosis. (Right) Apoptotic cells release DAMPs, which activate fibroblasts to produce TGF-β. GF-β binds its receptors (TGF-βRI/II), activating Smad2/3/4 and promoting transcription of fibrotic genes. This leads to ECM deposition (collagen I, fibronectin, α-SMA) and myocardial fibrosis).

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  Figure 2. The mechanism of pyroptosis in myocardial fibrosis. (Left) Both canonical (NLRP3/caspase-1) and non-canonical (caspase-11) inflammasome pathways are shown. Activation by PAMPs/DAMPs or oxidative stress leads to inflammasome assembly and cleavage of gasdermin D, forming membrane pores that trigger pyroptosis. This process also promotes release of pro-inflammatory cytokines IL-1β, IL-18, and DAMPs. (Right) The released mediators activate NF-κB signaling, upregulating TNF-α and IL-6, which promote fibroblast-to-myofibroblast transition and expression of fibronectin, resulting in myocardial fibrosis.

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  Figure 3. The mechanism of autophagy in myocardial fibrosis. Dual roles of autophagy in fibrosis. (A) Anti-fibrotic: functional autophagy inhibits signaling by degrading TGF-β type II receptors (TGF-β RII) and limits ROS via PINK1/Parkin-mediated mitophagy. (B) Pro-fibrotic: dysregulation promotes fibrosis through excessive degradation causing cell death, or flux blockade (by HSPA9/DNMT3A) leading to the accumulation of pro-fibrotic factors.

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  Figure 4. The mechanism of necrotic apoptosis in myocardial fibrosis. Upon stimulation by TNF-α, the necroptotic pathway is activated via phosphorylation of RIPK1 and RIPK3, leading to necrosome formation and downstream activation of p-MLKL. This triggers necrotic membrane rupture and the release of inflammatory cytokines. These cytokines stimulate fibroblast activation, transition into myofibroblasts, and promote ECM deposition, contributing to cardiac fibrosis.

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  Figure 5. The mechanism of ferroptosis in myocardial fibrosis. In cardiomyocytes, impaired GPX4 activity and GSH depletion lead to lipid peroxidation and membrane damage, characteristic of ferroptosis. Released Fe2+ and accumulated ROS further enhance TGF-β signaling, promoting cardiac fibroblast activation and myofibroblast differentiation. This results in fibrotic scar formation and collagen deposition, contributing to cardiac fibrosis.

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  Figure 6. The left module illustrates how apoptosis and necrotic cell death mutually constrain each other via the caspase-8/RIPK1 molecular switch, along with co-regulation by miR-1 and others. Apoptosis relatively limits fibrosis, whereas necrotic cell death exacerbates inflammation by releasing DAMPs and strongly promotes fibrosis. The right module illustrates the bidirectional regulation between autophagy and apoptosis: Protective autophagy suppresses apoptosis, while excessive autophagy or apoptotic feedback can promote cell death. Factors such as EMPA and miR-93 modulate this balance.

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  Figure 7. Mechanistic network and potential therapeutic targets for reversing myocardial fibrosis by targeting multiple programmed cell death pathways.

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  Figure 8. Roles of major programmed cell death (PCD) pathways in cardiac fibrosis and their targeted therapeutic strategies. (Left) PCD types—apoptosis, pyroptosis, necroptosis, ferroptosis, and autophagy—along with their key molecules. These PCD pathways collectively promote fibroblast activation and collagen deposition (middle section) by releasing DAMPs, activating TGF-β signaling, and inducing oxidative stress and inflammatory responses. (Right) Diverse therapeutic strategies targeting these pathways, including small-molecule inhibitors, gene editing, epigenetic modulators, and RAAS inhibitors, offering a multi-targeted therapeutic perspective for CF intervention.