Cardiomyocyte programmed cell death in dilated cardiomyopathy: molecular crosstalk and therapeutic implications

Progressive cardiomyocyte loss constitutes the pathological hallmark of dilated cardiomyopathy (DCM), a process driven by an intricate network of programmed cell death (PCD) pathways. This review systematically examines the molecular underpinnings and reciprocal crosstalk among six principal PCD modalities implicated in DCM: apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and cuproptosis. Apoptosis is triggered by genetic defects-most notably titin (TTN) truncating variants-epigenetic dysregulation, and endoplasmic reticulum stress, converging on the activation of both intrinsic and extrinsic caspase cascades. Necroptosis is distinguished by the aberrant nuclear accumulation of phosphorylated MLKL, particularly at the pThr³⁵⁷ residue, which selectively exacerbates cardiac dysfunction; upstream events governing this pathway include desmoplakin deficiency, PGC-1α downregulation, and TAB2 loss. Pyroptosis, orchestrated by the NLRP3-GSDMD-IL-1β axis, is robustly activated in the failing myocardium-often exceeding the magnitude of concurrent apoptosis-and propagates a pro-inflammatory milieu through the release of potent cytokines. Autophagy exhibits a pronounced bidirectional effect in DCM: while physiological autophagic flux exerts cardioprotective actions, impaired flux or hyperactivation accelerates cell demise. Ferroptosis is driven by the collapse of the System Xc^--GPX4 antioxidant axis and dysregulation of the FSP1 shunt, culminating in lethal lipid peroxidation; this process is subject to upstream regulation by the Hippo-Mst1-NFS1 cascade and m⁶A epigenetic modifications, and it engages in a vicious cycle with downstream inflammation and fibrosis. Cuproptosis ensues from FDX1-mediated copper binding to lipoylated tricarboxylic acid cycle enzymes, precipitating the loss of iron-sulfur cluster proteins and proteotoxic stress; bioinformatic analyses further implicate its interplay with immune infiltration. These PCD pathways do not operate in isolation but rather form a tightly woven molecular crosstalk network via shared signaling nodes-including RIPK1, reactive oxygen species (ROS), mitochondrial machinery, and the caspase family-and functional compensation, thereby collectively dictating cardiomyocyte fate and disease trajectory. In light of this network-centric framework, therapeutic strategies that target critical hubs such as GSDMD, GPX4, or RIPK1, or leverage pathway interdependencies for combinatorial intervention, hold considerable promise for disrupting maladaptive feed-forward loops and preserving myocardial integrity. Future investigations should prioritize the delineation of patient-specific PCD network topologies in DCM to pave the way for precision-based therapeutic targeting.