Editorial: Therapeutic targeting of cell death in cardiovascular diseases: from mechanisms to clinical applications

Le résumé fourni par la source

Recent advances in cell death research and therapeutics have significantly expanded beyond the traditional apoptosis-centered paradigm 1,2 . In last 50 years, we have experienced evolution of many cell death research focuses such as development-induced cell death, tumorigenesis-related cell death 3 , growth factor withdraw-induced cell death 4 , death receptor-triggered cell death, tissue injurytriggered cell death, antitumor chemotherapy-induced cell death, CD8 + cytotoxic T cell-mediated cell death, natural killer cell (NK)-mediated cell death, CD4 + Foxp3 + regulatory T cell (Treg)-mediated cell death 5,6 , and antibody complex/complementtriggered cell death, etc. More than 21 newly recognized forms of programmed cell death, including five types of new metabolic cell death. These cell death types include apoptosis (intrinsic and extrinsic) 4,[7][8][9][10] , mitochondrial permeability transition (MPT)driven necrosis, necroptosis [critically depends on mixed lineage kinase domain-Like (MLKL), receptor-interacting protein kinase 3 (RIPK3), and RIPK1] 11 , ferroptosis (oxidative cell death is under control by glutathione peroxidase 4 (GPX4) and can be inhibited by iron chelators and lipophilic antioxidants) 12,13 , pyroptosis (inflammatory cell death characterized by cell swelling, rupture, and the release of numerous proinflammatory factors) [14][15][16][17][18][19][20][21][22][23] , parthanatos [initiated by poly [ADP-ribose] polymerase 1 (PARP1) hyperactivation and precipitated by bioenergetic catastrophe coupled to apoptosis-induced factor (AIF)-and migration inhibitory factor (MIF)-dependent DNA degradation], entotic cell death [actomyosin-dependent cell-in-cell internalization (entosis) and is executed by lysosomes], neutrophil extracellular traps (NET)otic cell death 24 , lysosomal dependent cell death (LDCD), autophagy dependent cell death (ADCD), autosis (an ADCD that relies on the plasma membrane Na + /K + -ATPase), immunogenic cell death (ICD), mitotic death (driven by mitotic catastrophe), anoikis (loss of integrin-dependent anchorage) 25,26 , PANoptosis (differ from classical necroptosis, apoptosis and pyroptosis) 27 , disulfidptosis (a metabolic cell death modality that is triggered by the accumulation of abnormal disulfide bonds under conditions of glucose starvation) 1 , alkaliptosis (a metabolic cell death 28 characterized by intracellular alkalinization, typically mediated by aberrant activation of the Na⁺/H⁺ exchanger 1 (NHE1), which disrupts cellular pH homeostasis), oxeiptosis 10 [a noninflammatory, caspase-independent metabolic cell death triggered by high levels of reactive oxygen species (ROS) [29][30][31][32][33][34][35] ], cuproptosis [copper induces cell death by targeting lipoylated tricarboxylic acid (TCA) cycle proteins) 36 ], and lysozincrosis (a metabolic cell death initiated by the abnormal release of divalent zinc ions (Zn 2+ ) from lysosomal stores) 28 , necrosis by sodium overload (a newly identified metabolic cell death with a necrotic pathway driven by the accumulation of intracellular sodium ions (Na + ) , are now increasingly implicated in tissue injury and repair failure. Among them, ferroptosis has attracted particular attention because its dependence on iron metabolism and lipid peroxidation closely matches the metabolic and oxidative characteristics of cardiovascular tissues. Importantly, the field is shifting from asking whether cell death occurs to understanding when, where, and in which cell types it occurs. Emerging technologies such as spatial metabolomics, single-cell sequencing, and multi-omics integration have enabled investigators to uncover organelle-specific, cell-specific, and stage-specific heterogeneity of cell death. In parallel, increasing evidence demonstrates extensive crosstalk among oxidative stress, Ca²⁺ signaling, endoplasmic reticulum (ER) stress 37 , mitochondrial dysfunction [38][39] , inflammation, and metabolic remodeling 40 , positioning cell death as a dynamic systems-level process rather than an isolated event. Therapeutically, iron chelators, lipid peroxidation inhibitors, GPX4 stabilizers, NFE2 like BZIP transcription factor 2 (NFE2L2, Nrf2) 41 activators, mitochondrial protectors, natural compounds and metabolic cell death regulators have all shown promising potential. Future development of cell death therapeutics will likely depend on precise temporal intervention, cell-specific targeting, and integrated modulation of metabolism and immune signaling.Cardiovascular diseases (CVDs) are increasingly recognized not merely as disorders of hemodynamics or vascular obstruction, but as chronic inflammatory and metabolic propagation diseases driven by multiple forms of regulated cell death (RCD). Importantly, these pathways are no longer viewed as isolated terminal events. Instead, they are now understood as dynamic regulators of inflammation, redox homeostasis, mitochondrial integrity, cytoskeletal organization, and intercellular communication. Recent studies suggest that the therapeutic value of targeting cell death 42 in cardiovascular medicine lies not simply in preventing cellular loss, but in interrupting inflammatory propagation and maladaptive tissue remodeling.Among emerging RCD pathways, pyroptosis has become one of the most important inflammatory mechanisms in cardiovascular disease. Pyroptosis is initiated by inflammasome activation, particularly NLRP3 inflammasome assembly, followed by caspase-1 activation and cleavage of gasdermin D (GSDMD). The N-terminal fragment of GSDMD forms membrane pores that mediate release of interleukin-1β (IL-1β) and IL-18 together with membrane rupture. Recent evidence further demonstrated that pyroptotic macrophages may release extracellular vesicles (EVs) 43 containing functional GSDMD pores 44,45 , which can subsequently injure neighboring endothelial cells [46][47][48] , vascular smooth muscle cells (VSMCs) 49 , and macrophages 50 . This "EV-GSDMD propagation model" suggests that pyroptosis is not merely a cell-autonomous death event but rather a mechanism of intercellular inflammatory amplification 51,52 . In atherosclerosis, this process may contribute to plaque instability, necrotic core expansion, and diffuse vascular inflammation. These findings are supported by studies describing pyroptotic propagation and inflammatory signaling amplification in vascular disease and sterile inflammation.Ferroptosis represents another major advance in cardiovascular cell death biology. Unlike apoptosis, ferroptosis is fundamentally a metabolism-and redox-driven process characterized by iron-dependent lipid peroxidation 53 . Excessive reactive oxygen species (ROS), glutathione depletion, GPX4 dysfunction, and mitochondrial oxidative stress collectively drive catastrophic membrane lipid destruction. Ferroptosis appears especially important in ischemia-reperfusion injury, diabetic cardiomyopathy, and endothelial dysfunction because these diseases share a common metabolic background involving mitochondrial instability, nicotinamide adenine dinucleotide phosphate (NADPH) depletion, and oxidative injury. During myocardial reperfusion, restoration of oxygen paradoxically generates massive ROS bursts and iron mobilization, thereby creating ideal conditions for ferroptotic injury. Importantly, ferroptosis links mitochondrial dysfunction with systemic metabolic disease, making it one of the most promising therapeutic targets in cardiovascular medicine.The recently described disulfidptosis pathway further expands the conceptual relationship between metabolism and cell death. In this process, excessive cystine uptake through solute carrier family 7 member 11 (SLC7A11) under conditions of NADPH depletion results in disulfide accumulation and collapse of the actin cytoskeleton. Unlike ferroptosis, which centers on lipid oxidation, disulfidptosis highlights cytoskeletal integrity as a metabolic stress sensor 53 . This concept is particularly relevant for endothe

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