J Mol Cell Cardiol. 2026 Oct 25:S0022-2828(26)00164-1. doi: 10.1016/j.yjmcc.2026.10.009. Online ahead of print.
ABSTRACT
Cell death plays a well established role in the pathogenesis of heart disease, with increasing evidence highlighting the complexity and plasticity of different underlying molecular pathways in both cardiomyocytes and non-cardiomyocytes. The signal transduction mechanisms of cell death do not operate as isolated linear cascades but rather as interconnected regulatory networks governing distinct cell death modalities. Among them, apoptosis and necroptosis represent the principal forms of caspase-dependent and caspase-independent cell death, respectively. Although mechanistically linked, these forms of cell death are morphologically and immunogenically distinct. Importantly, these pathways may be activated simultaneously, shaping both the extent of cardiomyocyte loss and the immunogenic properties of dying cells through the release of damage-associated molecular patterns. The outcome of cell death associated myocardial damage is highly disease-specific, biological sex- and context-dependent, and is determined by factors such as the expression levels, post-translational modifications, and interactions of cell survival and cell death signal transduction proteins. Elucidating these mechanisms in cardiomyocytes, including the contribution of secondary signaling molecules derived from non-apoptotic cells and non-cardiomyocytes, is critical for advancing our understanding of cardiac dysfunction in heart disease as well as for the development of targeted therapeutic strategies. Furthermore, the relative contribution of individual cell death modalities in various types of heart diseases warrants particular attention, as shifts in their balance during disease progression may significantly influence the severity of cardiac dysfunction. Since several pathologic factors are involved in the genesis of heart disease, it is suggested that cell death due to apoptosis and necroptosis may be one of these mechanisms associated with the development of cardiac dysfunction in the failing heart.
PMID:42927830 | DOI:10.1016/j.yjmcc.2026.10.009