Ageing Res Rev. 2026 May 15:103177. doi: 10.1016/j.arr.2026.103177. Online ahead of print.
ABSTRACT
Chronic heart failure (CHF) is a leading cause of morbidity and mortality, characterized by the heart's progressive inability to maintain adequate circulation. While adverse cardiac remodeling, encompassing cardiomyocyte hypertrophy, fibrosis, and ultimately, cardiomyocyte loss, is central to CHF pathogenesis, the precise mechanisms driving this cellular demise remain incompletely understood. Dysregulation of programmed cell death (PCD) pathways plays a critical role. Beyond apoptosis, the canonical form of PCD, diverse modalities including necroptosis, mPTP-dependent necrosis, pyroptosis, ferroptosis, cuproptosis, disulfidptosis, and autophagy-dependent cell death contribute to cardiomyocyte loss and adverse remodeling, exacerbating CHF progression. These pathways are intricately interconnected, forming a complex "cell death interactome" in which activation of one death program can influence others, shaping the balance between adaptive and maladaptive responses. This review first provides core definitions for each PCD modality, followed by an analysis of their spatiotemporal dynamics, etiology-specific activation patterns, and crosstalk within the interactome. By integrating molecular, pathological, and preclinical evidence, we delineate the key regulatory nodes of the cell death interactome in CHF, highlight promising therapeutic targets, and ultimately accelerate the translation of these mechanistic findings into clinical interventions.
PMID:42142596 | DOI:10.1016/j.arr.2026.103177