Regulation of Autophagy, Apoptosis, and Cell Death in Cardiomyocytes and Potential Therapeutic Targets

Disruption of cardiomyocyte homeostasis is a fundamental pathological basis for the onset and progression of cardiovascular diseases (CVDs). Given the extremely limited regenerative capacity of cardiomyocytes, programmed cell death (PCD) has emerged as a critical determinant of disease pathogenesis and clinical outcomes. PCD comprises multiple forms of cell death, including necroptosis, pyroptosis, ferroptosis, cuproptosis, disulfidptosis, necrosis induced by sodium overload (NECSO), lysosomal cell death, oxeiptosis, PANoptosis, entotic cell death, netotic cell death, alkaliptosis, and poly(ADP-ribose) polymerase-1 (PARP-1)-dependent cell death (parthanatos). Complex molecular interactions and signaling crosstalk among these cell death pathways can lead to the dysregulation of these pathways and, in turn, induce various CVDs. Currently, the mechanisms linking cardiomyocyte PCD to CVDs remain incompletely understood. Therefore, this article systematically reviews advances in research over the past decade on autophagy, apoptosis, necrosis, and other forms of PCD in cardiomyocytes. Moreover, this review summarizes the molecular mechanisms and pathway interaction networks underlying these cell death modalities, examines key regulatory targets and the potential to develop and translate targeted inhibitors into clinical practice, and outlines strategies for targeted intervention in cardiomyocyte PCD to prevent and treat CVDs. Collectively, this review aims to provide a theoretical foundation for further research into precision therapies for heart diseases.