Epigenetic Regulation of Regulated Cell Death in Aging-Related Diseases: Clinical Perspectives

The intricate crosstalk between epigenetic modification and regulated cell death (RCD) constitutes a pivotal yet underexplored axis in aging and its associated diseases. This Perspective conceptualizes age-related epigenetic reprogramming as a master switch that recalibrates the execution thresholds of diverse RCD pathways-including pyroptosis, ferroptosis, cuproptosis, necroptosis, and autophagy-dependent cell death-across multiple organ systems. We systematically decode how this epigenetic-RCD axis drives the pathophysiology of major aging-related conditions, such as diabetes, neurodegenerative disorders, cardiovascular diseases, and cancer, by synthesizing evidence of how DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA methylation intricately govern RCD networks. Building upon this mechanistic framework, the therapeutic potential of targeting this axis is critically examined, highlighting both emerging opportunities and translational challenges for future intervention strategies. Our analysis provides a novel paradigm for understanding aging mechanisms and proposes a roadmap for developing next-generation therapeutics.