Non-canonical regulated cell death and epigenetic mechanisms in the nervous system

Classical apoptosis alone does not sufficiently elucidate neuronal loss in the developing, aging, and pathological nervous system. Growing data show that neurons and glial cells, under different physiological or pathological conditions, undergo multiple non-canonical regulated cell death (RCD) pathways, including necroptosis, ferroptosis, parthanatos, autophagy-dependent cell death, and inflammatory forms such as pyroptosis. These different types of death are highly context-dependent, often incomplete, and frequently overlap at the molecular and morphological levels. In this article, we examine the main non-canonical mechanisms of cell death in the nervous system. We discuss how they are specialized to specific cell types/pathological contexts. Epigenetic alterations in the aging brain can affect cell death by regulating gene expression, leading to either increased cell death or cellular senescence, a process by which cells develop resistance to apoptosis. The interplay between non-canonical RCD and epigenetic modifications is reciprocal, with epigenetic alterations serving as both a cause and a consequence of physiological and pathological aging, significantly influencing neuronal fate. We also review current knowledge of RCD regulation through direct epigenetic mechanisms, epigenetic permissiveness or priming through long-term chromatin remodeling, and indirect or associative links involving metabolic or stress-responsive pathways that converge on epigenetic modifiers.