REVIEW article
Front. Cell Death
Sec. Non-Apoptotic Regulated Cell Death
This article is part of the Research TopicReviews in Cell Death Research: Volume IIView all articles
Non-canonical regulated cell death and epigenetic mechanisms in the nervous system
Provisionally accepted
- University of Turin, Turin, Italy
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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 and how they may be epigenetically regulated. 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. In this paper, we review current knowledge of the different forms of non-canonical RCD in the nervous system and their epigenetic regulation through direct regulation of RCD, 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.
Keywords: Autophagy-dependent cell death, ferroptosis, necroptosis, parthanatos, pyroptosis
Received: 21 Jan 2026; Accepted: 09 Feb 2026.
Copyright: © 2026 Merighi, Castagna, Sbriz and Lossi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Adalberto Merighi
Laura Lossi
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