A Dual Breakthrough in Regulated Cell Death: From Cytoskeletal Disintegration in Anucleate Erythrocytes to Metabolic-immune Synergistic Membrane Lysis
10.3724/j.pibb.2026.0257CSTR：32369.14.pibb.20260257
- VernacularTitle:调节性细胞死亡的双重突破：从无核红细胞的骨架破坏到代谢-免疫协同的膜裂解
- Author:
Yi JIANG
1
;
Rong-Fang DAI
1
;
De-Jian CHEN
2
;
Ling-Yan CHEN
1
Author Information
1. School of Nursing, Wenzhou Medical University, Wenzhou 325035, China
2. School of Laboratory Medicine and Life Sciences, Ministry of Education, Wenzhou Medical University, Wenzhou 325035, China
- Publication Type:Journal Article
- Keywords:
regulated cell death;
spectosis;
mitoxypterilysis;
metabolism-immune synergy;
therapy targets
- From:
Progress in Biochemistry and Biophysics
2026;53(9):2519-2524
- CountryChina
- Language:Chinese
-
Abstract:
Regulated cell death (RCD) has long been conceptualized as an elaborate program orchestrated by the nucleus and mitochondria in eukaryotic cells. However, this paradigm was fundamentally changed in 2025 by two independent studies published in Cell. One revealed that mature, enucleated erythrocytes execute a cytoskeletal disintegration-driven lysis via a miniNLRP3-ASC-caspase-8‑β‑spectrin axis, termed spectrin-dependent death (spectosis), wherein caspase-8 undergoes a functional switch from an initiator to an executioner, reflecting an evolutionary adaptation in protein economy. The other uncovered mitoxypterilysis, a modality in which metabolic distress and innate immune signals converge to trigger mTORC2-mediated aberrant mitochondrial-plasma membrane contacts, culminating in localized lipid peroxidation and membrane rupture. Mitoxypterilysis shows a logic defined by dual metabolic-immune regulation. This paper systematically dissects the molecular architectures of both modalities, and through comparative analysis, delineates their distinctions from classical RCD pathways as well as their divergent dependencies on organellar integrity, triggering contexts, and executional programs. In parallel, we integrate the recent discovery of reductive death, which underscores a central metabolic checkpoint to contextualize these findings within an emerging framework. Finally, we evaluate their therapeutic implications in hemolytic diseases, oncology, and inflammatory pathologies, while critically reflecting on current limitations and future directions, with the aim of providing a renewed conceptual foundation for targeted intervention strategies.
