The lysosome as a central executioner: orchestrating multiple modalities of programmed cell death

Abstract

Lysosomes have emerged as key signaling hubs that dictate cell fate, extending far beyond their traditional degradative functions. Central to this role is the integrity of the lysosomal membrane, which serves as a key mechanism through which diverse stress signals are converted into programmed cell death (PCD). Despite accumulating evidence, a systematic framework that explains how lysosomes orchestrate distinct PCD pathways remains lacking. In this review, we consolidate current knowledge on the molecular mechanisms by which lysosomes regulate apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagic cell death. By integrating these findings, we propose a unified, lysosome-centered paradigm in which lysosomes function as central executors that translate stress inputs into specific cell death outputs.