Liquid-liquid phase separation-driven regulated cell death: from molecular mechanisms to therapeutic strategies.

Regulated cell death (RCD) is a tightly controlled biological process essential for development, tissue homeostasis, and host defense. Despite extensive investigation, how these signaling pathways are spatially and temporally organized to ensure precise cell death decisions remains incompletely understood. Liquid-liquid phase separation (LLPS), a biophysical mechanism driving the formation of dynamic biomolecular condensates, has emerged as a fundamental principle for cellular organization, signal integration, and stress adaptation. Increasing evidence indicates that LLPS plays a critical role in orchestrating cell fate decisions; however, its involvement in RCD has not yet been systematically defined. In this review, we provide a comprehensive overview of LLPS in the context of RCD. We summarize the physicochemical principles, molecular determinants, and regulatory factors governing LLPS, as well as the functional properties of phase-separated condensates, and then discuss how LLPS modulates key RCD pathways, including apoptosis, necroptosis, autophagy-dependent cell death, pyroptosis, and ferroptosis, highlighting shared and pathway-specific regulatory mechanisms. Furthermore, we examine the pathological consequences of aberrant phase separation-mediated RCD in human diseases and discuss emerging therapeutic strategies aimed at targeting LLPS-driven cell death processes. Finally, we catalog RCD-associated proteins with phase separation potential and outline major conceptual and technical challenges, proposing future directions for this rapidly evolving field.