Stress Granules: Novel Regulators of Programmed Cell Death

Stress granules (SGs) are membraneless cytoplasmic condensates formed through liquid-liquid phase separation (LLPS) in response to diverse cellular stressors. These dynamic macromolecular complexes serve as critical signaling hubs that orchestrate adaptive responses by sequestering translationally stalled mRNAs, RNA-binding proteins, and key signaling molecules. Substantial evidence implicates SGs in the pathogenesis of numerous disorders, where they dysregulate essential cellular pathways, including stress-induced cell death cascades. While regulated cell death constitutes a physiological process vital for tissue homeostasis, aberrant or excessive cell death represents a pathogenic driver in neurodegeneration, ischemic injuries, autoimmune disorders, infectious diseases, and oncological pathologies. Consequently, deciphering the molecular governance of cell death holds great potential for developing novel therapeutics. Although proteomic analyses reveal that SGs sequester multiple cell death regulators, the precise mechanisms through which these components modulate death pathways remain incompletely resolved. This review systematically examines the causal relationships between SGs dynamics and major cell death modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis. By synthesizing recent advances in SG biology and cell death regulation, we elucidate how stress-adapted SG proteomes functionally contribute to death pathway activation or suppression. This mechanistic synthesis not only resolves current controversies regarding SGs’ function in different cell death models but also identifies targetable vulnerabilities at the SGs-death pathway interface, offering innovative frameworks for treating SGs-associated pathologies.