Stress granule phase transitions and neuronal fate in cerebral ischemia-reperfusion injury.

Cerebral ischemia-reperfusion injury (CIRI) drives neuronal death through secondary molecular events that persist after blood flow is restored. How neurons commit to survival or death before individual death programs engage remains unclear. Liquid-liquid phase separation and its stress granules (SGs) offer one regulatory platform. Under CIRI stress, SGs assemble around G3BP1 and concentrate stalled mRNP complexes with RNA-binding proteins such as TDP-43, FUS, and DDX3X. The physical state of the condensate sets its function. Liquid-state SGs are cytoprotective. In a mechanism so far demonstrated outside CIRI itself, they sequester executioner caspase-3 and caspase-7. They also upregulate GPX4 protein through a G3BP1-IGF2BP1-m6A hub that limits ferroptosis. They further reduce DDX3X availability for NLRP3 inflammasome assembly, an effect now supported by direct evidence in ischemic brain tissue. When injury exceeds what liquid condensates can buffer, oxidative modification drives an irreversible liquid-to-solid transition. Cytoplasmic mislocalization of TDP-43 after nuclear pore damage, progressive FUS aggregation under sustained oxidative stress, and chaperone depletion accelerate this shift. The result is proteostasis collapse through joint failure of the ubiquitin-proteasome system and selective autophagy. Rodent occlusion models place this bifurcation in early reperfusion, broadly within the first day, though estimates remain approximate and the human interval is undefined. Muscone and icariin may stabilize acute-phase condensates, while melatonin and HDAC6 inhibition may resolve subacute aggregates. The account moves from the biophysical basis of SG formation through the distinct ischemic and reperfusion phases of assembly. It then covers the bifurcating protective and pathological trajectories before turning to therapeutic strategies and their translational limitations. This review argues that the SG checkpoint is an underappreciated node in CIRI. Progress requires defining its time window in human neurons, resolving SG behavior across the neurovascular unit, and validating topology-targeting approaches in primates.