Cardiac arrest (CA) and subsequent cardiopulmonary resuscitation (CPR) often cause severe neurological deficits due to ischemia–reperfusion (I/R) injury, marked by systemic inflammation, blood–brain barrier (BBB) dysfunction, and excessive autophagy. JS-K, a nitric oxide-releasing prodrug, has shown cytoprotective effects, but its role in CA-induced brain injury remains unclear. Here, we investigated the therapeutic potential of JS-K in a mouse CA/CPR model and an in vitro oxygen–glucose deprivation/reoxygenation (OGD/R) model. JS-K treatment improved neurological outcomes, preserved BBB function, and prolonged survival. Mechanistically, JS-K preserved tight junction proteins and improved BBB function and suppressed endothelial autophagy in vivo and in vitro. Further analyses revealed that HMGB1, after nuclear-cytoplasmic translocation, interacted with ATG5, inducing excessive autophagy and BBB injury. JS-K inhibited HMGB1 translocation, reduced HMGB1-ATG5 interaction, and consequently mitigated autophagy-driven BBB dysfunction. Notably, ATG5 silencing failed to enhance JS-K’s protective effects, supporting that JS-K acts at least in part through the HMGB1-ATG5 axis. These findings identify JS-K as a promising therapeutic agent that targets HMGB1-mediated autophagy to protect BBB function after cardiac arrest. JS-K protects brain microvascular endothelial cells and preserves BBB function, in association with modulation of HMGB1 nuclear-to-cytoplasmic translocation and subsequent HMGB1-ATG5-mediated endothelial autophagy during CA/CPR.
Duan et al. (Fri,) studied this question.