Curcumin normalizes stress–associated Annexin A1 signaling to promote neuronal survival and functional recovery after ischemic stroke

Background Ischemic stroke (IS) causes substantial long-term disability, and effective neuroprotective strategies remain limited. Post-ischemic neuroinflammation compromises neuronal survival and recovery. ANXA1 is strongly induced after ischemia, but whether stress-associated ANXA1 upregulation becomes maladaptive and therapeutically targetable remains unclear. Methods We integrated human and murine transcriptomics with in vitro oxygen–glucose deprivation (OGD) and in vivo MCAO experiments, followed by a focused natural-compound screen to identify modulators of ischemia-associated ANXA1 induction. Results Curcumin improved neuronal survival under OGD. In MCAO mice, curcumin reduced infarct burden and improved neurological and locomotor outcomes in both sexes. Curcumin attenuated ischemia-associated ANXA1 upregulation in neurons and microglia within the post-ischemic brain. This was accompanied by restoration of PI3K/AKT/mTOR signaling and suppression of p38 MAPK activity, with modest sex-associated differences. Curcumin also shifted peri-infarct brain tissue cytokine profiles toward a less pro-inflammatory state and showed no overt histopathological toxicity. Conclusions Together, these findings support an ANXA1-centered therapeutic framework in IS and nominate curcumin as a feasible lead compound to normalize stress-associated brain ANXA1 responses and enhance post-stroke recovery.