• Transcriptional profiling reveals age-, sex-, and cell type-specific upregulation of Annexin A1 (ANXA1) in ischemic stroke across mouse and human datasets. • A bioinformatics-guided drug screen identifies curcumin as a potent natural inhibitor of ANXA1 signaling. • Curcumin preserves neuronal morphology and inhibit ANXA1 expression during post ischemic stroke recovery. • Curcumin reactivates the PI3K/AKT/mTOR axis and suppresses p38 MAPK signaling, promoting neuroprotection and inflammation silence. • Systemic curcumin treatment reduces infarct volume, restores neurological function, and shows no histopathological toxicity in both male and female stroke models. 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. 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. 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. 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.
Si-Yang et al. (Wed,) studied this question.