Ciwujianoside C Attenuates Cerebral Ischemia-Reperfusion Injury by Suppressing Ferroptosis via NNAT-Mediated Inhibition of NF-κB Signaling.

Cerebral ischemia-reperfusion injury (CIRI) involves oxidative stress, inflammation, and regulated cell death, among which ferroptosis has emerged as a key contributor. However, therapeutic strategies targeting ferroptosis remain limited. This study investigated whether Ciwujianoside C (CC), a triterpenoid saponin from Acanthopanax senticosus, protects against CIRI by modulating ferroptosis via the NNAT/NF-κB pathway. In MCAO/R rats, CC reduced infarct size, improved neurological scores, and ameliorated oxidative stress and ferroptosis markers. In BV2 microglia and HT22 cells (a mouse hippocampal neuronal cell line) subjected to OGD/R, CC enhanced cell viability, decreased iron accumulation, and restored GPX4 and FTH1 expression while inhibiting NF-κB activation. Importantly, NNAT knockdown abolished these protective effects, demonstrating NNAT as a critical mediator. These findings reveal that CC protects against CIRI by suppressing ferroptosis through the NNAT/NF-κB axis, highlighting NNAT as a potential therapeutic target in CIRI.