FASEB J. 2026 May 31;40(10):e71826. doi: 10.1096/fj.202504432R.
ABSTRACT
This study aimed to elucidate the mechanism by which salvianolic acid B (Sal B) protects against reperfusion-induced vascular damage following cerebral infarction, specifically investigating its role in preserving microvascular integrity through the ACSL4/Nrf2 axis-mediated inhibition of ferroptosis. A mouse model of cerebral ischemia/reperfusion injury was established via middle cerebral artery occlusion (MCAO). Mice were divided into Sham, MCAO, MCAO+Sal B, and MCAO+Sal B + ML385 (Nrf2 inhibitor) groups. We employed RNA sequencing, TTC staining, behavioral tests, histopathology, and molecular biology techniques to assess infarct volume, neurological function, ferroptosis markers (ACSL4, GPX4, TFR1), iron deposition, oxidative stress, inflammation, and Nrf2 pathway activity. Sal B markedly reduced infarct volume and improved neurological outcomes. At the mechanistic level, Sal B suppressed pro-ferroptotic mediators ACSL4 and TFR1 while enhancing Nrf2 nuclear translocation and upregulating its downstream effectors HO-1 and GPX4. These changes were associated with decreased iron deposition, reduced lipid peroxidation, and alleviated neuroinflammation. Importantly, pharmacological inhibition of Nrf2 with ML385 largely abolished these protective effects, underscoring the central role of Nrf2 signaling. Sal B alleviates reperfusion-associated damage post-cerebral infarction by synergistically downregulating the pro-ferroptotic gene ACSL4 and activating the Nrf2/HO-1 antioxidant pathway, thereby cooperatively inhibiting ferroptosis, preserving BBB integrity, and reducing neuronal injury.
PMID:42186809 | DOI:10.1096/fj.202504432R