Ginsenoside Re attenuates ferroptosis induced by hepatic ischemia-reperfusion injury via the BAP1/SLC7A11 axis.

Hepatic ischemia-reperfusion injury (HIRI) is a complex clinical complication involving inflammation and multiple forms of regulated cell death, among which ferroptosis plays a critical role. Ginsenoside Re (Re) exhibits prominent antioxidant capabilities, but its exact molecular targets in HIRI are unidentified. Here, using in vivo HIRI and in vitro hypoxia/reoxygenation (H/R) models, we found that Re administration exhibited an optimal therapeutic window, significantly alleviating hepatocellular damage, inflammatory responses, and oxidative stress. Sequentially, Re suppressed ferroptosis, as characterized by reduced iron deposition, decreased lipid peroxidation, and restored expression of GPX4 and SLC7A11. Utilizing Drug Affinity Responsive Target Stability (DARTS) and 4D-DIA quantitative proteomics, we identified BRCA1-associated protein 1 (BAP1) as a direct intracellular target of Re. Re physically bound to BAP1 and down-regulated its expression, thereby relieving BAP1-mediated transcriptional suppression of SLC7A11 and bolstering glutathione synthesis. Conversely, BAP1 overexpression reversed the anti-ferroptotic and hepatoprotective effects of Re. In conclusion, our findings demonstrate that Ginsenoside Re mitigates HIRI by targeting the BAP1/SLC7A11 axis to inhibit ferroptosis, offering a promising therapeutic strategy for clinical intervention.