Leonurine Attenuates Ischemia–Reperfusion Injury Through <scp>PI3K</scp> / <scp>AKT</scp> / <scp>mTOR</scp> Pathway in Mouse Liver

Hepatic ischemia-reperfusion (I/R) injury complicates transplantation, resection, and shock, yet lacks effective pharmacotherapy. We evaluated Leonurine (SCM-198) as a hepatoprotective agent. Male C57BL/6 mice were pretreated with SCM-198 for 7 days, then subjected to hepatic I/R and sampled at the reperfusion endpoint. AML12 cells were pretreated with SCM-198 for 24 h, exposed to hypoxia/reoxygenation (H/R), and immediately analyzed. Injury, inflammation, apoptosis, and cell-cycle changes were assessed using assay kits, histology, IHC, WB, and qPCR; network pharmacology, docking, and MD simulations explored potential targets. SCM-198 sharply cut hepatic necrosis and serum transaminases, suppressed pro-inflammatory cytokines, reduced leukocyte infiltration, blocked apoptosis and restored cyclin D1/cyclin E1. In hypoxia-reoxygenation AML12 cells, it improved viability, limited oxidative stress and mirrored the anti-apoptotic effects. Network and dynamic simulation identified stable phosphoinositide 3-kinase (PI3K) binding, and the compound raised PI3K, protein kinase B and mammalian target of rapamycin phosphorylation; the PI3K inhibitor LY294002 abolished these changes. SCM-198 protects liver I/R by curbing inflammation, apoptosis, and cell-cycle arrest via PI3K/AKT/mTOR activation, offering a promising therapeutic candidate.