Kummerowia striata extract protects paracetamol-induced liver injury by modulating the S1P/Nrf2/Keap1 pathway

This study illustrates that Ks exerts a protective effect against APAP-induced acute liver injury by modulating oxidative stress and inflammatory responses through multiple mechanisms. Notably, Ks inhibited Keap1 expression and restored Nrf2 signaling, indicating a potential regulatory role in mitigating mitochondrial oxidative damage and ferroptosis. Furthermore, Ks downregulated SPHK1 expression and reduced levels of the bioactive sphingolipid S1P, as well as its receptors S1PR2 and S1PR4, unveiling a previously unreported involvement of the SPHK1/S1P/S1PR2/4 axis in liver injury. Interestingly, sex-based differences in APAP hepatotoxicity were observed, with female mice exhibiting lower susceptibility, yet still responding to Ks treatment. These findings not only validate the hepatoprotective potential of Ks but also provide new mechanistic insights involving the Nrf2/Keap1 and S1P/S1PR2/S1PR4 signaling pathways, thereby laying a foundation for its development as a candidate therapeutic agent for acute liver injury.