Protective effects of liensinine against acetaminophen-induced liver injury through relieving inflammation, oxidative stress, and apoptosis

Abstract Background Acetaminophen (APAP)-induced hepatotoxicity has attracted considerable attention in clinical settings due to the limited treatment options available. Liensinine stands out as a key alkaloid known for its pharmaceutical activities. However, the role of liensinine in mitigating APAP-induced liver injury remains unclear. Objective The aim of the study was to explore the protective effects of liensinine against APAP-induced liver injury. Methods C57BL/6 male mice were treated with a dose of 200 mg/kg N -acetylcysteine or varying doses of liensinine (10 or 20 mg/kg) for seven consecutive days. APAP (400 mg/kg, i.g .) was then administered to induce liver damage for 12 hours. Blood samples and hepatic tissues were collected for further analysis. Liver enzyme levels and histopathological analysis were employed to assess liver injury. RNA-seq was conducted to evaluate the dynamic changes in gene expression. Biochemical assays were used to measure oxidative stress and inflammation, while the TUNEL assay was performed to assess hepatocyte apoptosis. Results The results demonstrated that the administration of liensinine mitigated serum liver enzyme levels and tissue damage resulting from APAP overdose. Transcriptome analysis revealed significant and coordinated changes in genes related to the peroxisome proliferator-activated receptor signaling pathway, mitogen-activated protein kinase signaling pathway, and apoptosis pathway in response to APAP-induced hepatotoxicity. The expression alterations of key genes within these three pathways, associated with inflammation, oxidative stress, and cell apoptosis, were reversed by liensinine, indicating its potential in alleviating APAP-induced liver damage through multiple signaling pathways. This suggests the diverse therapeutic effects of liensinine, including inflammation suppression, oxidative stress reduction, and cell apoptosis inhibition. Indeed, pretreatment with liensinine effectively reduced inflammatory cytokines, oxidative stress indicators, and apoptotic cells induced by APAP. Conclusions Liensinine mitigates APAP-induced hepatotoxicity in mice through multifaceted pathways, providing anti-inflammatory, antioxidant, and anti-apoptotic benefits.