Targeting nucleoporin NUP85 ameliorates acetaminophen-induced liver injury by inhibiting inflammation and oxidative stress in hepatocytes

Liver injury induced by excessive acetaminophen (APAP) is the main cause of drug-induced liver failure, and its pathological process is closely related to oxidative stress and inflammatory response. Nucleoporin 85 (NUP85, also known as FROUNT) plays a regulatory role in liver diseases, but its function and mechanism in APAP-induced liver injury (AILI) remain unclear. This study explored the role of NUP85 and targeted intervention strategies through in vivo and in vitro experiments. The results showed that NUP85 expression was significantly upregulated in mouse and AML-12 cells after APAP treatment. Furthermore, targeted knockdown of NUP85 in vivo reduced serum transaminase expression level, alleviated liver pathological damage, decreased macrophage infiltration and inflammatory cytokines secretion, and improved oxidative stress. In vitro experiments demonstrated that silencing NUP85 attenuates inflammation via inhibition of NF‑κB signaling pathway and mitigates oxidative stress via activation of the Nrf2–Keap1 signaling pathway, while overexpression of NUP85 showed the opposite effect. It was found through virtual screening that crocin-I can specifically bind to NUP85 and inhibit its expression. In vivo experiments confirmed that crocin-I alleviates AILI in a dose-dependent manner and exerts comparable anti-inflammatory and antioxidant effects to the clinical drug N-acetylcysteine (NAC). In conclusion, NUP85 aggravates AILI by regulating the NF-κB and Nrf2-Keap1 signaling pathways. Crocin-I can target NUP85 to exert liver-protective effects, providing new targets and candidate drugs for the clinical treatment of AILI.