关键词: 顺铂；岩藻黄素；肝脏损伤；肠道菌群；核因子-E2相关因子2；铁死亡

Abstract: Objective: This study aims to investigate the effect of fucoxanthin on cisplatin-induced liver injury and gut microbiota dysbiosis in mice. Methods: To induce liver injury, mice were administered with 7 mg/kg cisplatin via intraperitoneal injection once a week for 4 consecutive weeks. Body mass was measured before each administration, and individual doses and injection volumes were calculated based on the daily body mass. Fucoxanthin was used for intervention, and amifostine was used as a positive control. The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), antioxidant enzymes, and inflammatory cytokines were measured. Liver and colon histological examination was carried out using hematoxylin-eosin (HE) staining. Western blot analysis was performed to detect the expression of ferroptosis-related proteins including nuclear factor erythroid 2-related factor 2 (Nrf2) family members and glutathione peroxidase 4 (GPX4) in liver tissue. 16S rRNA gene sequencing was conducted to analyze changes in the gut microbiota. Results: Fucoxanthin intervention decreased serum ALT and AST levels, reduced the levels of inflammatory cytokines in liver and colon tissues, increased antioxidant enzyme activities, and alleviated liver and colon histological lesions. Moreover, it increased the expression of proteins in liver tissue, including Nrf2, heme oxygenase 1 (HO-1), nicotinamide quinone oxidoreductase 1 (NQO1), and GPX4, restored colonic pathological damage, up-regulated the expression of tight junction proteins in the colonic epithelium, and ameliorated intestinal microbiota dysbiosis. Conclusion: Fucoxanthin likely restores cisplatin-induced liver injury in mice by alleviating inflammation and oxidative stress through an Nrf2/HO-1 axis-dependent ferroptosis signaling pathway and via multiple gut-liver axis routes by improving intestinal microecology and modulating the gut microbiota.

Key words: cisplatin; fucoxanthin; liver injury; gut microbiota; nuclear factor erythroid 2-related factor 2; ferroptosis