Fucoidan alleviates chemotherapy-induced steatohepatitis by regulating the gut–liver axis

Chemotherapy-associated hepatotoxicity represents a critical limitation in cancer treatment, decreasing patient survival and quality of life. Irinotecan (CPT-11) is a key chemotherapeutic agent commonly used in the treatment of gastrointestinal malignancies. However, its clinical use is frequently limited by severe adverse effects, among which steatohepatitis has emerged as a critical dose-limiting toxicity. The mechanism of irinotecan-induced steatohepatitis remains unclear. In this study, we treated mice with CPT-11 to induce steatohepatitis and monitored intestinal barrier function using in vivo imaging. CPT-11-induced barrier disruption allowed bacterial lipopolysaccharide (LPS) to reach the liver, triggering neutrophil extracellular trap (NETs) formation, which played a pivotal role in driving hepatic inflammation. Administration of Fucoidan, a fucose-rich sulfated polysaccharide, restored intestinal tight junction proteins, partially improved gut microbiota composition, reduced LPS translocation, and suppressed hepatic NETs accumulation. What's more, depletion of gut microbiota with antibiotics worsened CPT-11-induced hepatotoxicity, suggesting the irreplaceability of fucoidan. These findings indicate the intestinal barrier dysfunction-activated 8 NETs formation drive CPT-11-induced steatohepatitis and targeting NETs while preserving gut barrier integrity with fucoidan may offer a promising and practical strategy to prevent chemotherapy-induced liver injury. • We first demonstrated the pivotal role of NETs in chemotherapy-induced steatohepatitis. • Pad4 −/− attenuated hepatic inflammation and lipid accumulation, features characteristic of steatohepatitis. • Fucoidan inhibited NETs formation through modulation of gut-liver axis.