Sorafenib induces intestinal toxicity by disturbing gut microbiota and activating the LPS/TLR4/NF-κB signaling pathway in mice

Sorafenib is a multitargeted tyrosine kinase inhibitor approved by the FDA as a standard first-line therapy for advanced hepatocellular carcinoma. Nevertheless, the high incidence rate of gastrointestinal (GI) adverse effects substantially limits its clinical application. The molecular mechanisms underlying the GI damage remain poorly understood. In this study, we explored the critical role of gut microbiota in sorafenib-induced intestinal toxicity using a mouse model and proposed a potential therapeutic intervention strategy. Sorafenib administration caused intestinal pathological damage, systemic inflammation, and oxidative stress in mice. Antibiotic (ABX) treatment and fecal microbiota transplantation (FMT) experiments demonstrated that the GI toxicity induced by sorafenib was mediated by the gut microbiota. 16S rRNA sequencing analysis revealed that sorafenib dramatically disturbed gut microbial homeostasis, leading to an increased abundance of Gram-negative bacteria and upregulated biosynthesis of lipopolysaccharide (LPS). Intestinal transcriptomic sequencing further indicated that sorafenib induced Gram-negative bacterial-derived LPS leakage via the compromised intestinal barrier and exacerbated inflammation via TLR4/NF-κB pathway activation. Notably, the TLR4-specific inhibitor TAK-242 effectively attenuated sorafenib-induced intestinal damage. Taken together, our study unveils a novel mechanism by which sorafenib exacerbates intestinal injury through gut microbiota dysbiosis and LPS/TLR4/NF-κB signaling pathway, while proposing TAK-242 as a promising therapeutic strategy. This study underscores the critical role of the gut microbiota in sorafenib-induced intestinal damage and offers new avenues for clinical intervention.