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Kaempferol Alleviates Carbon Tetrachloride-Induced Liver Fibrosis in Mice by Regulating Intestinal Short-Chain Fatty Acids

Siqi Zhang,Fei Tang,Zhe Zhou,Linhui Li,Yang Tang,Kaiwen Fu,Yang Tan,Ling Li

Liver fibrosis remains a critical health concern with limited therapeutic options. Kaempferol (Kae) is a natural flavonoid widely present in natural plants, yet its role in modulating gut–liver axis interactions during fibrosis is unexplored. This study investigates the hepatoprotective effects of Kae on alleviating carbon tetrachloride (CCl4)-induced liver fibrosis, and its underlying mechanisms, focusing on oxidative stress, gut microbiota, and short-chain fatty acids (SCFAs), are revealed. A mouse model of hepatic fibrosis was built by the subcutaneous injection of CCl4. Meanwhile, Kae was administered by gavage at doses of 25, 50, and 100 mg/kg body weight. Serum biomarkers, liver histopathology, oxidative damage markers, and nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling were analyzed. AML12 hepatocytes were pretreated with Kae or SCFAs (acetate, propionate, butyrate) before H2O2-induced oxidative injury. The changes in gut microbiota and the levels of SCFAs were assessed via 16S rRNA sequencing and GC-MS, respectively. Kae effectively alleviated the destruction of the liver morphology and tissue structure, reduced the infiltration of inflammatory cells, collagen deposition in the liver, and the expression of fibrotic factors, and downregulated the oxidative stress level in the liver of mice with liver fibrosis by activating the Nrf2/Keap1/HO-1 pathway (p< 0.05 or 0.01). In vitro, Kae significantly mitigated H2O2-induced cytotoxicity and oxidative damage (p< 0.05 or 0.01). Furthermore, Kae restored gut microbiota diversity, increased beneficial genera (e.g.,Lactobacillus), and elevated both intestinal and hepatic SCFA levels (p< 0.01). The discrepant SCFA pretreatment similarly protected AML12 cells by activating Nrf2 signaling (p< 0.05 or 0.01). Our research suggests that Kae could inhibit CCl4-induced liver fibrosis by restoring the levels of intestinal metabolite SCFAs to reduce oxidative damage.