Kaempferol attenuates macrophage M1 polarization and liver fibrosis by inhibiting mitogen-activated protein kinase/nuclear factor κB signaling pathway

Chronic liver inflammation is a major cause of death in patients with liver fibrosis and cirrhosis, which pose a serious health threat worldwide, and there is no effective anti-hepatic fibrosis drug. Kaempferol (KA), a flavonoid polyphenol extracted from many edible plants and traditional Chinese medicine, has been reported to possess anti-inflammatory, antioxidant, and antitumor activities and has an ameliorating effect on liver fibrosis or other fibroproliferative diseases. However, the specific regulatory mechanism of KA-reversed macrophage M1 polarization is still obscure. This study aimed to investigate the protective effects of KA on carbon tetrachloride (CCl4)-induced liver fibrosis in mice through M1 polarization. C57BL/6 mice were intraperitoneally injected with CCl4 twice weekly to induce liver fibrosis. Male mice were randomly divided into 4 groups (n = 5): the oil group, the CCl4 group, the low-dose KA-treatment CCl4 group (50 mg/kg/day KA), and the high-dose KA-treatment CCl4 group (100 mg/kg/day KA). An equal amount of solvent was given to each group by intraperitoneal injection. The results indicated that KA decreased liver pathologic changes, hepatic macrophage recruitment, and serum alanine aminotransferase levels. Notably, it reduced the activation of M1-type macrophages in the liver. The expression of proinflammatory cytokines and genes associated with M1 macrophages, such as tumor necrosis factor-α, interleukin-6, interleukin-1β, and inducible nitric oxide synthase, was also decreased. The core targets, signaling pathways, and possible mechanisms related to the M1 polarization of KA were analyzed by network pharmacology and molecular docking. Further analysis revealed that KA regulated mitogen-activated protein kinase (MAPK)/nuclear factor κB (NF-κB) signaling pathways. Finally, the results indicated that KA regulates M1 macrophage activation by modulating the MAPK/NF-κB signaling pathways. This study revealed that KA ameliorated liver injury, inflammation, and fibrosis by inhibiting macrophage M1 polarization through the MAPK/NF-κB signaling pathway, highlighting KA as a potential novel agent for the prevention and treatment of liver fibrosis. SIGNIFICANCE STATEMENT: Chronic liver inflammation is a leading cause of mortality in patients with liver fibrosis and cirrhosis, presenting a significant global health threat. Kaempferol, as a traditional Chinese medicine, effectively suppresses M1 polarization of macrophages through the mitogen-activated protein kinase/nuclear factor κB signaling pathway, thereby ameliorating liver injury, inflammation, and fibrosis. These findings underscore the potential of kaempferol as an innovative therapeutic agent for the prevention and treatment of liver fibrosis.