Kaempferol alleviates high-fat-induced hepatocyte injury by inhibiting ferroptosis

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a key manifestation of metabolic syndrome in the liver. Its core pathological features are excessive lipid accumulation in hepatocytes and the subsequent lipotoxic damage. This not only drives the progression of the disease to hepatitis, liver fibrosis, and cirrhosis but also is significantly associated with an increased risk of hepatocellular carcinoma. NAFLD has become an increasingly serious global public health issue, and there is an urgent need to explore safe and effective prevention and treatment strategies. This study aimed to evaluate the intervention effect of kaempferol, a natural flavonoid compound, on palmitic acid (PA)-induced hepatocyte lipotoxicity. METHODS: A series of biochemical experiments were conducted to evaluate the effect of kaempferol on liver lipotoxicity. RESULTS: Our results demonstrated that kaempferol not only counteracted PA-induced suppression of hepatocyte proliferation and viability but also mitigated PA-triggered inflammatory response (TNF-α, IL-6, IL-1β) and oxidative stress (ROS). Importantly, we identified that these protective effects were achieved through the inhibition of ferroptosis, a novel form of cell death induced by PA. Mechanistically, kaempferol exerted its benefits primarily by activating the AMPK signaling pathway. AMPK activation led to a dual protective effect: first, by down-regulating the fatty acid transporter CD36 to reduce lipid accumulation; second, and more significantly, by effectively suppressing the ferroptosis cascade, thereby breaking the vicious cycle of lipid overload, oxidative stress, and cell death. CONCLUSIONS: This new finding provides a novel perspective for understanding the efficacy of Kaempferol. This study not only confirms that kaempferol synergistically combats lipid metabolism disorders and ferroptosis through the "AMPK-CD36" axis but also provides a solid experimental basis and innovative theoretical support for the development of kaempferol as a drug for the prevention and treatment of fatty liver disease.