The Vicious Cycle of Hepatic Ferroptosis and Inflammation Drives Lipid Accumulation and Injury in Dairy Cows with Fatty Liver

Abstract In dairy cows, the complex pathophysiology of fatty liver continues to pose substantial obstacles to both prevention and treatment. Here, we identified hepatic inflammatory injury and ferroptosis in fatty liver cows and reproduced these phenotypes by exposing bovine hepatocytes to NEFA. Mechanistically, NEFA disrupted TFR1/FPN-mediated iron metabolism and impaired the SLC7A11-GPX4 axis, thereby driving uncontrolled lipid peroxidation. These molecular events were consistent with the hepatic pathological changes observed in fatty liver cows. Importantly, ferroptosis blockade reduced lipid deposition and inflammatory injury during NEFA exposure in bovine hepatocytes more effectively than NF-κB inhibition. Furthermore, TNF-α alone induced ferroptosis, lipid accumulation, and cell injury , and these effects were further exacerbated by NEFA. Consequently, our work reveals that a vicious cycle between ferroptosis and inflammation is a key pathogenic mechanism in fatty liver, thereby pinpointing ferroptosis as a novel therapeutic target with high translational potential for dairy cows.