Sinensetin, a Citrus Polymethoxyflavone, Alleviates High-Fat Diet-Induced Colonic Ferroptosis via the TRPV4/Ca2+ Signaling Pathway

Abstract Long-term high-fat diet (HFD) strongly induces colon injury and metabolic disorders, with ferroptosis as a key mechanism. Sinensetin, a natural polymethoxyflavone, exhibits exceptional bioactivity; however, its potential to ameliorate HFD-induced colonic ferroptosis and underlying targeted mechanisms remains unclear. This study investigated sinensetin’s protective effects and modulation of TRPV4/Ca2+ signaling. In vivo and in vitro, sinensetin restored impaired intestinal morphology, decreased permeability, and upregulated tight junction proteins. It suppressed lipid peroxidation and iron overload by reducing ROS and Fe2+ accumulation. Antiferroptotic effects included increased glutathione peroxidase 4 (GPX4), ferroportin (FPN), and ferritin heavy chain (FTH), and decreased ACSL4 and transferrin receptor 1 (TfR1). Mechanistically, sinensetin negatively modulated TRPV4/Ca2+ signaling, preventing intracellular Ca2+ overload; a TRPV4 agonist reversed these benefits. These findings reveal a novel mechanism by which this citrus-derived compound mitigates HFD-induced intestinal damage via TRPV4/Ca2+-mediated ferroptosis inhibition, offering a potential preventive and therapeutic candidate for metabolic intestinal diseases.