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

Authors

Zhuoqun Meng, Qin Zhang, Zhichang Zhao, Ranran Zhang, Guirong Liu, Wenliang Xiang, Qing Zhang, Jie Tang

Published in

Journal of agricultural and food chemistry. Volume 74. Issue 44. Pages 35058-35075. Nov 11, 2026.

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.

PMID:
43012707
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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