Naringenin inhibits endothelial-mesenchymal transition and alleviates myocardial fibrosis in rats by regulating the AKT/GSK3β/β-catenin pathway.

Authors

Kai Huang, Chongyu Shao, Huifen Zhou, Guanfeng Xu, Bolin Li, Chengsi Jin, Haitong Wan

Published in

Molecular and cellular biochemistry. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

Endothelial-mesenchymal transition (EndMT) is increasingly recognized as a critical factor contributing to myocardial fibrosis, which ultimately leads to cardiac dysfunction. Naringenin (NAR), a major flavonoid derived from citrus fruits, exhibits various pharmacological properties, including anti-inflammatory, antioxidant, and cardioprotective effects. However, the pharmacological mechanism by which NAR counteracts EndMT remains unclear. In this study, a heart failure model was established in rats by subcutaneous injection of isoproterenol hydrochloride (ISO, 5 mg/kg for 7 days), and human umbilical vein endothelial cells (HUVECs) were stimulated with angiotensin II (Ang II, 1 µM) in vitro. NAR was administered orally (50 and 100 mg/kg/day) for 28 days after ISO induction. Echocardiography revealed that NAR significantly improved ejection fraction (EF) and fractional shortening (FS), and reduced systolic/diastolic diameters and volumes. Histological analyses (H&E and Masson's trichrome staining) showed that NAR attenuated ISO‑induced myocardial disarray, hypertrophy, and collagen deposition. Immunohistochemistry and Western blot demonstrated that NAR downregulated fibrosis markers (collagen I, collagen III) and the mesenchymal marker α‑SMA, while upregulating the endothelial marker CD31. Mechanistically, NAR increased the phosphorylation of AKT and GSK3β, as well as the expression of β‑catenin, indicating activation of the AKT/GSK3β/β‑catenin pathway. Consistently, the GSK3β inhibitor AR‑A014418 reversed the protective effects of NAR in HUVECs. In summary, our findings demonstrate that naringenin attenuates myocardial fibrosis by inhibiting EndMT via modulation of the AKT/GSK3β/β‑catenin signaling pathway. These results highlight the promising therapeutic potential of naringenin in managing myocardial fibrosis.

PMID:
42348139
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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