Luteolin alleviates myocardial fibrosis through the ERK1/2-GATA4 pathway by inhibiting oxidative stress and EndMT

Introduction Myocardial fibrosis is a common pathological feature of cardiovascular diseases and is closely associated with oxidative stress, apoptosis, extracellular matrix remodeling, and endothelial-to-mesenchymal transition (EndMT). Luteolin (Lut), a naturally occurring flavonoid, exhibits cardioprotective properties; however, its anti-fibrotic effects and underlying mechanisms remain unclear. Methods Myocardial fibrosis was induced in rats by subcutaneous isoproterenol injection for 7 days, followed by Lut treatment. Cardiac function was evaluated by echocardiography, while myocardial injury and fibrosis were assessed by histological and molecular analyses. Potential anti-fibrotic targets of Lut were identified using network pharmacology and validated by molecular docking and molecular dynamics simulation. In vitro , HUVECs were stimulated with angiotensin II (Ang II) and then incubated with Lut. Oxidative stress, mitochondrial membrane potential (MMP), apoptosis, and ERK1/2-GATA4 signaling were examined. The involvement of ERK1/2 was further confirmed using the pharmacological inhibitor PD98059. Results Lut significantly improved cardiac function, alleviated myocardial injury, reduced collagen deposition, and attenuated myocardial fibrosis in ISO-treated rats. In Ang II-induced HUVECs, Lut suppressed ROS generation, preserved MMP, and inhibited apoptosis. Mechanistically, Lut activated ERK1/2 and GATA4 phosphorylation, regulated apoptosis-related proteins, and inhibited EndMT by decreasing α-SMA and FSP-1 while restoring VE-cadherin and CD31 expression. These protective effects were partially abolished by PD98059 both in vivo and in vitro . Conclusion Our findings demonstrate that Lut attenuates myocardial fibrosis by regulating oxidative stress, apoptosis, and EndMT, at least in part, via activation of the ERK1/2-GATA4 phosphorylation axis, suggesting its therapeutic potential for myocardial fibrosis.