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.