Genistein inhibits oxidative stress and alleviate vascular remodeling in hypertension through the GSK3β/Fyn/Nrf2 pathway

Hypertension raises cardiovascular risk via vascular remodeling, worsened by oxidative stress-linked VSMC dysfunction. Gen, an antioxidant isoflavone, protects against cardiovascular diseases, but its role in hypertensive remodeling is unclear. This study explores if Gen eases remodeling by inhibiting oxidative stress via the GSK3β/FYN/Nrf2 pathway. In vivo, SHR and normotensive WKY rats got Gen (10−20 mg·kg⁻¹·d⁻¹) or valsartan (Val) for 10 weeks; aortic tissues were tested for morphology (HE/Masson), proliferation (PCNA), migration (MMP2/9), oxidative stress (NOX4), and VSMC phenotype (α-SMA/OPN). In vitro, SHR/WKY VSMCs were treated with Gen (10−40 μmol·L⁻¹) to check proliferation (EdU), migration (scratch/Transwell), ROS, and Nrf2 markers. Network pharmacology predicts Gen inhibits vascular remodeling via reducing hypertension-related oxidative stress, verified by EdU, scratch, Transwell, and Western blot. Gen reduced SHR blood pressure, vascular wall thickness, and fibrosis, reversing PCNA, MMP2/9, NOX4, OPN overexpression and α-SMA underexpression. In VSMCs, it dose-dependently inhibited proliferation/migration, reduced ROS, and restored Nrf2 pathway activity. Network analysis found 52 shared targets, with GSK3β, FYN, Nrf2 as key nodes. Gen and pGSK3β inhibitor SNP reversed GSK3β/FYN overexpression and Nrf2 underexpression; Nrf2 inhibitor ML385 barely affected pGSK3β/FYN. Thus, Nrf2 may lie downstream of GSK3β and FYN. Gen inhibits oxidative stress injury in the aortic tissue of SHR rats through the GSK3β/FYN/Nrf2 pathway, thereby reducing vascular remodeling in hypertension, lowering blood pressure, and exerting a protective effect on vascular lesions in hypertension. These findings provide new experimental evidence for Gen as a potential therapeutic agent against hypertensive vascular remodeling.