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Genistein inhibits oxidative stress and alleviates vascular remodeling in hypertension through the GSK3β/FYN/Nrf2 pathway
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Xiaotong Zhang1, 2, 3, Yixuan Xie1, 2, 4, Zhijing Wu1, 2, 3, Dongmei Xi1, 2, 3, Na Tang1, 2, 3, *, Xinzhi Li1, 2, 3, *, Ketao Ma1, 2, 4, *
Chinese Journal of Natural Medicines | 2026, 24(8) : 941 - 955
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Chinese Journal of Natural Medicines | 2026, 24(8): 941-955
• Original Article •
Genistein inhibits oxidative stress and alleviates vascular remodeling in hypertension through the GSK3β/FYN/Nrf2 pathway
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Xiaotong Zhang1, 2, 3, Yixuan Xie1, 2, 4, Zhijing Wu1, 2, 3, Dongmei Xi1, 2, 3, Na Tang1, 2, 3, *, Xinzhi Li1, 2, 3, *, Ketao Ma1, 2, 4, *
Affiliations
  • 1Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China
  • 2NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832003, China
  • 3Department of Pathophysiology, Shihezi University School of Medicine, Shihezi 832003, China
  • 4Department of Physiology, Shihezi University School of Medicine, Shihezi 832003, China
About Author:

∆

These authors contributed equally to this work.

Published: 2026-08-20 doi: 10.1016/S1875-5364(26)61195-8
Outline
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Hypertension raises cardiovascular risk via vascular remodeling, worsened by oxidative stress-linked VSMC dysfunction. Genistein (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, spontaneously hypertensive rats (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.

Hypertension vascular remodeling  /  Genistein  /  Oxidative stress  /  Network pharmacology  /  GSK3β
Xiaotong Zhang, Yixuan Xie, Zhijing Wu, Dongmei Xi, Na Tang, Xinzhi Li, Ketao Ma. Genistein inhibits oxidative stress and alleviates vascular remodeling in hypertension through the GSK3β/FYN/Nrf2 pathway[J]. Chinese Journal of Natural Medicines, 2026 , 24 (8) : 941 -955 . DOI: 10.1016/S1875-5364(26)61195-8
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Funding
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  • Training Program of Tianshan Talents(2024TSYCCX0113; 0305-CZ003101)
  • National Natural Science Foundation of China(82460088)
  • Science and Technology Program of XPCC(2023ZD035; 2022ZD042; 2023ZD031)
  • Shihezi University Undergraduate Research Training Program Project(20231014557)
Appendix
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Year 2026 volume 24 Issue 8
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76
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Article Info
doi: 10.1016/S1875-5364(26)61195-8
  • Receive Date：2025-11-17
  • Online Date：2026-08-20
  • Published：2026-08-20
Article Data
Affiliations
History
  • Received：2025-11-17
  • Revised：2026-01-02
  • Accepted：2026-02-06
Funding
Training Program of Tianshan Talents(2024TSYCCX0113; 0305-CZ003101)
National Natural Science Foundation of China(82460088)
Science and Technology Program of XPCC(2023ZD035; 2022ZD042; 2023ZD031)
Shihezi University Undergraduate Research Training Program Project(20231014557)
Affiliations
    1Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Ministry of Education, Shihezi University School of Medicine, Shihezi 832003, China
    2NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, First Affiliated Hospital, Shihezi University School of Medicine, Shihezi 832003, China
    3Department of Pathophysiology, Shihezi University School of Medicine, Shihezi 832003, China
    4Department of Physiology, Shihezi University School of Medicine, Shihezi 832003, China

Corresponding:

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E-mail address: (N. Tang)
(X. Li)
(K. Ma)
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小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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