Mechanism of Hippo/YAP Axis Mediating High Glucose-Induced Ferroptosis in HK-2 Cells

Mechanism of Hippo/YAP Axis Mediating High Glucose-Induced Ferroptosis in HK-2 Cells

Yifan Zhang,¹ Zhaoyu Lin,² Zhoutao Xie¹ and Yingxue He¹

¹Division of Nephrology, Wenzhou Central Hospital, The Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, Wenzhou, P.R. China
²Division of Endocrinology, Wenzhou Central Hospital, The Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, Wenzhou, P.R. China

The current study focused on the molecular mechanisms behind high glucose (HG)-induced ferroptosis in HK-2 cells. HG-induced epithelial-to-mesenchymal transition (EMT) HK-2 cell model displayed elevated Vimentin, α-SMA, Fe²⁺ and MDA expression, suppressed cell viability and proliferation capabilities, decreased E-cadherin, GPX4 and GSH levels, and increased cell death. Additionally, knockdown of Vimentin or α-SMA caused the opposite outcomes. Restaint of ferroptosis partially reversed the promotion role of knockdown of Vimentin or α-SMA in HK-2 cell proliferation. Further inhibition of the Hippo/YAP pathway could partly regulate the effects of Vimentin or α-SMA on HG-induced ferroptosis and proliferation in HK-2 cells. Conclusively, HG could increase the expression levels of Vimentin and α-SMA in HK-2 cells, and induce EMT, thereby inhibiting the activation of the Hippo/YAP signaling axis and cell proliferation, and promoting cell ferroptosis of HK-2 cells.

Key words —— epithelial-to-mesenchymal transition; ferroptosis; high glucose; hippo/yes-associated protein; HK-2 cells

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Tohoku J. Exp. Med., 2025 May, 266(3), 209-217.

Correspondence: Yifan Zhang, Division of Nephrology, Wenzhou Central Hospital, The Dingli Clinical College of Wenzhou Medical University, The Second Affiliated Hospital of Shanghai University, No. 252, Baili East Road, Wenzhou, Zhejiang province 325000, P.R. China.

e-mail: Yzfan252wz@163.com