2. Academic Validation
  3. Silencing of LOX-1 attenuates high glucose-induced ferroptosis in THVECs via the HIF-1α/SLC7A11 signaling pathway

Silencing of LOX-1 attenuates high glucose-induced ferroptosis in THVECs via the HIF-1α/SLC7A11 signaling pathway

  • Exp Cell Res. 2025 Mar 15;446(2):114451. doi: 10.1016/j.yexcr.2025.114451.
Haiqi Zhang 1,  Xinying Chang 1,  Xuan Liu 2,  Baozhuan Zhang 2,  Rongrong Wang 1,  Yuhui Wang 1,  Simeng Dai 1,  Tonghan Yao 1,  Qi Zhang 3
Affiliations

Affiliations

  • 1 The First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, 730000, China.
  • 2 The First Clinical Medical College, Lanzhou University, Lanzhou, 730000, China.
  • 3 Department of Gerontology, Gansu Provincial Hospital, Lanzhou, 730000, China. Electronic address: lzzq78@126.com.
PMID: 40015503 DOI: 10.1016/j.yexcr.2025.114451
Abstract

Objectives: Diabetic osteoporosis (DOP) represents a significant and serious complication associated with diabetes, characterized by a complex and inadequately understood pathophysiological mechanism. Recent studies have highlighted a robust association between DOP and Ferroptosis. H-type vessels play a critical role in osteoporosis, while lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is associated with endothelial dysfunction related to diabetes. In this study, we investigate how LOX-1 affects Ferroptosis in H-type vascular endothelial cells (THVECs) under high glucose (HG) conditions, aiming to elucidate the molecular mechanisms involved.

Methods: THVECs were isolated from rats employing an enzymatic digestion method and subsequently validated through immunofluorescence analysis. The silencing of LOX-1 was achieved via transfection with a lentiviral vector. Cell viability was assessed using the CCK-8 assay, and ROS, MMP, GSH, MDA, and Fe2+ levels were assessed utilizing specific commercial kits. Western blotting and PCR assessed LOX-1, HIF-1α, SLC7A11, and GPX4 expression levels.

Results: In high glucose conditions, LOX-1 expression at both protein and mRNA levels increased, while ROS, MDA, and Fe2+ rose, and MMP and GSH levels fell, resulting in Ferroptosis in THVECs. This condition could be reversed by silencing LOX-1 or by administering the Ferroptosis inhibitor (Fer-1). Further analysis showed that silencing LOX-1 enhanced the expression of HIF-1α, SLC7A11, and GPX4, which mitigated Ferroptosis in THVECs.

Conclusions: Downregulation of LOX-1 alleviates high glucose-induced Ferroptosis in THVECs via the HIF-1α/SLC7A11 pathway. This suggests that LOX-1 functions as a critical target for regulating Ferroptosis in THVECs, providing a novel insight into the pathological mechanisms associated with DOP.

Keywords

Diabetic osteoporosis; Ferroptosis; H-type vascular endothelial cells; LOX-1.

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