Metrnl Ameliorates Ferroptosis in Model of Diabetic Foot Ulcer Through the Inhibition of Mitochondrial Damage via LKB1/AMPK Signaling

Abstract

Objective

Diabetic foot ulcer (DFU) represents a severe complication of diabetes, mainly caused by peripheral vascular occlusion and infection, presenting significant clinical challenges in treatment and potentially resulting in gangrene, amputation, or even fatality. This study aimed to investigate the involvement and underlying mechanisms of Meteorin-like (Metrnl) in the pathogenic process of DFU.

Methods

Mice underwent diabetes induction by streptozotocin, while human umbilical vein endothelial cells (HUVECs) were exposed to 5.5, 10, 20 or 40 mM glucose. HUVECs were transfected with negative or Metrnl or si-nc or si-Metrnl plasmids via Lipofectamine 2000.

Results

The expression of Metrnl was down-regulated in both patients and the murine model of DFU. Elevated glucose levels diminished Metrnl through enhanced Metrnl ubiquitination. The suppression of Metrnl exacerbated foot ulcer in the mouse model of DFU. Metrnl alleviated oxidative stress and ferroptosis in the DFU model by inhibiting mitochondrial damage. Metrnl induced liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling in the DFU model. LKB1 attenuated the effects of Metrnl on oxidative stress and ferroptosis in the DFU model.

Discussion

  The data cumulatively demonstrate that Metrnl ameliorates ferroptosis in the DFU model by inhibiting mitochondrial damage via LKB1/AMPK signaling, suggesting that targeting Metrnl may emerge as a potential preventive approach against ferroptosis of DFU or other diabetes.

Keywords

Metrnl - Diabetic foot ulcer - LKB1 - AMPK - ferroptosis

Publication History

Received: 21 May 2024

Accepted after revision: 09 December 2024

Article published online:
12 March 2025

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