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
