Loss of MAF bZIP transcription factor G restores ATG7/BECN1-mediated autophagy to inhibit ferroptosis and improve angiogenesis in diabetic foot ulcer wound healing.

Abstract

Background: Diabetic foot ulcer (DFU), a complication of diabetes, is associated with an increased risk of major amputation and mortality. However, the underlying pathogenesis of DFU remains unclear. The goal of this study was to investigate the role and underlying mechanism of MAF bZIP transcription factor G (MAFG) in DFU wound healing.

Methods: HUVECs were subjected to high glucose (HG) treatment. RT-qPCR and western blot were used to determine the expression of MAFG and autophagy/ferroptosis-related markers. Cell proliferation was tested using CCK-8 assay. Wound healing and tube formation assays were used to assess cell migration and angiogenesis, respectively. ELISA and DCFH-DA staining were employed to measure intracellular oxidative stress and iron content. LC3B expression was detected by immunofluorescent staining. Luciferase reporter assay investigated MAFG-mediated transcriptional regulation of ATG7/BECN1.

Results: Increased MAFG level were observed in DFU patients and HG-exposed HUVECs. The suppression of MAFG resulted in improved proliferation and angiogenesis in HG-induced HUVECs. MAFG knockdown effectively mitigated HG-induced oxidative stress and ferroptosis. Notably, the beneficial effect of MAFG silence on HG-induced HUVECs was diminished after 3-methyladenine (3-MA) administration (a specific autophagy inhibitor). Biologically, MAFG acted as a transcriptional repressor in HUVECs by directly targeting the promoters of autophagy-related genes ATG7 and BECN1. The depletion of ATG7 or BECN1 reversed the protective effects of MAFG knockdown on HG-stimulated angiogenesis and ferroptosis inhibition in HUVECs.

Conclusion: Taken together, MAFG knockdown inhibited ferroptosis and promoted angiogenesis to impair DFU wound healing via modulating ATG7/BECN1-mediated autophagy, providing a novel therapeutic target for DFU treatment.