Loss of cGAS facilitates angiogenesis in diabetic foot ulcer healing by suppressing the STING/ferroptosis pathway.

Diabetic foot ulcers (DFUs) are a major complication associated with diabetes and frequently result in serious health consequences. The cGAS-STING pathway has been linked to various disorders through its modulation of inflammation and ferroptosis, yet its specific function in the context of DFUs remains poorly understood. This work sought to explore the impact of targeting cGAS to inhibit STING activation on DFU healing, as well as its regulatory role in angiogenesis and endothelial cell ferroptosis. We observed elevated levels of cGAS and STING in wound samples from DFU subjects and animal models. Knockdown of cGAS significantly accelerated wound healing in DFU rat models, improved histopathological changes, increased collagen synthesis, and enhanced angiogenesis. Furthermore, DFU tissues in rats with cGAS knockdown exhibited notably lower levels of STING, p-TBK1, p-IRF3, p-P65, and pro-inflammatory mediators. In high glucose (HG)-stimulated vascular endothelial cells, cGAS and STING expression was upregulated. Silencing cGAS effectively inhibited HG-induced STING activation, while enhancing cell viability, migration, and tube formation. Furthermore, HG-induced ferroptosis in vascular endothelial cells, characterized by increased lipid peroxidation and altered ferroptosis-related protein expression, was significantly reversed by cGAS knockdown, indicating its role in inhibiting ferroptosis. Notably, the addition of a ferroptosis inducer in cGAS-knockdown cells partially reversed the improvement in angiogenesis. In conclusion, cGAS knockdown effectively accelerates DFU wound healing by inhibiting STING activation and modulating ferroptosis in endothelial cells, underscoring the pivotal role of the cGAS-STING-ferroptosis axis in DFU progression and healing, with potential therapeutic implications.