RNA N(6)-methyladenosine demethylase FTO promotes diabetic wound healing through TRIB3-mediated autophagy in an m(6)A-YTHDF2-dependent manner.

N(6)-methyladenosine (m(6)A) RNA modification impaired autophagy results in delayed diabetic wound healing. In this study, it was found that fat mass and obesity-associated protein (FTO) was significantly downregulated in the epidermis of diabetic patients, STZ-induced mice and db/db mice (type I and II diabetic mice) with prolonged hyperglycemia, as well as in different types of keratinocyte cell lines treated with short-term high glucose medium. The knockout of FTO affected the biological functions of keratinocytes, including enhanced apoptosis, inhibited autophagy, and delayed wound healing, producing consistent results with high-glucose medium treatment. High-throughput analysis revealed that tribbles pseudokinase 3 (TRIB3) served as the downstream target gene of FTO. In addition, both in vitro and in vivo experiments, TRIB3 overexpression partially rescued biological functions caused by FTO-depletion, promoting keratinocyte migration and proliferation via autophagy. Epigenetically, FTO modulated m(6)A modification in the 3'UTR of TRIB3 mRNA and enhanced TRIB3 stability in a YTHDF2-dependent manner. Collectively, this study identifies FTO as an accelerator of diabetic wound healing and modulates autophagy via regulating TRIB3 in keratinocytes, thereby benefiting the development of a m(6)A-targeted therapy for refractory diabetic wounds.