Dong Zheng, Li Shiyan, Huang Yumeng, Chen Tianzhe, Ding Youjun, Tan Qian
Department of Burn and Plastic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, 210008, China.
Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing, Jiangsu, 210008, China.
Cell Death Dis. 2025 Mar 29;16(1):222. doi: 10.1038/s41419-025-07494-3.
N-methyladenosine (mA) 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 mA 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 mA-targeted therapy for refractory diabetic wounds.
N-甲基腺苷（mA）RNA修饰受损导致的自噬障碍会导致糖尿病伤口愈合延迟。在本研究中，发现脂肪量与肥胖相关蛋白（FTO）在糖尿病患者、链脲佐菌素诱导的小鼠以及db/db小鼠（I型和II型糖尿病小鼠）的表皮中显著下调，这些小鼠均存在长期高血糖，同时在短期高糖培养基处理的不同类型角质形成细胞系中也显著下调。FTO基因敲除影响了角质形成细胞的生物学功能，包括增强细胞凋亡、抑制自噬以及延迟伤口愈合，与高糖培养基处理产生了一致的结果。高通量分析表明，TRIB3（ Tribbles假激酶3）是FTO的下游靶基因。此外，在体外和体内实验中，TRIB3过表达部分挽救了FTO缺失导致的生物学功能，通过自噬促进角质形成细胞迁移和增殖。在表观遗传学上，FTO调节TRIB3 mRNA 3'UTR中的mA修饰，并以YTHDF2依赖的方式增强TRIB3的稳定性。总的来说，本研究确定FTO是糖尿病伤口愈合的促进因子，并通过调节角质形成细胞中的TRIB3来调节自噬，从而有利于开发针对难治性糖尿病伤口的mA靶向治疗方法。
