Peng Lingling, Tian Yaning, Wu Xiangkai, Liu Fengqi, Zhou Mingzhu, Wu Zixi, Xia Yumin, Liu Xiaoming, Cheng Chuantao
Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Horticulture, Xinjiang Agricultural University, Urumqi, China.
Wound Repair Regen. 2025 Jan-Feb;33(1):e13247. doi: 10.1111/wrr.13247.
Foot ulcers are amongst the most prevalent complications of diabetes, known for their delayed healing process. Recent research indicates that the transcription factor forkhead box M1 (FOXM1) plays a role in promoting diabetic ulcer repair. However, the precise mechanisms underlying FOXM1 functions in this context remain unclear. This study aimed to clarify the role of tripartite motif-containing protein 72 (TRIM72)-mediated endoplasmic reticulum stress in FOXM1 promotive effects. Immunohistochemistry revealed that FOXM1 expression was significantly reduced in the lesion tissues of diabetic foot ulcer patients. In vitro experiments revealed a decrease in FOXM1 expression in cultured dermal fibroblasts under high glucose conditions. Activating FOXM1 with a plasmid accelerated the proliferation, migration, and differentiation of dermal fibroblasts and mitigated endoplasmic reticulum stress under high glucose conditions. Additionally, ChIP and luciferase reporter gene assays confirmed that FOXM1 suppressed TRIM72 expression transcriptionally by binding to its promoter. Furthermore, high glucose induced ubiquitination of adenosine 5'-monophosphate-activated protein kinase alpha (AMPKα), whilst inactivation of AMPKα signalling reversed the aforementioned effects of FOXM1 on cells. Finally, the FOXM1-overexpressing plasmid was transfected in vivo, which promoted wound healing in a murine diabetic ulcer model. In conclusion, FOXM1 reduces endoplasmic reticulum stress by inhibiting TRIM72-mediated AMPKα ubiquitination, thereby accelerating the healing of diabetic ulcers.
足部溃疡是糖尿病最常见的并发症之一，以其愈合过程延迟而闻名。最近的研究表明，转录因子叉头框M1（FOXM1）在促进糖尿病溃疡修复中发挥作用。然而，在这种情况下，FOXM1发挥作用的精确机制仍不清楚。本研究旨在阐明含三联基序蛋白72（TRIM72）介导的内质网应激在FOXM1促进作用中的作用。免疫组织化学显示，糖尿病足溃疡患者病变组织中FOXM1表达显著降低。体外实验显示，在高糖条件下，培养的真皮成纤维细胞中FOXM1表达降低。用质粒激活FOXM1可加速真皮成纤维细胞的增殖、迁移和分化，并减轻高糖条件下的内质网应激。此外，染色质免疫沉淀和荧光素酶报告基因检测证实，FOXM1通过与TRIM72启动子结合转录抑制其表达。此外，高糖诱导腺苷5'-单磷酸激活蛋白激酶α（AMPKα）泛素化，而AMPKα信号失活则逆转了FOXM1对细胞的上述作用。最后，在体内转染了过表达FOXM1的质粒，其促进了小鼠糖尿病溃疡模型的伤口愈合。总之，FOXM1通过抑制TRIM72介导的AMPKα泛素化来减轻内质网应激，从而加速糖尿病溃疡的愈合。
