USP53 regulates the AMPK pathway by deubiquitinating TJP2 to control the keloid-derived fibroblasts proliferation, invasion, and telomerase activity.

Keloid formation originates from the abnormal activation of fibroblasts, which differentiate into myofibroblasts and excessively secrete collagen, leading to dysregulated deposition of extracellular matrix (ECM) and tissue fibrosis. We aim to explore the role and the mechanism of USP53 in keloid-derived fibroblasts (KFs) proliferation, invasion, and telomerase activity. Bioinformatics analysis was performed to obtain the genes differentially expressed between keloid tissue and normal tissue, as well as the enriched pathways. The KFs were isolated and transfected with USP53 silencing and overexpression plasmids. KFs proliferation, apoptosis, EMT and telomerase properties were explored. The protein expression of CDK1, Collagen I, E-cadherin, Snail, Slug, Cleaved-Caspase 3, and Caspase 3 was examined by western blotting. The interaction between USP53 and TJP2 was explored by Co-IP, and the rescue experiment was also performed. Finally, the in vivo experiments of keloid in nude mice was conducted. USP53 was downregulated in keloid tissues. Knockdown of USP53 promoted the proliferation, epithelial–mesenchymal transition (EMT), and telomerase activity, while inhibiting cell apoptosis in KFs. In contrast, USP53 overexpression exerted opposite effects. USP53 could interact with TJP2. Overexpression of USP53 led to slower TJP 2 degradation, and USP53 enhanced the stability of TJP 2. Moreover, USP53 activated the AMPK pathway. USP53 inhibited cell proliferation in vivo. USP53 regulates the AMPK pathway by deubiquitinating of TJP2 and inhibits the KFs proliferation, invasion, and telomerase activity.