USP25 deficiency suppresses diet-induced obesity via ubiquitination and degradation of PARP1 and Elovl3 downregulation

作者：Bowen Xie, Junbo Li, Guobin Huang, Yuanyuan Zhao, Dong Chen, Lai Wei, Fangyu Guo, Rodrigo M. Florentino, Lanuza A. P. Faccioli, Takeshi Kurihara, Zhenghao Liu, Yiyue Sun, Zhiping Hu, Ying Cheng, Bo Yang · 发表于：Journal of Lipid Research · 年份：2026 · DOI：10.1016/j.jlr.2026.101002 · 研究领域：Ubiquitin and proteasome pathways、Sirtuins and Resveratrol in Medicine、PARP inhibition in cancer therapy

Ubiquitin-specific protease 25 (USP25) is a key regulator of lipid metabolism and insulin-stimulated glucose transport. Nonetheless, its involvement in adipocyte maturation remains uncertain. In this study, we aimed to explore how the expression of USP25 contributes to obesity induced by a high-fat diet (HFD). Usp25-KO and WT mice, maintained on either a normal diet or an HFD, were evaluated for weight gain, insulin resistance status, adipose tissue development, energy metabolism, and systemic inflammation status. In vitro, 3T3-L1 cells were induced to mature adipocytes in a specific culture medium. We found that USP25 expression decreased in obese mice subjected to long-term HFD feeding and in mature adipocytes. Usp25-KO mice showed restrained adipose tissue development and improved insulin resistance, whereas USP25-deficient preadipocytes failed to differentiate. RNA sequencing analysis showed the downregulation of lipid synthesis-related pathways in Usp25-KO mice. Mechanistically, USP25 binds to and stabilizes poly (ADP-ribose) polymerase 1 through deubiquitination, whereas poly (ADP-ribose) polymerase 1 facilitates preadipocyte differentiation and maturation by regulating the elongation of very long-chain fatty acid protein 3. These findings show the essential role of USP25 in adipocyte differentiation and lipid metabolism, suggesting that targeting USP25 ablation in adipocytes could be a promising therapeutic strategy for obesity treatment.