Pharmacological inhibition of Ubiquitin-Specific Peptidase 10 (USP10) with spautin-1 attenuates adipogenesis through CCAAT/Enhancer-Binding Protein Beta (C/EBPβ) destabilization

The pharmacological control of lipid accumulation in white adipose tissue (WAT) is a key area of focus in obesity research, yet the role of deubiquitination in adipocyte lipid storage remains underexplored. We found that spautin-1, an inhibitor of the deubiquitinases ubiquitin-specific peptidase 10 (USP10) and 13 (USP13), suppressed lipid accumulation during adipogenesis. Therefore, we investigated whether blocking deubiquitination restricts adipogenesis and acts as the underlying mechanism. Mining public datasets revealed that USP10 expression is substantially increased in the adipose tissue (AT) from individuals with obesity. Moreover, USP10 exhibited a depot-specific expression pattern, with higher levels in visceral AT than in subcutaneous AT, whereas no such difference was observed for USP13. Consistently, in high-fat diet-fed mice, USP10 was markedly upregulated in gonadal WAT, whereas USP13 was undetectable. Genetic ablation of USP10 phenocopied spautin-1 treatment by reducing the expression of the components of the peroxisome proliferator-activated receptor gamma (PPARγ)/CCAAT/enhancer-binding protein alpha (C/EBPα) axis, while USP13 knockdown induced minimal effects, thus implicating USP10 as the principal mediator. Mechanistically, USP10 directly interacted with C/EBPβ and stabilized it via deubiquitination. However, spautin-1 or USP10 knockdown enhanced C/EBPβ ubiquitination and proteolysis, thereby impairing the adipogenic commitment. The overexpression of wild-type USP10, but not its catalytically inactive mutant, rescued C/EBPβ stability, thus confirming the requirement for its enzymatic activity. The administration of spautin-1 to high-fat diet-fed mice mitigated body weight gain and reduced adipose tissue mass in vivo. Notably, spautin-1 selectively suppressed USP10 and C/EBPβ in gonadal WAT without affecting the liver, which highlights the tissue-specific pharmacodynamics. Collectively, these findings define the USP10-C/EBPβ axis as a key regulator of adipogenesis and position spautin-1 as a mechanistically grounded anti-obesity candidate that warrants translational evaluation.