Ubiquitin-specific protease 25: a new regulator for cardiovascular and cerebrovascular diseases

Yingchun Shao, Shan Jiang, LI Zh, Fusheng Sun

Ubiquitin-specific protease 25 (USP25), a pivotal deubiquitinating enzyme, has attracted increasing attention in cardiovascular and cerebrovascular research due to its regulatory function in maintaining ubiquitination homeostasis. Considerable advances have been achieved in elucidating the molecular mechanisms through which USP25 participates in the pathological progression of diverse cardiovascular and cerebrovascular disorders. From the perspective of translational medicine, notable progress has also been observed in the development of USP25-targeted therapeutics, with several inhibitors having advanced to preclinical and early-phase clinical trials, thereby offering promising targets for precision treatment. Nevertheless, a systematic synthesis of fundamental biological properties, the trajectory of research development, and the intricate upstream–downstream regulatory networks of USP25, together with its mechanistic roles and therapeutic potential in these diseases, remains absent. In response, this review provides an in-depth summary of the essential biological features of USP25, elucidates the interplay between its upstream regulators and downstream substrates, and highlights its specific molecular mechanisms in cardiovascular and cerebrovascular disease pathogenesis. Additionally, the feasibility and strategic approaches of targeting USP25 for therapeutic purposes are analyzed, while the limitations and potential breakthroughs in the development of USP25 inhibitors are discussed. Finally, priority research directions are proposed to guide future exploration, with the ultimate aim of contributing theoretical foundations and novel perspectives for clinical management of cardiovascular and cerebrovascular diseases.