UBA2: the gatekeeper of the sumoylation pathway and its multifaceted roles in human diseases and therapeutic prospects.

Ubiquitin-like modifier-activating enzyme 2 (UBA2), the core catalytic subunit of the ubiquitin-activating enzyme (E1) for the small ubiquitin-like modifier (SUMO)ylation pathway, is the "gatekeeper" determining cellular SUMOylation levels. However, a systematic, cross-disease integration of its pathogenic mechanisms and translational value in human diseases is currently lacking. In this review, a disease taxonomy framework was used for the first time to systematically elucidate the multidimensional pathogenic mechanisms of UBA2 in tumors, developmental malformations, autoimmune diseases, and infectious diseases. Research indicates that functional dysregulation of UBA2 is a central node connecting diverse diseases: Driving malignant progression and therapy resistance in tumors, causing congenital malformations during development, acting as a pathogenic factor or autoantigen in autoimmunity, and being targeted by various pathogens for immune evasion. Based on its pivotal role, UBA2 has emerged as an important prognostic biomarker and therapeutic target, with related inhibitors demonstrating promise in preclinical studies. This article further elucidates the strategies and challenges in the clinical translation of precision therapies targeting UBA2, providing a theoretical foundation and translational roadmap.