USP50 is a deubiquitinating enzyme that removes conjugated ubiquitin from specific protein substrates to regulate multiple cellular processes. Mechanistically, USP50 cleaves lysine-63-linked polyubiquitin chains on target proteins, with well-characterized substrates including the PYCARD/ASC inflammasome adapter protein 1, the ACE2 receptor 2, and carnitine palmitoyltransferase 1a (CPT1a) 3. USP50 promotes inflammasome activation by deubiquitinating ASC, enhancing NLRP3-mediated IL-1β and IL-18 secretion 1. However, USP50 also suppresses NLRP3 inflammasome-driven pyroptosis in sepsis-induced acute lung injury through K48-linked ubiquitination-mediated NLRP3 degradation 4. Beyond inflammation, USP50 stabilizes CPT1a to drive fatty acid oxidation in LPS-treated macrophages 3 and regulates replication fork dynamics by promoting WRN-FEN1 localization while suppressing DNA2 nuclease and RECQL helicase activities 5. Clinically, USP50 upregulation associates with sepsis-induced acute respiratory distress syndrome 4, duodenogastric reflux-induced gastric tumorigenesis 6, and tendinopathy pathogenesis 7. USP50 represents a potential therapeutic target for inflammatory and infectious diseases.