心血管疾患におけるユビキチン化を介したタンパク質恒常性：分子メカニズムと治療機会

Cardiovascular diseases (CVDs) remain one of the leading causes of death worldwide. Although the well-known risk factors include hypertension, hyperglycemia, dyslipidemia and obesity, the latest studies implicate involvement of pathological mechanisms at the molecular level. Various cellular processes, including oxidative stress, inflammatory response, mitochondrial dysfunction, and ferroptosis, are regarded as contributors to the initiation and progression of CVDs. Ubiquitination, a post-translational modification essential for the maintenance of protein homeostasis, influences the pathogenesis of CVD through regulating protein degradation, signal transduction and cellular functionality. The enzymes E1, E2 and several E3 ligases (e.g., TRAF6, TRIM21, TRIM35) participate in autophagy, inflammation and cardiac remodelling, while deubiquitinating enzymes (DUBs) (e.g., USP25, OTUB1) modulate cardiac function by stabilizing calcium pumps or regulating key signalling molecules. For example, ubiquitination of TRPC3 Ca²⁺ channels prevents them from functioning closely with phospholipase C; excessive accumulation of TRPC3 lowers cardiac contractility. On the other hand, new protein degradation technologies like Proteolysis-Targeting Chimera (PROTAC) are promising for precise selective down-regulation of disease-related proteins. This study will systematically summarize the molecular mechanisms of ubiquitination in CVDs and its potential therapeutics to provide theoretical support for mechanistic research and the development of new targeted drugs.