《生命科学》 2026, 38(9): 1634-1645
泛素化修饰在动脉粥样硬化发生发展中的作用
摘 要：
动脉粥样硬化（AS）是心血管疾病的核心病理基础，其高发病率与高死亡率已构成全球重大公共卫生负担，深入挖掘其病理调控机制并探寻新型治疗靶点具有重要的理论与临床意义。泛素化修饰作为关键的翻译后修饰，通过泛素蛋白酶体系统精准调控蛋白质的稳定性、定位及功能活性，广泛参与AS的发生发展进程。本文系统综述了泛素化修饰在AS病理进程中的调控机制，重点阐述其通过调控清道夫受体、低密度脂蛋白受体、胆固醇外流蛋白等关键分子参与脂质代谢紊乱与泡沫细胞形成，以及通过靶向NF-κB信号通路、调控NLRP3炎症小体激活介导血管炎症反应的核心机制，同时探讨泛素化相关分子作为AS诊断生物标志物的潜力及临床挑战。现有研究提示，部分泛素化分子可能具有潜在的临床应用价值，可能成为未来重要的候选生物标志物。目前，相关证据仍主要来源于细胞和动物实验，其临床有效性与安全性仍需通过大样本、多中心研究进一步验证。未来需强化机制研究和临床研究的连接，推进检测技术标准化，以促进研究成果向临床转化，提升AS的精准诊疗水平。
通讯作者：张英梅 , Email:zhang.yingmei@zs-hospital.sh.cn
Abstract:
Atherosclerosis (AS) constitutes the primary pathological substrate of cardiovascular diseases (CVDs). Given its high global morbidity and mortality, AS imposes a substantial burden on public health systems and socioeconomic development. Although current therapeutic strategies, such as lipid-lowering statins and antiplatelet agents, can partially mitigate the risk of adverse cardiovascular events, approximately 20%-30% of patients still exhibit residual risk, and existing interventions fail to reverse established atherosclerotic plaques, which remain a major trigger of acute CVD events. Thus, deciphering the intricate
pathological regulatory mechanisms underlying AS progression and identifying novel, effective therapeutic targets and early diagnostic biomarkers are of profound theoretical significance and urgent clinical imperative. Ubiquitination, a pivotal and highly conserved post-translational modification in eukaryotes, precisely modulates the stability, subcellular localization, and functional activity of target proteins via the ubiquitin-proteasome system (UPS). Accumulating evidence has corroborated that ubiquitination serves as a key regulatory node across all stages of AS, offering a promising frontier for clinical intervention. This review aims to systematically synthesize and update the regulatory roles and molecular mechanisms of ubiquitination in AS pathogenesis, focusing on its involvement in core pathological processes and potential clinical translational value. Specifically, we elaborate on how ubiquitination orchestrates lipid metabolic disorders and foam cell formation. We highlight how key receptors and transporters are targeted by specific E3 ubiquitin ligases and deubiquitinating enzymes (DUBs), including the degradation of LOX-1 by TRIM31, the stabilization of CD36 by USP14/UCHL1, and the negative feedback of LDLR by IDOL or RNF130. Conversely, we discuss protective pathways such as LTN1-mediated K63-linked ubiquitination of ABCA1 and USP18-mediated deubiquitination of ABCG1, both of which preserve cholesterol efflux. Additionally, we dissect the regulatory role of ubiquitination in vascular inflammation, analyzing how the Rnd3/TRAF6 and MVP/TRAF6 axes constrain the NF-κB pathway, and how NLRP3 inflammasome activation is directly controlled by TRIM31-mediated degradation or triggered by BRCC3-mediated deubiquitination. Based on current evidence, we propose that while ubiquitination-related molecules (e.g., RNF128, Peli1, TRIM25) hold considerable promise as diagnostic biomarkers and therapeutic targets, several critical bottlenecks must be addressed. Currently, evidence is predominantly confined to preclinical models, and clinical translation faces challenges such as low cell-type specificity and a lack of high-throughput, standardized detection methods. To bridge this gap, future research should prioritize multi-center prospective validation and leverage multi-omics integration. Crucially, innovative pharmacological strategies should be explored, such as drug repurposing (e.g., Remdesivir targeting TRAF6 K63-ubiquitination) and the development of substrate-domain competitive peptides (e.g., FBXW2-P3). Advancing these technological and translational frameworks will be essential to elevate personalized medicine and precision workflows for AS, ultimately mitigating the global burden of CVDs.
Communication Author：ZHANG Ying-Mei , Email:zhang.yingmei@zs-hospital.sh.cn
SciCloud投稿系统