Regulatory mechanisms of E3 ubiquitin ligases in cholesterol homeostasis

Dysregulated cholesterol homeostasis fundamentally drives atherosclerotic cardiovascular disease (ASCVD) and related metabolic disorders. Some E3 ubiquitin ligases have emerged as central post-translational nodes that orchestrate cholesterol balance via a sophisticated dual-mode mechanism. Chronologically, they execute rapid, direct ubiquitination and degradation of rate-limiting enzymes (e.g., HMGCR, SQLE), LDL receptors, and cholesterol efflux transporters for acute lipid adaptation, while simultaneously orchestrating slower, transcriptional reprogramming by targeting upstream sensors (e.g., Insigs and LXRs) to reset long-term homeostatic setpoints. This review systematically dissects how distinct classes of E3 ligases-including RING-, HECT-, and RBR-type-coordinately govern cholesterol synthesis, uptake, efflux, and esterification. Furthermore, we discuss the therapeutic prospects of targeting these ligase networks in combating dyslipidemia and its cardiovascular sequelae.