RNF145 is an E3 ubiquitin ligase with dual roles in lipid homeostasis and immune regulation. As a cholesterol metabolism regulator, RNF145 responds to elevated sterol concentrations by ubiquitinating and promoting degradation of HMGCR, the rate-limiting cholesterol biosynthetic enzyme 1. This function requires interaction with INSIG proteins and operates through the ERAD pathway 2. RNF145 also senses membrane cholesterol directly, altering its oligomerization and activity to coordinate ubiquitin transfer with other E3 ligases 2. Genetic variation in RNF145 (rs17056583, rs12188266) significantly associates with total cholesterol and LDL-C levels in population studies 3, establishing clinical relevance for dyslipidemia and coronary heart disease risk. Beyond lipid metabolism, RNF145 functions in immune homeostasis. Single-cell transcriptomic studies identify RNF145 as a causal gene in systemic lupus erythematosus with strong colocalization evidence (PP.H4 >80%) across immune cell types 4. Similarly, RNF145 emerges as a shared genetic risk locus in systemic vasculitides, with functional annotation suggesting roles in inflammation regulation 5. In cancer biology, RNF145 is upregulated in hypoxic hepatocellular carcinoma cells and promotes tumor progression 6, while in oral squamous cell carcinoma, RNF145 activation triggers NFκB signaling and IL-8 transcription, accelerating cancer progression 7. These diverse disease associations highlight RNF145's multifaceted role in metabolic and immune regulation.