INSIG1 is an oxysterol-binding protein that serves as a critical negative regulator of cholesterol biosynthesis 1. Its primary function involves controlling the SREBP (sterol regulatory element-binding protein) signaling pathway through two key mechanisms: (1) retention of the SCAP-SREBP complex in the endoplasmic reticulum when bound to oxysterols like 25-hydroxycholesterol, preventing SREBP activation 1; and (2) mediating ubiquitin-dependent degradation of HMGCR, the rate-limiting enzyme in cholesterol synthesis 2. INSIG1 function is dynamically regulated—sterol depletion or phosphorylation by PCK1 and PKR reduces oxysterol binding, disrupting INSIG1-SCAP interaction and enabling SREBP translocation to the Golgi for activation 13. Disease relevance is substantial across multiple conditions. In hepatocellular carcinoma, PCK1-mediated phosphorylation of INSIG1 drives lipogenesis and tumorigenesis, with phosphorylation levels correlating with poor prognosis 1. In metabolic dysfunction-associated steatohepatitis (MASH), TRIM25-mediated ubiquitination and degradation of INSIG1 promotes lipid accumulation and inflammation 2. In colorectal cancer, a circular RNA-encoded protein promotes INSIG1 degradation to enhance cholesterol biosynthesis 4. Additionally, tumor-derived exosomal microRNAs suppress INSIG1 expression to facilitate breast cancer liver metastasis 5, while in diabetic kidney disease, reduced HSPA8 allows PKR-mediated INSIG1 phosphorylation, driving SREBP activation and lipid accumulation 3. Notably, common genetic variations in INSIG1 show no significant association with type 2 diabetes or obesity in European populations 6.