INSIG2 is an oxysterol-binding protein that functions as a master negative regulator of cholesterol synthesis through dual mechanisms 1. Structurally, INSIG2 binds oxysterols (including 25-hydroxycholesterol) in the endoplasmic reticulum (ER) membrane and uses this binding to retain the SCAP-SREBP complex at the ER, preventing SREBP transcription factors from translocating to the Golgi for activation 2. Under sterol deprivation or upon phosphorylation by PCK1, INSIG2-oxysterol binding weakens, allowing SCAP-SREBP release and lipogenic gene activation 1. Additionally, INSIG2 mediates degradation of HMG-CoA reductase (HMGCR) via ER-associated degradation, further suppressing cholesterol synthesis 3. Disease relevance is substantial: CD36 overexpression in hepatocytes disrupts CD36-INSIG2 interaction, promoting SREBP1 processing and hepatic steatosis in NAFLD 4. Tumor-derived exosomal miR-9-5p downregulates INSIG2 in liver, enhancing cholesterol synthesis and promoting metastatic progression 5. In diabetic kidney disease, HSPA8 dysfunction leads to excessive INSIG2 phosphorylation and SREBP activation, promoting lipid accumulation 6. Clinically, INSIG2 polymorphisms associate with elevated triglycerides and blood pressure in obese patients 7, and minor intron splicing defects causing INSIG1/2 truncation drive metabolic dysfunction-associated steatotic liver disease progression 8.