TMEM147 is a transmembrane protein with dual roles in membrane protein insertion and disease pathogenesis. As a component of the multi-pass translocon (MPT) complex, TMEM147 mediates insertion of multi-pass membrane proteins into the ER lipid bilayer by occluding the SEC61 complex lateral gate after initial transmembrane segment insertion 1. Beyond this structural function, TMEM147 regulates cholesterol homeostasis by physically interacting with key sterol reductases DHCR7 and lamin B receptor (LBR), controlling their localization and protein levels 2. TMEM147 demonstrates significant disease relevance across multiple cancer types. In hepatocellular carcinoma, TMEM147 promotes tumorigenesis by upregulating DHCR7 via STAT2, increasing extracellular 27-hydroxycholesterol (27HC) which suppresses ferroptosis and activates M2 macrophage polarization 3. High TMEM147 expression correlates with poor HCC prognosis and immune infiltration patterns 4. In tongue squamous cell carcinoma, calcium-mediated TMEM147 upregulation enhances radiotherapy sensitivity through autophagy and apoptosis 5. TMEM147 also participates in Warburg effect promotion in prostate and gastric cancers, and maintains cisplatin resistance in ovarian cancer through a feedback loop involving AURKA, DDX5, and let-7 microRNAs 6, 7, 8. Clinically, TMEM147 represents a potential therapeutic target and prognostic biomarker, particularly in hepatocellular carcinoma and chemotherapy-resistant cancers. The protein's role in both fundamental membrane biology and metabolic pathways supporting tumorigenesis makes it relevant to neurodevelopmental disorders and diverse malignancies.