TMBIM1 is a transmembrane protein that functions as a multivesicular body regulator, controlling protein degradation through the lysosomal pathway. The protein negatively regulates toll-like receptor 4 (TLR4) by promoting its lysosomal degradation via interaction with the ESCRT complex, and it also suppresses aortic matrix metalloproteinase-9 production. Beyond its canonical degradative functions, TMBIM1 participates in autophagy regulation and modulates immune responses through transcription factor interactions. Pathologically, TMBIM1 is dysregulated across multiple disease contexts. In metabolic disease, hepatic TMBIM1 overexpression protects against non-alcoholic fatty liver disease and steatohepatitis in mice and monkeys by suppressing TLR4-driven inflammation 1. In cardiovascular disease, cardiac-specific TMBIM1 overexpression alleviates aortic banding-induced hypertrophy in mice and monkeys through TLR4-dependent mechanisms 2, while TMBIM1 upregulation reduces sepsis-induced cardiac dysfunction via Parkin-mediated mitophagy 3. Conversely, TMBIM1 is pathologically elevated in pancreatic cancer, where the TMBIM1-YBX1 axis drives immunosuppression by upregulating CCL2 and PD-L1, promoting myeloid-derived suppressor cell infiltration 4. In glioblastoma, TMBIM1 overexpression promotes epithelial-mesenchymal transition and associates with poor survival through enhanced autophagic degradation of E-cadherin 5. At the population level, common variants at 2q35 near TMBIM1 increase colorectal cancer risk and show pleiotropic effects with inflammatory bowel disease 6, with epigenetic modifications at nearby CpG sites linked to air pollution-associated colorectal cancer risk 7. Therapeutically, TMBIM1 inhibition combined with anti-PD-1 immunotherapy shows synergistic antitumor effects in pancreatic cancer models, highlighting TMBIM1 as a candidate therapeutic target.