CLSTN3 (calsyntenin-3) is a transmembrane protein with distinct tissue-specific functions. In brown adipose tissue, the adipocyte-selective CLSTN3β isoform enforces multilocular lipid droplet morphology by localizing to endoplasmic reticulum-lipid droplet contact sites and inhibiting CIDEA/CIDEC-mediated lipid droplet fusion, thereby promoting efficient fatty acid oxidation and thermogenesis 1. Conversely, in white adipose tissue, CLSTN3 overexpression impairs lipolysis and promotes metabolic dysfunction; the obesity-associated rs7296261 variant increases CLSTN3 expression and disrupts adipose tissue function via interaction with APP and mitochondrial dysfunction 2. Beyond metabolism, CLSTN3 functions as a potent suppressor of TLR-mediated inflammation by inhibiting OST complex assembly and reducing N-glycosylation-dependent TLR4 membrane translocation 3. Reduced CLSTN3 expression correlates with elevated inflammatory markers in sepsis and other inflammatory diseases. CLSTN3 has emerged as a biomarker across multiple disease contexts, including associations with colorectal cancer, psoriatic arthritis, and ALS risk 4 5 6, suggesting pleiotropic roles in immunity and neurodegeneration. In neuroinflammatory contexts, CLSTN3 elevation exacerbates intracerebral hemorrhage-induced neuronal injury via miR-488 regulation 7.