STARD3NL is a late endosome-anchored tethering protein that mediates inter-organellar communication between late endosomes and the endoplasmic reticulum (ER) 1. The protein functions as part of a molecular tether complex by using a conserved FFAT (two phenylalanines in an acidic tract) motif to interact with ER-anchored VAP proteins (VAPA and VAPB), thereby creating membrane contact sites that enable metabolite exchange and affect endosome dynamics 2. Beyond its canonical role in vesicle tethering, STARD3NL has emerged as a negative regulator of bone metabolism. High STARD3NL expression is associated with low bone mass in osteoporosis patients and osteoporotic mouse models 3. Mechanistically, STARD3NL suppresses osteogenic differentiation by binding to Annexin A2, which inactivates the Wnt/β-catenin signaling pathway 3. Genome-wide association studies identified STARD3NL as a significant BMD locus 4, with evidence suggesting nearby genes like EPDR1 regulate osteoblastogenesis through chr7 contact with STARD3NL-associated variants 5. Additionally, STARD3NL has been identified as a potential sepsis therapeutic target and associates with inflammatory pathways involving IL10 and interferon regulatory factors 67.