GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE309nnn/GSE309211/primaryOK200GenomicsMus musculusGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE309211GEOGSEfalseAdipocyte-Specific TMEM41B Deficiency Enhances Bone Formation and Attenuates Osteoporosis via the YY1-Calreticulin AxisOsteoporosis (OP) is a prevalent skeletal disorder characterized by excessive bone marrow adiposity and impaired osteogenesis. Here, we identify TMEM41B, an endoplasmic reticulum-resident protein, as a critical regulator of bone homeostasis through its actions in bone marrow adipocytes (BMAs). Adipocyte-specific deletion of TMEM41B in mice (TMEM41B AKO) significantly increased bone mass, improved trabecular and cortical bone parameters, and enhanced mechanical strength, particularly in long bones. These effects were observed in both physiological settings and pathological models, including high-fat diet-induced osteopenia and ovariectomy-induced osteoporosis. Mechanistically, TMEM41B deficiency upregulated calreticulin (Calr) expression specifically in BMAs, which promoted osteoblast differentiation and bone formation. Mechanistically, we identified the transcription factor YY1 as a key intermediary, binding to the Calr promoter to drive its expression upon TMEM41B loss. Chromatin accessibility profiling revealed enhanced osteogenic and suppressed adipogenic gene accessibility in TMEM41B AKO mice, while proteomic and transcriptomic analyses highlighted Calr as a paracrine mediator of BMAs-osteoblast crosstalk. Our findings establish TMEM41B as a novel therapeutic target for osteoporosis, with its inhibition in BMAs rescuing bone loss through the YY1-Calr axis.2026/09/25GSE309211GSM9263224GSM9263223GSM9263222GSM926322124247309211Mus musculus