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The IRE1\u2010XBP1s axis, a major unfolded protein response pathway, regulates cellular homeostasis, but its role in inflammatory osteoclastogenesis remained unexplored. Single\u2010cell RNA\u2010seq showed increased osteoclast precursor cells and activated IRE1\u2010XBP1s in LPS\u2010induced osteolysis. Inhibition of this axis reduced osteoclastogenesis and bone loss in vitro and in vivo. RNA\u2010seq indicated that blocking IRE1\u2010XBP1s suppressed Slc6a4 transcription, with gene set enrichment analysis confirming its role in 5\u2010HT transport. Dual\u2010luciferase assays and ChIP\u2010PCR demonstrated XBP1s\u2019 direct transcriptional regulation targeting the Slc6a4 promoter. The 5\u2010HT transporter inhibitor escitalopram also inhibited osteoclastogenesis, highlighting the IRE1\u2010XBP1s\u2010Slc6a4 axis's importance. Notably, untargeted metabolomics suggested 5\u2010HT inhibited intracellular 3\u2010methyladenine (3MA) metabolism, a compound previously considered unnatural. HPLC\u2010MS confirmed the presence of 3MA metabolism in inflammatory osteoclasts, and 3MA supplementation attenuated 5\u2010HT\u2010induced autophagy and osteoclast differentiation. Blocking the IRE1\u2010XBP1s\u2010Slc6a4 axis reduced pro\u2010osteoclastogenic effects in inflammatory bone disease patient\u2010derived PBMCs. This study demonstrates that IRE1\u2010XBP1s inhibition alleviates inflammatory osteoclastogenesis and osteolysis via a 5\u2010HT\u2010dependent anti\u2010autophagy mechanism, proposing this pathway as a therapeutic target for inflammatory bone loss.<\/jats:p>","DOI":"10.1002\/advs.76755","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T19:15:37Z","timestamp":1784834137000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The IRE1\u2010XBP1s Axis Drives Inflammatory Osteolysis by Regulating a 5\u2010HT Dependent Endogenous Anti\u2010Autophagy Mechanism"],"prefix":"10.1002","volume":"13","author":[{"given":"Pengchao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Orthopedics Tongji Hospital Tongji Medical College Huazhong University of Science and Technology  Wuhan China"},{"name":"Hubei Provincial Clinical Medical Research Center for Spinal Surgery  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