{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T07:02:19Z","timestamp":1782975739673,"version":"3.54.5"},"reference-count":85,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100013076","name":"National Major Science and Technology Projects of China","doi-asserted-by":"publisher","award":["2025ZD1801401"],"award-info":[{"award-number":["2025ZD1801401"]}],"id":[{"id":"10.13039\/501100013076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Steroid-induced osteonecrosis of the femoral head (SONFH) is a crippling orthopedic disease. While glucocorticoids are a well-established etiological factor, the molecular framework driving the cascading tissue destruction remains elusive. Endoplasmic reticulum stress (ERS) has emerged as a central pathogenic hub. This review comprehensively synthesizes current evidence on how ERS orchestrates the multi-dimensional pathological network in SONFH, focusing on specific signaling paradoxes and translational barriers. Mechanistically, ERS drives irreversible osteoblast apoptosis via the PERK-CHOP axis and impairs endothelial regeneration by suppressing mTOR signaling. Notably, ERS exhibits profound microenvironmental heterogeneity: in articular chondrocytes, it aberrantly stabilizes HIF-1\u03b1 to precipitate matrix degradation\u2014a stark contrast to its canonical vasculoprotective role. Furthermore, ERS exacerbates intraosseous ischemia through a positive feedback loop with lipid metabolism. Importantly, we identify the \u201cischemic island\u201d effect (a physical sclerotic barrier) and inherent biomechanical discrepancies in quadrupedal animal models as primary bottlenecks hindering the clinical translation of potent ERS inhibitors. To bridge this translational chasm, we propose combinatorial interventions coupling ERS modulators with advanced bone-targeted delivery systems (e.g., Asp8-modified nanocarriers) to breach the ischemic barrier, offering a pivotal strategy for future precision joint-preserving therapies.<\/jats:p>","DOI":"10.3389\/fphar.2026.1856325","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T05:34:50Z","timestamp":1782970490000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Endoplasmic reticulum stress in steroid-induced osteonecrosis: translational bottlenecks and targeted therapeutic strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Tianpeng","family":"Liu","sequence":"first","affiliation":[{"name":"Longhua Hospital, Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]},{"name":"Institute of Spine, Shanghai University of Traditional Chinese 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