{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:08:23Z","timestamp":1792458503349,"version":"4.5.0"},"reference-count":61,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82472517"],"award-info":[{"award-number":["82472517"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82472517"],"award-info":[{"award-number":["82472517"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Key Projects in Technological Innovation and Application Development of Chongqing Municipality","award":["CSTB2024NSCQ-KJFZMSX0052"],"award-info":[{"award-number":["CSTB2024NSCQ-KJFZMSX0052"]}]},{"DOI":"10.13039\/501100012397","name":"Army Medical University","doi-asserted-by":"crossref","award":["2023XJS34"],"award-info":[{"award-number":["2023XJS34"]}],"id":[{"id":"10.13039\/501100012397","id-type":"DOI","asserted-by":"crossref"}]},{"award":["2023XJS34"],"award-info":[{"award-number":["2023XJS34"]}],"id":[{"id":"https:\/\/ror.org\/05w21nn13","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Atrophic fracture nonunion is a clinically challenging form of failed bone repair, particularly under inflammatory conditions, but the cell-intrinsic programs that impair the function of skeletal stem\/progenitor cells (SSPCs) remain incompletely defined. Here, we integrated public and in-house single-cell RNA sequencing datasets from mouse periosteum, normal fracture healing, and inflammation-associated fracture nonunion models to characterize stromal cell fate changes. Trajectory inference, transcription factor network analysis, and intercellular communication modeling were combined with in vitro and in vivo validation experiments. SSPCs in the nonunion microenvironment were arrested in an undifferentiated state and acquired a pro-inflammatory and pro-ferroptotic phenotype, with enrichment of ferroptosis-related genes including Acsl4. Computational analyses nominated IL-1\u03b2 as a candidate upstream inflammatory signal, with neutrophils representing a potential source, and linked this signal to NF-\u03baB activation and increased Epas1 activity in SSPCs. In primary SSPCs, IL-1\u03b2 induced lipid peroxidation, intracellular ferrous iron accumulation, ferroptosis-related protein expression, and impaired osteochondrogenic differentiation. Ferroptosis inhibitor treatment further attenuated IL-1\u03b2-induced ferroptosis-related protein changes, supporting pathway specificity. Pharmacological inhibition of EPAS1 with PT2385 attenuated IL-1\u03b2-induced ferroptotic stress and restored SSPC differentiation in vitro, while also improving IL-1\u03b2-impaired fracture repair in vivo. Mendelian randomization analysis provided additional genetic evidence supporting potential links among IL-1\u03b2, EPAS1, and human nonunion risk. Together, these findings suggest that an IL-1\u03b2\/EPAS1-associated ferroptotic program contributes to SSPC dysfunction during inflammation-associated fracture nonunion and may represent a potential targetable mechanism for improving impaired bone repair.<\/jats:p>","DOI":"10.3390\/cimb48060606","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T09:25:17Z","timestamp":1781083517000},"page":"606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["IL-1\u03b2\/EPAS1-Associated Ferroptotic Stress Impairs Skeletal Stem\/Progenitor Cell Function in Inflammation-Associated Fracture Nonunion"],"prefix":"10.3390","volume":"48","author":[{"given":"Ruoyu","family":"Wang","sequence":"first","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhai","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Musculoskeletal Regeneration and Translational Medicine, Orthopedic Research Laboratory of Chongqing Medical University, Department of Orthopedic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Song","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Xia","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bowen","family":"Jiang","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghang","family":"Chen","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghan","family":"Liu","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"},{"name":"Department of Orthopedics, The Second Affiliated Hospital (Xinqiao Hospital), Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changqing","family":"Li","sequence":"additional","affiliation":[{"name":"Chongqing Municipal Health Commission Key Laboratory of Precise Orthopedics, Army Medical University (Third Military Medical University), Chongqing 400038, China"},{"name":"Department of Orthopedics, The Second Affiliated Hospital (Xinqiao Hospital), Army Medical University (Third Military Medical University), Chongqing 400038, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1080\/17453674.2017.1321351","article-title":"The Risk of Non-Union per Fracture: Current Myths and Revised Figures from a Population of over 4 Million Adults","volume":"88","author":"Mills","year":"2017","journal-title":"Acta Orthop."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e162775","DOI":"10.1001\/jamasurg.2016.2775","article-title":"Epidemiology of Fracture Nonunion in 18 Human Bones","volume":"151","author":"Zura","year":"2016","journal-title":"JAMA Surg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1007\/s00264-017-3734-5","article-title":"Diaphyseal Long Bone Nonunions-Types, Aetiology, Economics, and Treatment Recommendations","volume":"42","author":"Rupp","year":"2018","journal-title":"Int. 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