{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T23:01:43Z","timestamp":1775084503361,"version":"3.50.1"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T00:00:00Z","timestamp":1775088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Osteoporosis (OP) is characterized by impaired bone homeostasis in which bone resorption exceeds bone formation. Disulfidptosis, a recently described disulfide stress\u2013induced cell death program linked to cytoskeletal collapse, has been suggested to contribute to OP, yet its cell-type\u2013specific relevance within the bone marrow mesenchymal stem cell (BM-MSC) osteogenic lineage\u2014and the upstream upstream transcriptional and epigenetic programs shaping this stress response\u2014remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study integrated a peripheral blood monocyte microarray dataset (GSE56815; 20 OP vs. 20 controls) with single-cell RNA sequencing to characterize disulfidptosis-related programs in OP. OP-associated disulfidptosis genes and molecular subtypes were identified using co-expression and differential analyses. Disulfidptosis score and upstream regulators across bone marrow cell populations were inferred from single-cell data using regulon analysis with motif\/cis-regulatory evidence. Chromatin remodeling\u2013related gene modules in osteoblasts were additionally scored to assess epigenetic activation\/repression programs and their association with BHLHE41.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Integrated WGCNA with gene-overlap screening pinpointed 17 OP-linked disulfidptosis signature genes, highlighted by a marked increase of SLC7A11, and unsupervised stratification separated OP into two molecular subtypes. Single-cell analyses showed that disulfidptosis score was enriched in the osteoblast-like subset of BM-MSCs, implicating osteoblasts as a major affected population. Network inference further nominated BHLHE41 as a potential upstream driver of SLC7A11 and connected its expression with a disulfidptosis-tolerant phenotype in OP-derived BM-MSCs. Chromatin remodeling pathway scoring indicated altered epigenetic state programs in OP osteoblasts, and SIRT1 was preferentially upregulated in BHLHE41-high osteoblasts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides a cell-type\u2013resolved map of disulfidptosis-related stress in osteoporosis by integrating bulk and single-cell transcriptomics. We propose a BM-MSC osteogenic-lineage\u2013associated BHLHE41\u2013SLC7A11 axis and link it to chromatin remodeling signatures in osteoblasts, offering a rationale for precision strategies targeting disulfide-stress vulnerability in OP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fgene.2026.1794298","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T22:10:25Z","timestamp":1775081425000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["BHLHE41\u2013SLC7A11 transcriptional axis and chromatin remodeling signatures in osteogenic-lineage disulfidptosis-like stress in osteoporosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Xiaoming","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenya","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Xi\u2019an Fengcheng Hospital","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yilei","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Institute of Molecular and Translational Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University Health Science Center","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinghong","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Endemic Diseases, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, National Health Commission (NHC) Key Laboratory of Environment and Endemic Diseases","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, The First Affiliated Hospital, Xi\u2019an Jiaotong University","place":["Xi\u2019an, Shaanxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song","family":"Long","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Honghe Hospital Affiliated to Kunming Medical University","place":["Honghe, Yunnan, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"20098","DOI":"10.1074\/jbc.M210427200","article-title":"mSharp-1\/DEC2, a basic helix-loop-helix protein functions as a transcriptional repressor of E box activity and Stra13 expression","volume":"278","author":"Azmi","year":"2003","journal-title":"J. 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