BHLHE41–SLC7A11 transcriptional axis and chromatin remodeling signatures in osteogenic-lineage disulfidptosis-like stress in osteoporosis

Background: Osteoporosis (OP) is characterized by impaired bone homeostasis in which bone resorption exceeds bone formation. Disulfidptosis, a recently described disulfide stress-induced cell death program linked to cytoskeletal collapse, has been suggested to contribute to OP, yet its cell-type-specific relevance within the bone marrow mesenchymal stem cell (BM-MSC) osteogenic lineage-and the upstream upstream transcriptional and epigenetic programs shaping this stress response-remain unclear. Methods: 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-related gene modules in osteoblasts were additionally scored to assess epigenetic activation/repression programs and their association with BHLHE41. Results: 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. Conclusion: This study provides a cell-type-resolved map of disulfidptosis-related stress in osteoporosis by integrating bulk and single-cell transcriptomics. We propose a BM-MSC osteogenic-lineage-associated BHLHE41-SLC7A11 axis and link it to chromatin remodeling signatures in osteoblasts, offering a rationale for precision strategies targeting disulfide-stress vulnerability in OP.