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Vol 59(2025) N 6 p. 1019-1034; DOI 10.1134/S002689332570044X Full Text

Y. Liu1*, Z. Liu1, Y. Shi1

The Critical Role of m6A-Related HNRNPA1 in Osteoporosis: Modulating Macrophage Polarization via the Glycolytic Pathway

1Department of Spine Surgery, The Third Hospital of Shijiazhuang, Shijiazhuang Hebei, 050000 China

*doctorliuyanbing@163.com
Received - 2025-01-14; Revised - 2025-05-24; Accepted - 2025-06-25

Osteoporosis represents a significant public health challenge. Recent studies suggest that macrophage polarization plays a pivotal role in bone homeostasis, with potential modulation by N6-methyladenosine (m6A) modifications. However, the exact mechanisms through which m6A-related genes regulate macrophage polarization and contribute to osteoporosis remain poorly understood. This study aims to explore the involvement of m6A-related genes in osteoporosis, focusing particularly on their effects on macrophage polarization and glycolytic metabolism. Gene expression data related to osteoporosis were retrieved from the GEO database (GSE56816), and differential expression analysis was conducted using the limma package in R. Functional enrichment analysis was performed with clusterProfiler and Metascape, while Weighted Gene Co-expression Network Analysis (WGCNA) was utilized to identify gene modules associated with osteoporosis. The overlap between m6A-related genes, differentially expressed genes (DEGs), and WGCNA-derived genes was examined using Venn diagrams. The role of HNRNPA1 was further investigated both in vitro and in vivo through various techniques, including qRT-PCR, Western blotting, immunofluorescence staining, and ELISA. Differential expression analysis identified 284 key genes linked to osteoporosis. WGCNA clustered these genes into six modules, revealing distinct correlation patterns (positive, negative, or no significant correlation) with osteoporosis. Overexpression of HNRNPA1 was found to upregulate pro-inflammatory cytokines (CXCL9, CXCL10) and glycolytic genes (GLUT1, PFKFB3). In vivo, HNRNPA1 knockdown significantly improved bone metabolic markers in an osteoporosis model, alongside a reduction in the M1 macrophage marker iNOS, an increase in the M2 macrophage marker CD206, and a decrease in the glycolytic gene GLUT1 expression. These results highlight the critical role of HNRNPA1 in regulating macrophage polarization via the glycolytic pathway in the context of osteoporosis. Targeting HNRNPA1 may provide new therapeutic approaches for enhancing bone health and alleviating osteoporosis.

HNRNPA1, osteoporosis, macrophage polarization, glycolysis, bioinformatics



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