Single-cell transcriptomic atlas of Kidney-Yang and Kidney-Yin deficiency syndromes reveals distinct osteoimmune-stromal programs underlying osteopenia and osteoporosis

Abstract

Osteopenia and osteoporosis are escalating health burdens lacking precise therapeutic strategies owing to pronounced disease heterogeneity. Kidney-Yang deficiency (KYangD, “cold syndrome”) and Kidney-Yin deficiency (KYinD, “heat syndrome”) represent two major traditional Chinese medicine (TCM)-defined syndromes underlying these conditions, but their molecular basis remains obscure. Here, we performed single-cell RNA sequencing on bone tissue from osteopenia/osteoporosis patients stratified by KYangD, KYinD, or non-deficiency group, generating the first transcriptomic atlas of syndrome-specific osteoimmune and stromal programs. KYangD exhibited an energy- and perfusion-limited, low-grade inflammation in type H-like capillary endothelial cells (CD31^highEMCN^high), marked by incomplete angiogenic activation, reduced phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT)/hypoxia-inducible factor 1 (HIF-1)/nitric oxide (NO) signaling despite compensatory Notch signaling pathway (NOTCH), and weakened extracellular matrix/adhesion that restrict osteoblast maturation. KYinD was dominated by inflammation and endoplasmic reticulum (ER) stress with nuclear factor kappa B (NF-κB)/tumor necrosis factor (TNF)/interleukin (IL)-17 activation, protease-rich matrix remodeling, and secreted phosphoprotein 1 (SPP1)-mediated adhesion, alongside broad attenuation of NOTCH, vascular endothelial growth factor (VEGF), angiopoietin 1 (ANGPT1), and C-X-C motif chemokine ligand 12 (CXCL12) scaffolds and loss of bone morphogenetic protein (BMP), transforming growth factor beta (TGF-β), and Wnt osteogenic pathways. These alterations spanned endothelial, stromal, osteolineage, and immune compartments with network-level rewiring of intercellular communication. Collectively, our findings establish the first single-cell molecular bridge between TCM-defined syndromes and osteoporotic pathology, providing a framework for syndrome-specific precision interventions, namely, restoring energy metabolism and vascular-osteogenic coupling in KYangD, and suppressing hyper-inflammation while rebuilding endothelial scaffolds in KYinD.

Keywords

osteopenia and osteoporosis / Kidney-Yang deficiency / Kidney-Yin deficiency / single-cell RNA sequencing / bone microenvironment

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Higher Education Press 2026

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