Journal of advanced research · 2026
Hyodeoxycholic acid rejuvenates BMSCs against postmenopausal osteoporosis by attenuating senescence and aberrant adipogenesis via TGR5-ESR1-mediated mitophagy.
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Zeng Chenying, Yu Wenhui, Kang Yunze, Liu Wenjie, Chen Zibin, Xiao Zipeng, Liu Zhidong, Zhang Weihao, Li Qibo, Zeng Yipeng, Li Zhiwen, Pan Baiqi, Xie Zhongyu, Zhang Ziji
Аннотация
INTRODUCTION: Postmenopausal osteoporosis (PMOP) is driven by bone marrow stromal cell (BMSC) senescence and aberrant adipogenesis, with 17β-estradiol (E2) deficiency as a primary trigger. However, the metabolic mediators linking systemic E2 loss to BMSC dysfunction remain undefined. Bile acids are established endogenous "metabolic rejuvenators," but the functional relevance of hyodeoxycholic acid (HDCA) to BMSC dysfunction and the development of PMOP has not been elucidated.
OBJECTIVES: This study aimed to determine the role of HDCA in the metabolic regulation of BMSC homeostasis and to characterize its therapeutic potential and underlying molecular mechanisms in the context of PMOP.
METHODS: Comprehensive serum bile acid profiling was performed in PMOP patients and healthy donors. Patient-derived BMSCs were treated with HDCA to evaluate its regulatory effects on senescence and lineage determination. The underlying molecular mechanisms involving the TGR5 (G protein‑coupled bile acid receptor 1)-ESR1 (Estrogen receptor 1) axis and mitochondrial quality control were explored through molecular docking, RNA sequencing, and pharmacological/genetic interventions, including the H2O2‑induced senescence model, TGR5/ESR1 siRNA knockdown, PKA inhibition, and the ovariectomized (OVX) mouse model.
RESULTS: Serum HDCA showed the largest reduction among the differential bile acids in PMOP patients, and its levels correlated negatively with BMSC senescence and adipogenesis. Exogenous HDCA treatment dose-dependently inhibited senescence and corrected aberrant adipogenesis in patient-derived BMSCs. Mechanistically, HDCA bound the membrane receptor TGR5 with higher affinity than for the nuclear farnesoid X receptor (FXR), activating a cAMP-PKA signaling cascade that upregulates ESR1 expression and triggers PINK1/Parkin-mediated mitophagy to restore mitochondrial quality control. In OVX mice, oral HDCA administration replenished systemic HDCA levels, reversed bone architecture deterioration, and activated TGR5-ESR1 signaling in both intestinal and bone tissues.
CONCLUSION: HDCA supplementation alleviates BMSC senescence and aberrant adipogenesis through the TGR5-ESR1-mitophagy axis, providing a basis for the development of endogenous metabolite-based, non-hormonal strategies for PMOP.
OBJECTIVES: This study aimed to determine the role of HDCA in the metabolic regulation of BMSC homeostasis and to characterize its therapeutic potential and underlying molecular mechanisms in the context of PMOP.
METHODS: Comprehensive serum bile acid profiling was performed in PMOP patients and healthy donors. Patient-derived BMSCs were treated with HDCA to evaluate its regulatory effects on senescence and lineage determination. The underlying molecular mechanisms involving the TGR5 (G protein‑coupled bile acid receptor 1)-ESR1 (Estrogen receptor 1) axis and mitochondrial quality control were explored through molecular docking, RNA sequencing, and pharmacological/genetic interventions, including the H2O2‑induced senescence model, TGR5/ESR1 siRNA knockdown, PKA inhibition, and the ovariectomized (OVX) mouse model.
RESULTS: Serum HDCA showed the largest reduction among the differential bile acids in PMOP patients, and its levels correlated negatively with BMSC senescence and adipogenesis. Exogenous HDCA treatment dose-dependently inhibited senescence and corrected aberrant adipogenesis in patient-derived BMSCs. Mechanistically, HDCA bound the membrane receptor TGR5 with higher affinity than for the nuclear farnesoid X receptor (FXR), activating a cAMP-PKA signaling cascade that upregulates ESR1 expression and triggers PINK1/Parkin-mediated mitophagy to restore mitochondrial quality control. In OVX mice, oral HDCA administration replenished systemic HDCA levels, reversed bone architecture deterioration, and activated TGR5-ESR1 signaling in both intestinal and bone tissues.
CONCLUSION: HDCA supplementation alleviates BMSC senescence and aberrant adipogenesis through the TGR5-ESR1-mitophagy axis, providing a basis for the development of endogenous metabolite-based, non-hormonal strategies for PMOP.