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Войти в исследования Redox report : communications in free radical research · 2026
Macrophage metabolic reprogramming via HIF-1α-glycolysis drives osteoblast ferroptosis and bone loss through an IL-6-STAT3-dependent redox axis.
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Gu Yifan, Wang Kun, Wang Yicong, Wang Ziru, Li Yiheng, Li Lei, Jiang Shuai, Zheng Yu, Feng Run, Yang Min
Аннотация
BACKGROUND: Postmenopausal osteoporosis (PMOP) is characterized by exacerbated bone resorption and inadequate bone formation, with macrophage-driven inflammation playing a key role. However, how immunometabolic reprogramming of macrophages modulates osteoblast fate remains unknown.
METHODS: Using integrated single-cell and bulk transcriptomics, we identified a hypermetabolic macrophage subpopulation in PMOP marrow reliant on HIF-1α-glycolysis. We pharmacologically disrupted this axis with the HDAC inhibitor valproic acid (VPA) and validated its function using the HIF-1α stabilizer DMOG. The paracrine effects on osteoblasts were assessed via conditioned medium, focusing on ferroptosis and differentiation. Therapeutic efficacy was tested in ovariectomized rats.
RESULTS: VPA upregulated HIF1AN, enhancing its binding to HIF-1α and promoting its degradation. This suppressed glycolytic flux and M1 polarization, reducing IL-6 secretion. The altered secretome protected osteoblasts from ferroptosis by inhibiting the IL-6/p-STAT3/HIF-1α/TFRC axis and rebalancing GPX4/ACSL4. Osteogenic differentiation was restored. In OVX rats, VPA improved bone mass and microstructure, effects abolished by DMOG.
CONCLUSION: We unveil a macrophage-centric immunometabolic checkpoint that is linked to osteoblast ferroptosis via IL-6/STAT3 signaling. Targeting this HIF-1α-glycolysis axis, exemplified by VPA, represents a novel therapeutic strategy for PMOP.
METHODS: Using integrated single-cell and bulk transcriptomics, we identified a hypermetabolic macrophage subpopulation in PMOP marrow reliant on HIF-1α-glycolysis. We pharmacologically disrupted this axis with the HDAC inhibitor valproic acid (VPA) and validated its function using the HIF-1α stabilizer DMOG. The paracrine effects on osteoblasts were assessed via conditioned medium, focusing on ferroptosis and differentiation. Therapeutic efficacy was tested in ovariectomized rats.
RESULTS: VPA upregulated HIF1AN, enhancing its binding to HIF-1α and promoting its degradation. This suppressed glycolytic flux and M1 polarization, reducing IL-6 secretion. The altered secretome protected osteoblasts from ferroptosis by inhibiting the IL-6/p-STAT3/HIF-1α/TFRC axis and rebalancing GPX4/ACSL4. Osteogenic differentiation was restored. In OVX rats, VPA improved bone mass and microstructure, effects abolished by DMOG.
CONCLUSION: We unveil a macrophage-centric immunometabolic checkpoint that is linked to osteoblast ferroptosis via IL-6/STAT3 signaling. Targeting this HIF-1α-glycolysis axis, exemplified by VPA, represents a novel therapeutic strategy for PMOP.