Macrophage metabolic reprogramming via HIF-1α-glycolysis drives osteoblast ferroptosis and bone loss through an IL-6-STAT3-dependent redox axis

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.