Macrophage immunometabolic reprogramming in inflammatory repair failure in osteonecrosis of the femoral head.

The classical "vascular occlusion" model does not fully account for osteonecrosis of the femoral head (ONFH). Femoral head collapse may progress despite restored perfusion, and ischemia alone cannot adequately explain steroid-associated ONFH. We propose that ONFH involves disruption of bone-vascular-immune homeostasis, with macrophage immunometabolic reprogramming in response to hypoxic and lipotoxic stress acting as a potential driver of inflammatory repair failure. Among the metabolic mechanisms implicated in ONFH, the strongest disease-specific evidence supports roles for hypoxia, oxidative stress, disordered lipid metabolism, macrophage imbalance, and ferroptosis-associated injury. By contrast, macrophage-specific glycolytic reprogramming, remodeling of the tricarboxylic acid (TCA) cycle, epigenetic fixation, osteomac dysfunction, and cuproptosis remain less well established. Regulated cell death pathways, particularly ferroptosis and pyroptosis, may exacerbate local tissue injury by releasing damage-associated molecular patterns (DAMPs) and inflammatory mediators that disrupt type H vessel-osteogenesis coupling and shift repair toward fibrosis. Establishing causal relationships rather than correlative associations will require lineage-tracing experiments, spatial validation, metabolic flux analyses, and genetic loss-of-function studies in ONFH models. The translational potential of this article: Viewing ONFH as an immunometabolic disorder identifies experimentally tractable targets beyond conventional anti-inflammatory strategies, including SLC7A11/GPX4-dependent ferroptosis defense, NLRP3 inflammasome signaling, and HIF-1α-associated macrophage metabolic adaptation. Extracellular vesicle- or biomaterial-based delivery systems designed for prolonged local retention should currently be considered experimental platforms for assessing lesion-specific target engagement in early-stage ONFH. Their clinical relevance must be established through ONFH-specific studies evaluating efficacy, safety, biodistribution, manufacturability, and long-term structural outcomes.