Cell Type-Specific Ferroptosis Regulatory Networks in the Bone Microenvironment: Implications for the Pathogenesis and Treatment of Osteoporosis.

Ferroptosis has emerged as an important regulator of skeletal homeostasis, yet its role in osteoporosis (OP) remains incompletely understood. Accumulating evidence indicates that ferroptosis is not a uniform cell death program within bone, but rather a cell type-specific fate governed by distinct iron-handling capacities, redox buffering systems, and microenvironmental cues. This heterogeneity provides a new lens through which the complex pathogenesis of OP can be reinterpreted. In this review, we integrate recent advances to delineate ferroptosis-regulatory networks across major bone-resident cell populations, including osteoblasts, osteoclasts, osteocytes, and bone marrow mesenchymal stem cells (BMSCs). We highlight how ferroptosis suppresses osteogenic function in osteoblasts, amplifies differentiation and inflammatory signaling in osteoclasts, acts as an early vulnerability node in osteocytes, and reshapes lineage commitment in BMSCs. Importantly, ferroptosis in these cells is dynamically modulated by intercellular communication and niche-derived metabolic and mechanical signals. Building on this cell type-resolved framework, we propose that OP represents a disorder of multicellular ferroptotic dysregulation within the bone microenvironment rather than a simple imbalance of formation and resorption. Finally, we discuss translational implications, emphasizing ferroptosis-informed therapeutic strategies, including redox reprogramming, iron flux modulation, extracellular vesicle-based approaches, and microenvironment-responsive biomaterials. This integrative perspective provides a conceptual foundation for precision interventions targeting skeletal fragility across aging and disease contexts.