Hydrogen sulfide in bone homeostasis: Mechanisms and therapeutic potential

Hydrogen sulfide (H₂S), as an endogenous gaseous signaling molecule, plays a central and complex regulatory role in maintaining bone homeostasis. This review summarizes the current evidence that H₂S participates in skeletal remodeling through coordinated regulation of osteoblast-lineage cells, osteoclasts, macrophage-mediated immune responses, and metabolic stress adaptation. Rather than acting as a simple unidirectional bone-protective factor, H₂S exerts context-dependent effects that are shaped by local concentration, release kinetics, cellular source, disease state, and the surrounding immune-metabolic microenvironment. These properties allow H₂S to serve as a dynamic mediator linking cellular function, microenvironmental remodeling, and skeletal homeostasis. With the development of sustained-release donors, microenvironment-responsive biomaterials, enzyme-modulating approaches, and combination strategies, H₂S-targeted interventions have become a promising direction for bone repair and regeneration. This review integrates cellular mechanisms, disease-associated H₂S synthesis disorders, and translational strategies to clarify the context-dependent role of H₂S in bone homeostasis and to provide perspectives for precision skeletal repair.