Metabolic reprogramming is a central regulator of cell fate and tissue homeostasis. By systematically remodeling metabolic pathways, cells adapt to specific physiological or pathological conditions to support survival and proliferation, often through enhanced glycolysis and lactate accumulation. Emerging evidence suggests that lactate accumulation can drive histone and nonhistone lactylation, thereby reshaping gene regulation and promoting inflammatory activation, matrix catabolism, and cellular senescence, which contribute to the initiation and progression of skeletal disorders such as osteoarthritis, osteoporosis, intervertebral disc degeneration, and rheumatoid arthritis. Importantly, these mechanisms also reveal actionable therapeutic opportunities involving lactate clearance and redox balance, mitochondrial quality control, and epigenetic modulation. Biomaterial-based strategies have emerged as powerful tools for modulating metabolic reprogramming through spatiotemporal and stimuli-responsive regulation. Representative systems include metabolism-responsive nanoparticles, cell-derived systems, composite hydrogels, and scaffold-based platforms. By restoring metabolic homeostasis, such biomaterials offer promising opportunities to slow degeneration and promote tissue regeneration. Overall, biomaterials represent an emerging strategy for modulating metabolic reprogramming in skeletal disorders, although most current evidence remains preclinical, and further mechanistic and translational validation is still needed.
