Lactate targeting: Regulatory networks and therapeutic potential in bone diseases.

Lactate, once regarded as a metabolic waste product, has emerged as a multifunctional regulator in skeletal pathophysiology. This review systematically elucidates the pivotal mechanisms underlying the role of lactate in bone-related pathologies, including inflammatory arthritis, osteoarthritis, osteoporosis, nonunion fractures, and primary bone tumors. Lactate functions through five integrated mechanisms: i serving as a rapid energy substrate; ii acting as an immunomodulatory mediator; iii enhancing osteoclast-mediated bone resorption through microenvironmental acidification; iv driving inflammatory cascades via G protein-coupled receptors (GPCRs); and v functioning as an epigenetic effector through histone and protein lactylation (Kla) to reprogram osteoblast and macrophage transcription. This review details the cell-specific effects of lactate on key bone-associated cells, including dynamic lactate-driven macrophage polarization, suppression or reprogramming of dendritic- and T-cell effector functions, glycolytic activation of fibroblast-like synoviocytes promoting joint inflammation, stimulation of osteoclastogenesis and bone resorption, and dose-dependent regulation of osteoblast differentiation and chondrocyte degradation. Therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2) inhibitors, glycolysis modulators, monocarboxylate transporter (MCT) inhibitors, and potential interventions targeting "writers/readers/erasers" of lactylation, are evaluated. Finally, we propose future research directions regarding the role of lactate in bone diseases. This review highlights lactate as a strategic node that coordinates the bone immune-metabolic network, offering a promising target for the precise regulation of skeletal homeostasis and inflammation.