[L-lactylation regulatory network in orthopedic degenerative diseases]

To explore the therapeutic potential of L-lactylation in degenerative disc disease, arthritis, muscle degeneration, exercise metabolism, and osteoporosis.

Literatures about L-lactylation in metabolic regulation, inflammatory response, and bone homeostasis at home and abroad in recent years were extensively reviewed. Emphasis was placed on analyzing the molecular regulatory networks of L-lactylation and its related clinical therapeutic potential in intervertebral disc degenerative diseases, arthritis, muscle degeneration and exercise metabolism, and osteoporosis.

L-lactylation reprograms metabolic flux by modifying key enzymes, and regulates chromatin dynamics through histone/non-histone modifications, thereby modulating macrophage polarization, osteoclast-osteoblast balance, and extracellular matrix remodeling. In intervertebral disc degeneration, tumor necrosis factor α activates glycolytic enzymes to promote L-lactylation, while glutamine supplementation reduces L-lactylation levels and activates the adenosine monophosphate-activated protein kinase catalytic subunit α pathway; hypoxia inducible factor 1α promotes the extracellular transport of L-lactylation by upregulating monocarboxylate transporter 4. In osteoarthritis, lactate dehydrogenase A (LDHA) overexpression leads to elevated histone L-lactylation levels, which in turn upregulates the transcriptional activity of triosephosphate isomerase 1 and accelerates cartilage degradation. In rheumatoid arthritis, artemisinin induces L-lactylation of pyruvate kinase M2 and inhibits the proliferation and migration of fibroblast-like synoviocytes. In tendinopathy, L-lactylation exerts regulatory effects in the aspects of extracellular matrix, immunity, nerves and blood vessels. In osteoporosis, L-lactylation affects osteogenic differentiation and bone resorption through regulatory axes such as Forkhead box F1, crystallin alpha B/ferritin heavy chain 1, and JunB, and interventions including LDHA regulation and scopolamine administration can promote osteogenic differentiation.

L-lactylation plays a dual regulatory role in orthopedic degenerative diseases, and its spatiotemporal dynamics and tissue specificity provide new opportunities for precise treatment. Although target specificity and clinical validation still face challenges, targeting L-lactylation modification is expected to become a new direction for disease-modifying therapy of orthopedic degenerative diseases.