[ L- Lactylation Regulatory Network in Orthopedic Degenerative Diseases]

Jianlin Shen; Yiting Xu; Jialin Yang; Miao Xu; Xuan Lin; Xiaoning Lin; Yue Lai; Yunfeng Rui; Huan Liu;

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ABSTRACT

To explore the therapeutic potential of -lactylation in degenerative disc disease, arthritis, muscle degeneration, exercise metabolism, and osteoporosis. Literatures about 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 lactylation and its related clinical therapeutic potential in intervertebral disc degenerative diseases, arthritis, muscle degeneration and exercise metabolism, and osteoporosis. 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 lactylation, while glutamine supplementation reduces lactylation levels and activates the adenosine monophosphate-activated protein kinase catalytic subunit α pathway; hypoxia inducible factor 1α promotes the extracellular transport of lactylation by upregulating monocarboxylate transporter 4. In osteoarthritis, lactate dehydrogenase A (LDHA) overexpression leads to elevated histone lactylation levels, which in turn upregulates the transcriptional activity of triosephosphate isomerase 1 and accelerates cartilage degradation. In rheumatoid arthritis, artemisinin induces lactylation of pyruvate kinase M2 and inhibits the proliferation and migration of fibroblast-like synoviocytes. In tendinopathy, lactylation exerts regulatory effects in the aspects of extracellular matrix, immunity, nerves and blood vessels. In osteoporosis, 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. 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 lactylation modification is expected to become a new direction for disease-modifying therapy of orthopedic degenerative diseases.

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