Lactate Metabolism in the Intervertebral Disc: Mechanistic Insights and Pathological Implications

Intervertebral disc (IVD), the largest avascular structure in the human body, contains nucleus pulposus (NP) cells that generate an abundant quantity of lactate from anaerobic glycolysis as an adaptation to hypoxia. Historically, IVD lactate was viewed as a metabolic toxic byproduct necessitating clearance to maintain IVD health. This is because accumulation of lactic acid, the protonated form of lactate, acidifies the IVD microenvironment, impairs cell viability, disrupts extracellular matrix integrity, and promotes degeneration. However, recent studies discovered that lactate serves as an important IVD biofuel in a process known as lactate-dependent metabolic symbiosis in which lactate produced by NP is shuttled into cells of the neighboring annulus fibrosus (AF), and cartilage endplate (CEP) to be metabolized via the tricarboxylic acid cycle and oxidative phosphorylation to generate ATP and amino acids to maintain IVD matrix homeostasis. Additionally, lactate is found to function as a signaling molecule and epigenetic regulator in IVD: it regulates transcription via histone lactylation that modulates ferroptosis and other cell fate decisions. Lactate also modulates senescence, apoptosis, and inflammatory responses through pathways such as Phosphatidylinositol 3-kinase/Protein kinase B (PI3K/Akt) in IVD and other organs. This review synthesizes current knowledge on lactate production, transport, and clearance in the IVD along with the emerging roles of lactate in IVD health and pathophysiology. The review also provides research perspectives and directions aimed at advancing our understanding of lactate biology and evaluating its potential as a therapeutic target for treating intervertebral disc degeneration.