Mechanism study on lactic acid promoting intervertebral disc degeneration by regulating senescence and DNA damage of cartilage endplate stem cells

Abstract Intervertebral disc degeneration, a leading cause of low back pain with incompletely elucidated molecular mechanisms, was studied via integrated in vivo/vitro approaches. This study first reveals that lactic acid accelerates intervertebral disc degeneration by inducing cartilage endplate stem cells senescence and DNA damage, thereby activating the P16/P21/P53-centered senescence pathway. In a rat tail vertebra puncture-induced intervertebral disc degeneration model, degenerated discs exhibited increased lactic acid levels, narrowed intervertebral spaces, and disrupted nucleus pulposus structure ( P <0.05). In vitro, 0/2/6/10 mM lactic acid dose-dependently suppressed cartilage endplate stem cells viability (10 mM group: 15.7% of the control), elevated intracellular reactive oxygen species (ROS, 2.8-fold relative to the control), induced G0 cell cycle arrest (10 mM group: 85.63%), reduced EdU-positive cells (8.62%), and increased β-galactosidase-positive cells (10 mM group: 33.06%) and γ-H2AX foci (all P <0.01).Molecularly, lactic acid significantly upregulated P16 (2.1-fold), P21 (3.1-fold), P53 (2.4-fold), and γ-H2AX (1.8-fold). In vivo intervertebral disc injection confirmed a positive correlation between lactic acid concentration and intervertebral disc degeneration severity. This study clarifies lactic acid’s role in intervertebral disc degeneration via the “oxidative stress–cell cycle arrest–cellular senescence” axis, advancing understanding of intervertebral disc degeneration pathogenesis and providing a basis for targeted therapies against lactic acid metabolism.