Glycolysis‐Derived Lactate Induces ACSL4 Expression and Lactylation to Activate Ferroptosis during Intervertebral Disc Degeneration

The abnormal activation of the inflammatory microenvironment is frequently accompanied by metabolic changes that affect the development of various diseases. However, the relationship between metabolic reprogramming and intervertebral disc degeneration (IVDD) remains unclear. This study aims to reveal the metabolic changes in nucleus pulposus (NPCs) during IVDD and investigate the mechanism of glycolysis-derived lactate on NPCs. Single-cell RNA sequencing reveals that during IVDD, NPCs are characterized by excessively elevated glycolysis, and the resultant lactate causes the dysfunction of NPCs via ferroptosis activation. Mechanistically, lactate results in the transcription of Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) via promoting Histon H3K18 lactylation. Interestingly, lactate can also increase the lactylation of ACSL4 at K412 site. In addition, lactate-induced decreased expression of Sirtuin-3 (SIRT3), and further cause the elevation of ACSL4 lactylation. Finally, animal experiments demonstrate that inhibiting glycolysis through gene silencing with adenoviral-associated viruses 9 (AAV9)-si-Ldha or chemical treatment using 2-deoxy-D-glucose can suppress lactate production and lactylation, thereby ameliorating ferroptosis and NPC dysfunction. The findings of this study indicate that lactate plays a crucial role in IVDD by activating ferroptosis and that interventions aimed at lactate production can offer a potential therapeutical option for patients with IVDD.