HADHA K406 Lactylation Regulates Metabolic Reprogramming and Suppresses Immune Responses in Gastric Cancer

ABSTRACT Gastric cancer (GC) represents a substantial global health challenge and is among the most prevalent and deadly malignancies worldwide. Emerging evidence suggests that protein lactylation plays a pivotal role in the progression of various cancers. However, the specific levels and regulatory mechanisms of protein lactylation in GC remain poorly understood. In this study, we detected elevated pan‐lactylation modification levels in GC tissues. Notably, lactylation at the K406 site of hydroxyacyl‐CoA dehydrogenase (HADHA) was significantly upregulated in GC tissues. This site‐specific lactylation modification enhanced GC progression. Disrupting lactylation at the HADHA K406 site markedly reduced its enzymatic activity, thereby mitigating GC progression by impairing fatty acid β‐oxidation and glycolysis. Furthermore, inhibiting HADHA K406 lactylation (HADHA K406la) suppressed the HMG‐CoA reductase (HMGCR)‐mediated cholesterol synthesis pathway, which, in turn, improved the immunosuppressive tumor microenvironment in GC. Finally, combining an HMGCR inhibitor with a lactate dehydrogenase A (LDHA) inhibitor effectively enhanced the immune response against GC and inhibited tumor progression. In conclusion, this study demonstrated that HADHA K406la regulates GC progression through its impact on metabolic pathways, suggesting its potential as a therapeutic target for GC treatment.