Rhaponticin Blocks Glycolysis‐Mediated Histone Lactylation to Suppress Tongue Squamous Cell Carcinoma via <scp>HIF</scp> ‐1α Activity Inhibition

ABSTRACT Tongue squamous cell carcinoma (TSCC) often develops therapeutic resistance. Metabolic reprogramming, particularly the glycolysis/lactate/histone lactylation axis, is a critical driver of tumor progression and therapy resistance. This study investigated the anti‐tumor mechanism of Rhaponticin (Rha), focusing on the metabolic/epigenetic axis involving hypoxia‐inducible factor 1α (HIF‐1α), glycolysis, and histone H3K18 lactylation (H3K18la). SCC9 and SCC9‐CisR cells were treated with Rha alone or in combination with 2‐deoxy‐D‐glucose (2‐DG) or sodium lactate (LacNa). The effects of Rha on glycolysis and H3K18la were evaluated by extracellular acidification rate assays, glucose/lactate quantification, and western blotting. Gain‐ and loss‐of‐function studies targeting HIF‐1α were conducted to determine the mechanistic dependency of Rha‐mediated effects. Subcutaneous and liver metastasis xenograft models were established for in vivo validation. Rha significantly suppressed glycolysis, glucose consumption, and lactate production, concomitant with the downregulation of HK2, LDHA, GLUT1, and H3K18la levels. Rha not only mimicked the effects of 2‐DG by inhibiting clonogenicity, migration, and invasion and decreasing cisplatin resistance in SCC9 or SCC9‐CisR cells but also reversed LacNa‐mediated promotion of these parameters, indicating that Rha acts through the glycolysis/lactate pathway. Rha inhibited tumor growth and liver metastasis, enhanced cisplatin sensitivity, and decreased H3K18la levels in mouse models. Mechanistically, Rha inhibited HIF‐1α, thereby attenuating glycolytic flux and decreasing lactate‐driven H3K18la. Rha inhibits TSCC progression and enhances cisplatin sensitivity by targeting HIF‐1α and repressing the glycolysis/lactate/H3K18la axis, suggesting that Rha is a promising candidate for disrupting metabolic/epigenetic crosstalk in TSCC.