Tamarixetin Improves Metabolic Dysfunction by Inhibiting the p300-Mediated Epigenetic Activation of Pyruvate Dehydrogenase Kinase 4

Excessive lipid accumulation is a hallmark of metabolic disorders which includes obesity and insulin resistance; however, effective therapeutic strategies remain limited. Tamarixetin (Tx), a naturally occurring flavonoid with diverse pharmacological properties, has not been fully characterized in the context of lipid metabolism. In this study, we explored the metabolic benefits and molecular mechanisms of Tx in a Western diet (WD)-induced obesity model. Transcriptomic profiling revealed that Tx reversed WD-induced gene expression patterns, notably suppressing Pdk4 and inducing Phlda1 expression. Mechanistically, docking analysis suggested that Tx interacts with the acetyl-CoA-binding region within the p300 histone acetyltransferase domain, thereby attenuating H3K9 acetylation at the Pdk4 promoter. This epigenetic inhibition of Pdk4 led to activation of the p38/AMPK signaling cascade, upregulation of PPARGC1A and CPT1A , and enhanced insulin sensitivity in vitro . Collectively, our findings identify Tx as a novel epigenetic modulator that simultaneously suppresses lipogenic gene expression and restores metabolic signaling. Given its natural origin and multifaceted mode of action, Tx emerges as a promising candidate for therapeutic intervention in metabolic disorders.