Mechanisms and therapeutic implications of metabolic heterogeneity and histone lactylation in clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is characterized by metabolic reprogramming and epigenetic dysregulation, primarily attributable to the loss of the Von Hippel-Lindau(VHL) gene and the resulting stabilization of HIF.Its metabolism is predominantly driven by the Warburg effect. However, metabolic patterns vary both across different tumors and within individual tumors.Histone lactylation is a recently discovered epigenetic mark linking glycolysis-derived lactate to gene expression.Lactate accumulation drives histone lactylation, thereby regulating the expression of genes involved in tumor progression and other malignant phenotypes.The interplay between metabolic diversity and histone modifications shapes distinct tumor phenotypes and their microenvironments.Finally, emerging therapies-including HIF-2α inhibitors, metabolic enzyme inhibitors, and epigenetic regulators-are introduced along with their potential use in combination with immunotherapy.