Alterations in the epigenome and cell metabolism are two hallmarks of autosomal dominant polycystic kidney disease (ADPKD). Emerging evidence suggests that metabolic rewiring and epigenetic remodeling are closely interrelated and reciprocally regulate each other to drive cyst growth. Key metabolic changes during cystogenesis include elevated aerobic glycolysis, heightened pentose phosphate pathway activity, and dysregulated methionine and glutamine metabolism, alongside impaired fatty acid β-oxidation and mitochondrial function. These perturbations profoundly affect the levels of intermediates, such as α-ketoglutarate, S-adenosyl-methionine, and acetyl coenzyme A, which can serve as substrates or cofactors for chromatin-modifying enzymes, thereby directly linking metabolic signals to gene transcription. In this review, we explore how metabolic reprogramming contributes to epigenetic modifications in cystic cells, activates a cyst-associated gene expression program, and accelerates ADPKD progression. We also highlight the potential of dietary and pharmacological interventions, and of traditional Chinese medicine (TCM)—all of which target this metabolic–epigenetic axis—as therapeutic strategies for ADPKD. Finally, we propose future directions for investigating the mechanisms and therapeutic potential of metabolic-epigenetic crosstalk in ADPKD.
X et al. (Thu,) studied this question.