Intermittent Fasting and Androgen Receptor Signaling in Prostate Cancer: Metabolic Crosstalk and Therapeutic Implications.

Abstract

Prostate cancer (PCa) progression is critically driven by androgen receptor (AR) signaling, which integrates hormonal cues with metabolic programs supporting tumor growth, survival, and therapy resistance. Emerging evidence suggests that intermittent fasting (IF) and related dietary interventions-such as time-restricted eating (TRE), alternate-day fasting (ADF), and fasting-mimicking diet (FMD)-modulate systemic metabolism, including reductions in insulin and insulin-like growth factor 1 (IGF-1), and induce intracellular nutrient stress that can influence AR activity, splice variant expression (e.g., AR-V7), and downstream metabolic pathways. This systematic literature review (Scopus, PubMed, Web of Science; publications up to December 2025; search terms: "prostate cancer," "androgen receptor," "AR splice variants," "intermittent fasting," "fasting mimicking diet", "metabolism," "therapy resistance") summarizes preclinical and clinical studies addressing the impact of IF on AR signaling, lipogenesis, mitochondrial function, redox homeostasis, and therapy response. Preclinical studies indicate that IF can reduce AR expression, impair nuclear translocation, modulate AR splice variants such as AR-V7 via nutrient-sensitive splicing mechanisms, and enhance sensitivity to androgen deprivation therapy and AR-targeted agents. Mechanistically, IF-induced metabolic stress engages AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and sirtuin pathways, alters lipid and mitochondrial metabolism, and transiently increases reactive oxygen species (ROS), creating vulnerabilities in prostate tumor cells. Translational evidence suggests potential benefits of integrating IF with standard therapy, but effects may depend on fasting regimen, caloric intake, macronutrient composition, and patient metabolic context, including risk of lean mass loss. This review highlights the metabolic crosstalk between IF and AR signaling and emphasizes the need for future clinical studies incorporating biomarker-guided approaches and body composition monitoring to fully exploit this intersection for improved therapeutic outcomes in prostate cancer.