Intermittent Fasting May Weaken Prostate Cancer's Androgen Receptor Defenses

Prostate cancer is one of the most common male malignancies globally, and its progression is fundamentally driven by androgen receptor (AR) signaling. While androgen deprivation therapy and second-generation AR inhibitors like enzalutamide offer meaningful benefit, resistance inevitably emerges — often through AR amplification, mutation, or constitutively active splice variants such as AR-V7 that bypass ligand-dependent activation. This review asks whether dietary interventions, specifically forms of intermittent fasting, can metabolically disrupt AR signaling and improve therapeutic outcomes.

The authors conducted a systematic literature search across Scopus, PubMed, and Web of Science through December 2025, focusing on preclinical and clinical studies linking IF regimens to AR signaling, lipid metabolism, mitochondrial function, redox homeostasis, and therapy resistance in prostate cancer. Fasting regimens examined included time-restricted eating (TRE), alternate-day fasting (ADF), fasting-mimicking diets (FMD), and chronic caloric restriction.

The most mechanistically compelling evidence came from ADF studies, which showed that amino acid deprivation during fasting impairs AR mRNA translation, significantly reducing AR protein levels and AR-driven transcription. Crucially, this metabolic suppression enhanced the efficacy of enzalutamide in vivo beyond what pharmacologic therapy alone achieved. FMD was shown to consistently lower circulating insulin, IGF-1, and glucose — suppressing PI3K/AKT/mTOR signaling that cross-talks with AR activity. IF also activates AMPK and sirtuin pathways, alters lipogenesis (downregulating FASN, ACACA, SCD1), and transiently elevates reactive oxygen species, creating selective metabolic vulnerabilities in rapidly proliferating tumor cells. Nutrient deprivation may additionally alter RNA splicing factors like SRSF1, potentially reducing AR-V7 expression and thereby re-sensitizing castration-resistant prostate cancer to AR-targeted agents.

AR itself functions as a metabolic sensor — directly promoting lipogenic enzyme expression, supporting mitochondrial biogenesis via PGC-1α, and maintaining redox balance through NADPH-generating pathways. IF disrupts each of these axes, suggesting a multi-pronged mechanism by which fasting could impair AR-dependent tumor survival programs.

Despite promising preclinical signals, clinical evidence directly linking IF to AR modulation in prostate cancer patients remains sparse. Indirect benefits — improved metabolic profiles, reduced systemic inflammation, lower IGF-1 — have been observed in cancer patients on FMD cycles. However, the optimal fasting regimen, caloric targets, macronutrient composition, and patient selection criteria are not yet established. Muscle mass loss is a real concern, particularly in older men or those on ADT who are already vulnerable to sarcopenia.