Sodium-Glucose Cotransporter 2 Inhibitors in Prostate Cancer: From Metabolic Vulnerability and Mitochondrial Targeting to Clinical Translation

This preprint by Dr. Sam Khodayari provides a narrative and translational review of sodium-glucose cotransporter 2 (SGLT2) inhibitors as potential drug-repurposing candidates in prostate cancer. The article examines evidence spanning prostate cancer metabolic reprogramming, mitochondrial bioenergetics, androgen-deprivation therapy (ADT), canagliflozin-associated mitochondrial complex I effects, experimental radiotherapy sensitization, genetic and causal-inference studies, human observational evidence, and ongoing clinical investigation of dapagliflozin. Particular attention is given to a dual host-tumor hypothesis in which SGLT2 inhibitors may have relevance both to the cardiometabolic complications associated with prostate cancer treatment and to selected tumor metabolic vulnerabilities. The review critically distinguishes mechanistic and preclinical findings from observational associations and prospective clinical evidence, emphasizing that SGLT2 inhibitors are not currently established anticancer treatments for prostate cancer. The article also discusses pharmaceutical and clinical considerations including molecule-specific effects, intratumoral drug exposure, biomarker selection, genitourinary adverse effects, and perioperative ketoacidosis risk, combination strategies with androgen-directed therapy and radiotherapy, and priorities for future randomized clinical investigation. Author: Dr. Sam KhodayariORCID: 0009-0003-6134-574XDocument type: Preprint / Narrative ReviewVersion: 1.0Reserved DOI: 10.5281/zenodo.21492945