Placebo-Controlled Trial of Urolithin A Supplementation in Men With Prostate Cancer Undergoing Radical Prostatectomy, URO-PRO Trial

This trial is testing whether a natural compound called urolithin A (Uro-A), derived from the breakdown of pomegranate and berry polyphenols by gut bacteria, can reduce oxidative stress in prostate tumor tissue before surgery. Men with biopsy-confirmed prostate cancer who are already scheduled for surgical removal of the prostate (radical prostatectomy) are being recruited and randomly assigned to take either Uro-A capsules or a placebo for 3–6 weeks before their operation. The key scientific hook is that Uro-A is the best-characterized natural inducer of mitophagy — the cellular housekeeping process that removes damaged mitochondria — and dysfunctional mitochondria are a major source of the reactive oxygen species that drive cancer progression. By measuring oxidative DNA damage (using the biomarker 8-OHdG) directly in the surgically removed tumor tissue, the trial gets a rare window into what the drug is actually doing inside the tumor rather than relying on blood surrogates. With 90 participants split evenly between active treatment and placebo, this Phase II trial is sized to detect a biologically meaningful signal rather than prove clinical efficacy. If Uro-A successfully lowers 8-OHdG in tumor tissue, it would provide the first human proof-of-concept that orally dosed mitophagy induction can reduce the oxidative microenvironment of a solid tumor. The results could justify larger trials exploring whether mitochondrial quality control is a druggable axis in prostate cancer management.

• Trial is currently recruiting (status as of 2026-05-13); no efficacy results are yet available — all findings below reflect pre-specified design parameters.
• Primary endpoint: change in 8-hydroxydeoxyguanosine (8-OHdG) — a validated marker of oxidative DNA damage — measured directly in radical prostatectomy tissue from Uro-A vs. placebo arms.
• Intervention dose: the study reports 1,000 mg Uro-A daily, administered as two 250 mg capsules taken orally twice daily (BID), for 3 to 6 weeks prior to surgery in 90 randomized men (1:1 allocation).

URO-PRO is a Phase II, randomized, double-arm, placebo-controlled trial enrolling 90 men with biopsy-confirmed prostate cancer scheduled for radical prostatectomy. Participants are randomized 1:1 to receive 1,000 mg/day Uro-A (two 250 mg capsules PO BID) or matched placebo capsules for 3–6 weeks immediately preceding surgery. The primary outcome is tissue-level oxidative stress assessed by 8-OHdG immunohistochemistry or quantitative assay in the resected prostate specimen, providing a direct pharmacodynamic readout in the target organ. The trial is sponsored by the National Cancer Institute (NCI) and registered under NCT06022822.

Because this is a pre-surgical window-of-opportunity design, the treatment window is short (3–6 weeks) and the trial cannot address longer-term oncological outcomes such as biochemical recurrence, metastasis, or survival. The primary endpoint (8-OHdG reduction) is a mechanistic surrogate; whether lowering oxidative stress in this window translates into any clinical benefit remains unproven and would require a separate, larger trial with survival or recurrence endpoints. Urolithin A bioavailability is highly variable depending on individual gut microbiome composition, and the trial does not appear to pre-stratify by urolithin-producer phenotype, which could dilute the treatment effect in non-producers. Future experiments should include microbiome profiling and plasma Uro-A pharmacokinetics to distinguish pharmacological non-responders from true biological non-responders.

This trial sits at the translational frontier of the mitophagy-cancer axis represented across the corpus, extending the mechanistic work on PINK1/Parkin-mediated mitochondrial quality control (paralleled conceptually in [§42], which examines PINK1-driven mitophagy in a disease context) into a first-in-class human interventional setting. The choice of 8-OHdG as the primary endpoint directly links to the oxidative stress consequences of impaired mitophagy catalogued in animal and cell models throughout the database, including work on mitochondrial dysfunction and reactive oxygen species in aging and disease contexts explored in [§116] and [§134]. The corpus is otherwise dominated by preliminary rodent or cell-line studies of mitophagy modulators ([§136], [§124], [§125]), making URO-PRO a methodologically distinct contribution — a controlled human tissue biopsy design — that none of the existing preliminary-tier articles can currently match. If the trial demonstrates that oral mitophagy induction reduces tumor oxidative stress, it would provide clinical validation that partly corroborates the anti-inflammatory and cytoprotective mitophagy signals observed across these preclinical models, while also highlighting the translational gap between animal dosing paradigms and the 1,000 mg/day human dose reported here.

• Hirudin Promotes Peripheral Nerve Repair by Enhancing Mitophagy to Suppress NLRP3 Inflammasome Activation
  Both studies use mitophagy induction as the therapeutic mechanism to suppress downstream oxidative/inflammatory damage, but in opposite disease contexts (prostate cancer vs. peripheral nerve injury), making this a useful cross-indication comparison of whether PINK1/Parkin-linked mitophagy activation produces consistent tissue-protective signals.
• Exercise hormone irisin alleviates rheumatoid arthritis by removing dysfunctional mitochondria
  Irisin and urolithin A share the functional endpoint of clearing dysfunctional mitochondria to reduce oxidative pathology; comparing these two studies highlights how different upstream triggers (exercise hormone vs. dietary polyphenol metabolite) converge on mitophagy as a common effector mechanism.
• Impact of aldehyde dehydrogenase 2 deficiency on tissue-specific mitochondrial metabolism in aging mice
  This aging-mouse study of tissue-specific mitochondrial metabolism provides a relevant mechanistic baseline: understanding how mitochondrial dysfunction evolves in tissue offers context for interpreting why reducing oxidative stress via mitophagy (as URO-PRO tests) might matter in a tumor microenvironment.
• Mitigating Mitochondrial RNA Release During Aging to Control Inflammation and Senescence
  This article on mitigating mitochondrial RNA release during aging to control inflammation and senescence is mechanistically adjacent — both studies concern the downstream consequences of failing mitochondrial quality control — and together they illustrate complementary strategies (clearance via mitophagy vs. suppressing inflammatory signaling from damaged mitochondria) that could ultimately be com
• Cardiomyocyte BMAL1 deficiency worsens obesity-related cardiomyopathy with heightened PINK1/Parkin-linked mitophagy and mitochondrial dysfunction
  The BMAL1-deficiency cardiomyopathy model reports heightened PINK1/Parkin-linked mitophagy as a stress response, raising the question of whether constitutively elevated mitophagy is protective or maladaptive in cancer tissue — a direct conceptual counterpoint to the URO-PRO hypothesis that pharmacologically boosting mitophagy will be beneficial.