The Dietary Polyphenol Resveratrol in Intestinal Ischemia–Reperfusion Injury: From Multifaceted Protective Mechanisms to Clinical Translation Challenges

ABSTRACT Intestinal ischemia–reperfusion (I/R) injury constitutes a life‐threatening condition with mortality approaching 50%, yet effective therapeutic interventions remain limited. Resveratrol, a natural polyphenolic compound, has demonstrated promising multi‐targeted protective effects in preclinical models by simultaneously enhancing antioxidant defense, suppressing inflammatory cascades, inhibiting ferroptosis, stabilizing mast cells, and preserving intestinal barrier integrity through SIRT1/SIRT3‐mediated pathways. Novel delivery systems, including exosome‐based carriers and nanoformulations, have shown enhanced therapeutic efficacy in overcoming bioavailability limitations. However, a critical translational gap persists between experimental promise and clinical reality. Three interconnected obstacles impede progress: the complete absence of human clinical trials in intestinal I/R contexts, poor pharmacokinetics characterized by extensive first‐pass metabolism that raises fundamental questions about achievable therapeutic tissue concentrations, and the lack of large animal validation studies bridging rodent models and human pathophysiology. This review provides critical analysis of evidence quality, identifies specific knowledge gaps, and proposes a structured translational roadmap prioritizing clinically relevant post‐ischemic treatment paradigms, comprehensive pharmacokinetic characterization, biomarker development, and proof‐of‐concept clinical trials to advance resveratrol toward clinical benefit.