Resveratrol Ameliorates Diabetic Peripheral Neuropathy via the AMPK/mTOR/Bcl‐2 Axis: Integrative Evidence From Network Pharmacology, Mendelian Randomization, and Binding‐Site Evolutionary Constraint

Background Diabetic peripheral neuropathy (DPN) is a common diabetic complication with unclear pathogenesis. Current therapies are limited, and resveratrol shows potential in DPN but its therapeutic mechanisms remain unclear. Methods Candidate targets and pathways were identified via network pharmacology and protein–protein interaction analysis. Two‐sample MR was performed using eQTL and GWAS data to assess causal associations of PRKAA1, PRKAA2, MTOR, and BCL2 with DPN. Molecular docking was used to characterize ligand‐target interactions, followed by mutational constraint analysis based on gnomAD to evaluate evolutionary conservation of binding‐site residues. Functional validation was conducted in streptozotocin (STZ)‐induced DPN mice and high‐glucose‐treated RSC96 Schwann cells and RAW264.7 macrophages, assessing nerve function, oxidative stress, apoptosis, and macrophage polarization. Results Resveratrol significantly improved motor nerve conduction velocity, sensory function, and sciatic nerve integrity in DPN mice, while reducing oxidative stress and neuronal apoptosis. It promoted M2 macrophage polarization, with increased IL‐10 and decreased TNF‐ α levels. Network analysis identified the AMPK/mTOR/Bcl‐2 axis as a central pathway. MR supported MTOR as a risk factor and BCL2 and PRKAA1 as protective factors for DPN. Mutational constraint analysis revealed marked depletion of missense variants and higher pathogenicity scores in resveratrol‐binding residues of MTOR and BCL2, indicating strong evolutionary constraint. Integration of genetic, structural, and functional evidence consistently prioritized MTOR and BCL2 as key targets. Conclusions Resveratrol alleviates DPN by modulating oxidative stress, apoptosis, and neuroinflammation via the AMPK/mTOR/Bcl‐2 axis and macrophage polarization. The integration of causal inference and binding‐site evolutionary constraint strengthens target validity and highlights resveratrol as a multitarget therapeutic candidate.