Resveratrol Mimics Exercise-Induced Metabolic Stress to Suppress CIP2A and Epithelial–Mesenchymal Transition in 3D Renal Carcinoma Spheroids

<b>Background/Objectives:</b> We evaluated a 6-day repeated resveratrol exposure regimen in a three-dimensional (3D) culture model of human renal cell carcinoma (Caki-1) spheroids to examine phenotypic responses and changes in CIP2A abundance and epithelial-mesenchymal transition (EMT)-associated marker expression. <b>Methods:</b> Over 6 days, we assessed morphology and 2D cell viability and quantified CIP2A, fibronectin, and α-SMA by immunoblotting and immunofluorescence. <b>Results:</b> Resveratrol reduced 2D viability and increased cytoplasmic vacuoles, consistent with a stress-associated morphological response. In 3D spheroids, resveratrol treatment was associated with reduced CIP2A protein levels and decreased fibronectin and α-SMA, consistent with attenuation of a mesenchymal marker profile. <b>Conclusions:</b> These proof-of-concept data link 6-day resveratrol exposure to CIP2A reduction and decreased mesenchymal marker expression in a human 3D RCC spheroid system; however, PP2A activity and downstream signaling, AMPK/SIRT1 activation, and EMT-relevant functional assays were not assessed, and validation across additional RCC models will be required.