Resveratrol Modulates Phosphatidylcholine Metabolism-Related Enzymes and Enhances Chemosensitivity in Colorectal Cancer Models

Colorectal cancer (CRC) remains a major cause of cancer-related mortality worldwide, largely due to the emergence of chemoresistance driven by metabolic adaptations. Among these alterations, lipid metabolic reprogramming has emerged as a critical determinant of tumor progression and therapeutic response. In particular, dysregulation of enzymes involved in phosphatidylcholine (PC) synthesis and remodeling, through the Kennedy pathway and the Lands cycle, has been associated with therapeutic resistance. Lysophosphatidylcholine acyltransferase 2 (LPCAT2), a key enzyme involved in PC remodeling, notably promotes lipid droplets (LD) accumulation in CRC cells and contributes to chemoresistance. In this context, natural compounds capable of modulating PC metabolism, such as the polyphenol resveratrol (RSV), may represent a relevant strategy to improve sensitivity to chemotherapies in chemoresistant colon tumor cells. In this study, RSV induced apoptosis and significantly reduced the proliferation of intrinsically resistant HT29 cells and SW620 cells engineered to overexpress LPCAT2. RSV also decreased the expression of key enzymes involved in the Kennedy pathway in chemoresistant CRC cell lines. These changes were accompanied by distinct time-dependent patterns of lipid droplet accumulation in the two cellular models. In addition, drug combination studies showed that RSV enhanced the response to 5-fluorouracil (5-FU), oxaliplatin (OXA) and the FOX regimen (5-FU + OXA, 1:1 ratio) with synergistic interactions for several dose combinations, together with favorable dose-reduction indices. Collectively, these in vitro findings indicate that RSV modulates PC-metabolism-related proteins and enhances chemotherapy sensitivity in resistant CRC models. Overall, our results identify RSV as a promising therapeutic strategy to target metabolic vulnerabilities associated with PC metabolism and overcome chemoresistance in CRC.