Gastric adenocarcinoma (GA) ranks as the fourth most deadly cancer worldwide. The effectiveness of chemotherapy in GA patients is often limited, largely due to the enhanced function of ATP-binding cassette (ABC) transporters that promote drug resistance. Addressing this challenge, our study explores, for the first time, the role of a natural ellagitannin derivative in improving chemotherapy response in GA cells. The expression of ABC transporters and their clinical significance were validated in GA tissues. Urolithin A (UroA) was synthesized and MKN-45 cells were treated, alone and in combination with doxorubicin (DXR). Cell viability was assessed by resazurin, flow cytometry was performed for apoptosis detection and molecular docking was carried out to predict the interaction of UroA with ABC transporters. Upregulations of ABCG2, ABCB1, and ABCC1 were detected in GA tissue samples, correlating with poorer patient survival. Combining UroA with DXR enhanced the toxic impact of chemotherapy on MKN-45 cells. Docking studies supported the strong interaction between UroA and the selected ABC transporters. These results offer new mechanistic understanding of UroA ability to counteract chemoresistance and underscore the therapeutic promise of targeting ABC transporters to boost chemotherapy success in gastric adenocarcinoma

Keywords