Gastrointestinal (GI) carcinomas are among the leading cause of cancer-related deaths worldwide, and chemoradioresistance severely limits the long-term effectiveness of their treatment. Aldo-keto reductase family 1 member C3 (AKR1C3) is a therapeutic target in cancer treatment, particularly for addressing therapy resistance. The objective of present study was to explore the potential of natural, structurally similar coumarins to target AKR1C3 and improve sensitivity of cancer cells to chemotherapy and ionizing radiation (IR). Upon identification of potential targets, interactome mapping and gene set enrichment analyses were carried out, and the expression of AKR1C3 was assessed in GI samples. Coumarins were subjected to molecular docking and dynamics simulations to provide insight into their binding propensity with AKR1C3. For experimental validation, umbelliprenin (UMB) was extracted from Ferula persica by preparative thin layer chromatography, and then, KYSE-30 cells were treated with UMB, alone and in combination with paclitaxel (PTX) for 48 h. Additionally, cells were pretreated with UMB, exposed to IR (3–6 Gy), and recovered for 72 h. At the end of combinatorial treatments, cells were evaluated for viability and apoptosis. Predictions indicated AKR1C3 as a potential target of esculetin, scopoletin, umbelliferone and UMB. Enrichment analyses confirmed the involvement of AKR1C3 in several biological processes and pathways, and expression analyses indicated upregulation of AKR1C3 in pancreatic, liver and esophageal carcinomas. Molecular docking and dynamics simulations revealed favorable and stable interactions of coumarins with the NADPH binding site of AKR1C3. Experimental studies revealed significant (p < 0.0001) enhancement in the cytotoxicity and apoptosis-inducing effects of 5 nM PTX upon combinatorial use with 100 μM UMB. Moreover, 48 h pretreatment with UMB significantly (p < 0.01) enhanced IR-induced cytotoxicity and apoptosis. The present findings highlight the potential of natural coumarins, particularly UMB, to inhibit the reductase activity of AKR1C3, thereby enhancing the efficacy of chemotherapy and radiotherapy. This positions UMB as a promising candidate for overcoming chemoradioresistance in GI carcinomas and paves the way for the development of innovative therapeutic strategies.

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