Aloe Vera Modulates Transcriptomic Landscapes and Cell Death Pathways to Enhance The Response of Colorectal Cancer Cells To 5-Fluorouracil

Background: Colorectal cancer (CRC), the third most prevalent malignancy globally, causes ~1.9 million annual cases, necessitating novel therapies.Although 5-fluorouracil (5-FU) is a first-line chemotherapy, its efficacy is limited by resistance and toxicity, with response rates of only 10-15% in metastatic CRC.Combining 5-FU with natural compounds, such as Aloe barbadensis Miller (AVE), may enhance therapeutic outcomes by modulating resistance mechanisms. Materials and Methods:This study evaluated the combined treatment effects of 5-FU and AVE in HCT116 and HT29 CRC cells using real-time proliferation (xCELLigence), mitochondrial stress assays (Seahorse XFe24), and total RNA sequencing.Results: The combination of 5-FU and AVE (5-FuAve) significantly reduced cell proliferation and mitochondrial respiration in both cell lines.Transcriptome analysis revealed 524 upregulated and 98 downregulated genes in HCT116 and 57 upregulated and 17 downregulated genes in HT29.Seven tumor-suppressor genes, including FBLN2, INPP5D, and TP53INP1, were commonly upregulated, while oncogenic regulators such as PLK1 and CDC20 were downregulated in both lines.HT29 cells displayed an apoptosis-associated transcriptomic signature, supported by MAPK pathway enrichment, whereas HCT116 cells showed transcriptomic features consistent with a potential ferroptotic response., as indicated by ALOX5 upregulation and arachidonic acid pathway engagement.Despite differing molecular mechanisms, both cell lines exhibited comparable antitumor responses.Conclusion: These findings suggest that 5-FuAve exerts multi-modal anti-cancer effects through cell-type-specific mechanisms, offering a promising strategy for addressing chemoresistance in CRC.Future studies should dissect the individual contributions of 5-FU and AVE to validate these observations and support therapeutic development.