Authors
Liangyu Zhang, Wei Wen, Xianyan Lu
Published in
Pathology, research and practice. Volume 286. Pages 156639. Jul 31, 2026. Epub Jul 31, 2026.
Abstract
Fusobacterium nucleatum (Fn) drives chemotherapy resistance in colorectal cancer (CRC) by activating hypoxia-mimicking signaling pathways, yet the molecular mechanisms linking Fn to 5-fluorouracil (5-FU) resistance remain unclear. We investigated how Fn-induced hypoxia-related gene expression contributes to 5-FU resistance and identified a pharmacological strategy to overcome it.
DEGs from Fn-infected CRC cells (GSE90944) were intersected with GSEA hypoxia-related genes, and Cox regression on TCGA-CRC data prioritized the top candidate, DDIT3. Its role in 5-FU resistance was characterized in vitro by Western blotting, qPCR, cell viability, and flow cytometry. LinkedOmics co-expression analysis mapped DDIT3-associated networks, and Salvia miltiorrhiza constituents were screened for DDIT3 inhibition.
DDIT3 was the most prognostically significant Fn-regulated hypoxia gene in CRC (HR: 1.544 [1.083-2.201], p = 0.016). Fn upregulated DDIT3 and activated the mitochondrial unfolded protein response (mitoUPR), suppressing 5-FU-induced ROS and reducing chemosensitivity; DDIT3 knockdown reversed these effects. A DDIT3-SLC3A2-CARS axis was identified as the key downstream pathway sustaining mitochondrial homeostasis. Salvianolic acid B (SAB) selectively suppressed this axis, restored ROS cytotoxicity, and improved 5-FU chemosensitivity in Fn-infected CRC cells.
Fn drives 5-FU resistance via DDIT3-mediated mitoUPR activation and ROS suppression through the DDIT3-SLC3A2-CARS axis. SAB disrupts this pathway, providing a rational basis for SAB-5-FU combination therapy in Fn-associated CRC.
PMID:
42546401
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.
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