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Shewanella algae promotes colorectal adenoma development by inducing ferroptosis in macrophages

ABSTRACT: Shewanella algae (S. algae), an emerging opportunistic pathogen, has been increasingly associated with severe gastrointestinal infections, particularly among immunocompromised individuals, including those with colorectal adenomas. To evaluate its potential role in the progression of colorectal adenomas, we conducted both in vivo and in vitro studies. In the in vivo model, mice bearing adenomas were orally administered S. algae to simulate natural ingestion. Concurrently, macrophages were exposed to S. algae in vitro to assess cellular responses. Oral administration of S. algae was found to exacerbate intestinal inflammation and increase colorectal adenoma burden. Transcriptomic analyses revealed elevated levels of reactive oxygen species (ROS) and upregulated expression of acyl-CoA synthetase long-chain family member 4 (Acsl4), indicative of enhanced iron metabolism and lipid peroxidation, key features of ferroptosis. Furthermore, the expression of key ferroptosis suppressors, including glutathione peroxidase 4 (Gpx4) and solute carrier family 7 member 11 (Slc7a11), was significantly downregulated. These pathological changes were effectively reversed upon treatment with ferrostatin-1 (Fer-1), a specific inhibitor of ferroptosis. In vitro experiments corroborated the in vivo findings, demonstrating consistent activation of ferroptotic pathways in macrophages. Collectively, these results suggest that S. algae may promote the progression of colorectal adenomas by inducting ferroptosis in both colonic tissues and macrophages. Therefore, therapeutic strategies targeting ferroptosis may offer a promising approach for managing high-risk individuals infected with S. algae, potentially improving clinical outcomes and quality of life.

ORGANISM(S): Mus musculus

PROVIDER: GSE345022 | GEO | 2026/08/30

REPOSITORIES: GEO

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Project description:Purpose: 5-FU resistance is considered to be a possible reason for the failure of conventional drug treatment of colorectal cancer (CRC). Recently, salinomycin (SAL), as a selective inhibitor of cancer stem cells (CSCs), has been used to sensitize and attenuate a variety of solid tumor chemotherapy drugs. In our study, our goal was to combine SAL with 5-FU to explore whether increase the sensitivity of CRC to 5-FU and the molecular mechanism that involved in enhancing 5-FU sensitivity and promoting tumor cell chemotherapeutic death. Methods: ComboSyn software was used to study whether dual drug combinations synergistically promote each other and their dosage. CCK8, EdU and Annexin V/PI assays were used to study the cell proliferation and apoptosis of SW480 and HCT116 cells in response to SAL single-drug and dual-drug co-treatment. Cell cycle staining was used to assess cycle arrest. Wound healing and migration and invasion experiments were used to identify changes in migration and invasion capabilities under the influence of different drugs. Transcriptome sequencing is used to explore the molecular mechanisms of drugs. ROS fluorescence staining and MDA level measurement were used to confirm the changes in ferroptosis levels of SW480 and HCT116 cells after drug treatment. Nude xenograft mice were used to detect antitumor in vivo. Changes in the protein level expression of ferroptosis GPX4 and SLC7A11 were also determined in the treated cells.Results: SAL alone and combination of 5-FU were found to significantly increase cell mortality and apoptosis. At the same time, our results show that the blending of SAL and 5-FU not only inhibits the proliferation, migration, and invasion of CRC colorectal cancer cell lines in vivo and in vitro, but also promotes ferroptosis of CRC cell lines by downregulating the expression of GPX4 and SLC7A11. It may provide more and novel solutions and treatment perspectives for 5-FU or other drug-resistant chemotherapy strategies for CRC patients.Conclusions: SAL inhibiting colorectal cancer whose effect is achieved by reducing GPX4 and SLC7A11 protein levels to mediate ferroptosis activation in collaboration with 5-fluorouracil.

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Shewanella algae promotes colorectal adenoma development by inducing ferroptosis in macrophages

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