bims-instec 2026-02-01 papers

Nat Commun. 2026 Jan 27.

Ether lipids influence cancer cell fate by modulating iron uptake.

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, resulting in significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids from plasma membranes also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-026-68547-5

Redox Biol. 2026 Jan 19. pii: S2213-2317(26)00041-8. [Epub ahead of print]90 104043

p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer.

Jing Tong, Tao Han, Jun Deng, Yu Gan, Ruiwen Ruan, Wei Zhao, Chen Xiong, Quan Liao, Shiqi Chen, Huitong Bu, Jianping Xiong, Xiang Zhou, Qian Hao.

In colorectal cancer (CRC), p53 can either suppress or potentiate tumor sensitivity to ferroptosis under oxidative stress conditions. However, it remains to be elucidated how p53 differentially regulates ferroptosis, and whether it can initiate ferroptosis. Our findings reveal that p53 induces ferroptosis in the presence of abundant polyunsaturated fatty acids (PUFAs). FBXO2, which is encoded by a p53-inducible target gene, interacts with FABP5 and promotes the lysosomal degradation of FABP5 through chaperone-mediated autophagy. This results in a decrease in the levels of PUFAs, thereby increasing resistance to ferroptosis in CRC. Notably, the supplementation of arachidonic acid not only reverses p53-mediated ferroptosis resistance, but also coordinates with p53 to initiate ferroptosis independently of additional oxidative stress, effectively suppressing the growth of CRC cells both in vitro and in vivo. Altogether, our study uncovers that the availability of PUFAs is crucial for p53 to exert a pro-ferroptotic function in CRC.

Keywords: Cancer therapy; Chaperone-mediated autophagy (CMA); Ferroptosis; Polyunsaturated fatty acid (PUFA); p53

DOI: https://doi.org/10.1016/j.redox.2026.104043

Life Sci. 2026 Jan 27. pii: S0024-3205(26)00044-5. [Epub ahead of print] 124236

A protective role of ECSIT in chemotherapy-induced intestinal mucositis by maintaining Lgr5+ intestinal stem cells and gut homeostasis.

Shuai Wang, Yuying Jiang, Jie Yu, Pingping Cao, Yan Chen, Tianqi Shen, Jukun Zhang, Shuo Yang, Ping Wang, Fan Lin, Yingjian Zhang.

AIMS: Chemotherapy-induced intestinal mucositis (CIM) is a common and severe side effect linked to disrupted intestinal stem cell (ISC) balance, though its molecular regulation remains unclear. The principal objective of this research was to elucidate the role of evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) in intestinal stem cell balance and mucosal repair during CIM, with a specific focus on the Wnt/β-catenin pathway.
MATERIALS AND METHODS: This study used multi-omics and gene editing to elucidate ECSIT's role in intestinal stem cell balance and mucosal repair via the Wnt/β-catenin pathway. Multi-omics and Gene Set Enrichment Analyses (GSEA) identified ECSIT as a key CIM regulator.
KEY FINDINGS: Chemotherapeutic drugs dose-dependently reduced ECSIT expression in intestinal epithelial cells. Clinical analysis revealed that ECSIT expression decreased with increasing pathological severity (normal > inflammation > adenocarcinoma). In intestinal epithelium-specific knockout mice, ECSIT deficiency worsened irinotecan (CPT11)-induced CIM and blocked β-catenin nuclear translocation. ECSIT stabilized the β-catenin complex, regulating Wnt target genes like Axis inhibition protein (AXIN) and Cyclin D1 (CCND1); its knockout reduced Wnt signaling. Single-cell sequencing (scRNA-seq) revealed that ECSIT knockout reduced Lgr5 stem cells and increased inflammatory cell infiltration. Lgr5-specific inducible knockout and ECSIT complementation demonstrated that restoring ECSIT reversed β-catenin inhibition and improved CIM pathology.
SIGNIFICANCE: This study clarified ECSIT's dual role in stabilizing β-catenin and sustaining Wnt signaling-regulating Lgr5 intestinal stem cell proliferation and differentiation, epithelial renewal, and immune balance. These findings offer insights into CIM pathogenesis and establish the basis for developing targeted therapy through ECSIT-Wnt axis regulation.

Keywords: Chemotherapy-induced intestinal mucositis; ECSIT; Intestinal stem cells; Lgr5; Wnt/β-catenin pathway

DOI: https://doi.org/10.1016/j.lfs.2026.124236

Transl Oncol. 2026 Jan 27. pii: S1936-5233(26)00006-9. [Epub ahead of print]65 102669

Targeting cancer stem cells as the most aggressive and tumor-initiating cells.

Maryam Sadri, Zahra Shafaghat, Mona Roozbehani, Maryam Dorfaki, Fatemeh Kheiri, Sahel Heidari, Ali Mahmoudi, Fatemeh Faraji.

Cancer stem cells (CSCs) are a small subpopulation of tumor cells characterized by their self-renewal capacity and the ability to differentiate into different cell types. These partially differentiated cells exhibit properties of both stem cells and cancer cells. CSCs drive tumor initiation and progression by generating additional stem cells through self-renewal and differentiation into heterogeneous populations of tumor cell. They are among the most aggressive tumor cells that contribute to the development of key features of malignancy such as increased proliferation, metastasis, tumor growth, multidrug resistance (MDR), and resistance to radiotherapy and chemotherapy. CSCs are also associated with relapse and minimal residual disease, highlighting their critical role in cancer persistence. Therefore, targeting CSCs is essential to achieve complete tumor eradication. Available evidence suggests that combination therapies that integrate immunotherapy with cytotoxic therapies to concurrently eliminate CSCs and non-CSCs offer a promising approach to completely eradicate cancer. This review summarizes the current strategies employed to target CSCs and improve cancer treatment outcomes.

Keywords: CSCs; Cancer stem cell; Immunotherapy; Targeting; Tumor initiating cells

DOI: https://doi.org/10.1016/j.tranon.2026.102669

J Proteome Res. 2026 Jan 28.

A Multiomic Approach Integrating Genomic and Metabolomic Data Highlights Colorectal Cancer Pathways.

Aikaterini Iliou, Elena Chekmeneva, Rui Climaco Pinto, Fotini E Koukouzeli, Yiannis Ntounias, Konstantina Georgakopoulou, Marialena Pouliou, Marios Agelopoulos, Konstantinos K Tsilidis, Marc J Gunter, Paul Elliott, Julian L Griffin, Abbas Dehghan, Apostolos Klinakis, Emmanuel Mikros, Ioanna Tzoulaki.

Numerous genetic variants have been identified by genome-wide association studies as being associated with colorectal cancer (CRC) risk. Metabolome-wide association analysis was performed for 187 CRC-associated genetic variants using genomic data and untargeted 1H nuclear magnetic resonance urine metabolomics from 1951 Airwave Health Monitoring Study participants. We identified statistically significant associations between seven CRC single-nucleotide polymorphisms (SNPs) and urinary metabolites. This included SNPs within or close to RHPN2 with sucrose (P = 1.2 × 10-7), SLC6A18 with amino acids (P = 6.9 × 10-5 with tyrosine, P = 9.9 × 10-5 with leucine), and MAP2K5 and BMP2 with gut microbial metabolites (P = 1.6 × 10-4 and P = 4.4 × 10-4). The most significant correlation was followed by functional experiments in Caco-2 colon cancer cells. CRISPR-mediated knockout of a 48-nt RHPN2 intronic region containing rs10411210 in colon cancer cells compromised cell growth. RNA sequencing was performed in the two sets of clones (3 edited and 3 unedited) followed by pathway enrichment, and gene ontology analysis depicted extensive deregulation of genes (448 up- and 195 downregulated) involved in cell division and several metabolic processes. Overall, these findings demonstrate that integrating genetic and metabolomic data highlights the importance of the RHPN2 intronic locus in CRC potentially through metabolic processes affecting excretion of dietary and other metabolites.

Keywords: GWAS; Rho GTPase; colorectal cancer; metabolomics; multiomics; urine

DOI: https://doi.org/10.1021/acs.jproteome.5c00459

Gut. 2026 Jan 28. pii: gutjnl-2025-337583. [Epub ahead of print]

Hydroxylation matters! Microbial bile acid metabolism and colorectal cancer.

Matam Vijay-Kumar, Beng San Yeoh, Andrew T Gewirtz.

Keywords: BILE ACID; COLORECTAL CANCER; GUT INFLAMMATION; MICROBIOME

DOI: https://doi.org/10.1136/gutjnl-2025-337583