Cuproptosis is a new form of copper-dependent programmed cell death commonly occurring within the body. There is emerging evidence indicating that cuproptosis has a significant regulatory function in the onset and progression of cancer. However, it is still unclear how cuproptosis regulates cancer and whether other genes are involved in the regulation. Using the TCGA-COAD dataset of 512 samples, we found that seven of ten cuproptosis markers showed prognostic value in colorectal cancer (CRC) using Kaplan–Meier survival analysis. Furthermore, 31 prognostic cuproptosis-related genes were identified using weighted gene co-expression network analysis and univariate Cox analysis. Subsequently, we constructed a 7-PCRG signature using least absolute shrinkage and selection operator (LASSO)–Cox regression analysis. The risk score predicting survival in patients with CRC was evaluated. Two risk groups were classified based on their risk scores. The two groups revealed a significant difference in immune cells, such as B and T cells. Furthermore, we identified differences in many immune functions and checkpoints, including CD276 and CD28. In vitro experiments showed that a hub cuproptosis-related gene, TIGD1, could significantly regulate cuproptosis in CRC after exposure to elesclomol. This study validated that cuproptosis was closely related to the progression of CRC. Seven new cuproptosis-related genes were identified, and the function of TIGD1 in cuproptosis was preliminarily understood. Since a certain concentration of copper in CRC cells is important, cuproptosis may provide a new target for cancer therapy. This study may provide novel insights into the treatment of CRC.

Necroptosis is a newly defined form of programmed cell death that plays an important role in cancers. However, necroptosis-related lncRNAs (NRLs) involved in colorectal cancer (CRC) have not yet been thoroughly studied. Methods: In this study, a 4-NRL model was developed based on the least absolute shrinkage and selection operator (LASSO) algorithm. A series of informatic, in vitro and in vivo analyses were applied to validate the prognostic value of the model and the potential function of the hub lncRNA MYOSLID. Results: The model exhibited an excellent capacity for the prediction of overall survival and other clinicopathological features of CRC patients using Kaplan–Meier (K–M) survival curves and receiver operating characteristic (ROC) curves. Furthermore, a significant difference in the levels of immune cells, such as CD4 memory T cells and activated mast cells, between two risk groups was observed. The low-risk patients had a higher expression of immune checkpoints, such as PDCD1 (PD-1) and CD274 (PD-L1). The levels of MYOSLID, a hub lncRNA in our model, were higher in CRC tissues than in normal tissues. Knockdown of MYOSLID induced necroptosis and inhibited the proliferation of CRC cells in vitro and in vivo. Interestingly, knockdown of MYOSLID also increased the percentage of CD4⁺ and CD8⁺ T cells in subcutaneously transplanted tumours. Conclusion: Our model is a promising biomarker that can be used to predict clinical outcomes in CRC patients, and MYOSLID plays an important role in regulating necroptosis and immune cell infiltration in CRC.

Transcription factors are frequently aberrantly reactivated in various cancers, including colorectal cancer (CRC). However, as a transcription factor, the role of GMEB2 in cancer is still unclear, and further studies are needed. Here, we aimed to identify the function and mechanism of GMEB2 in regulating the malignant progression of CRC. GMEB2 was found to be highly expressed in online data analyses. We demonstrated that GMEB2 was markedly upregulated at both the mRNA and protein levels in CRC cells and tissues. GMEB2 knockdown inhibited CRC cell growth in vitro and in vivo. Mechanistically, as a transcription factor, GMEB2 transactivated the ADRM1 promoter to increase its transcription. Rescue experiments showed that ADRM1 downregulation partially reversed the promoting effects of GMEB2 on CRC growth in vitro. Moreover, the GMEB2/ADRM1 axis induced nuclear translocation of NF-κB, thus activating NF-κB signalling. Finally, we further revealed that YTHDF1 recognized and bound to the m⁶A site on GMEB2 mRNA, which enhanced its stability. Taken together, our findings reveal the crucial role and regulatory mechanism of GMEB2 in CRC for the first time and provide a novel potential therapeutic target for CRC therapy.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by persistent mucosal inflammation. While fibroblasts contribute to tissue repair and fibrosis, their role in UC pathogenesis remains incompletely understood. Single-cell RNA sequencing (GSE114374, GSE231993) and cell-cell communication analysis were performed to profile fibroblast interactions. Weighted Gene Co-expression Network Analysis (WGCNA) identified fibroblast-related modules. Machine learning models predicted diagnostic biomarkers. IF, ELISA and WB assays were used to validate the expression of ANGPTL2 in UC samples. In vivo validation using a DSS-induced UC mouse model evaluated ANGPTL2 expression and therapeutic response to GDC-0152. Spatial transcriptomics (GSE189184) was used to analyze tissue regionalization, cell-type spatial distribution, and the localized expression of ANGPTL2 and its colocalization with fibroblasts. Single-cell analysis identified fibroblasts as a key cell type in UC. WGCNA revealed a strong correlation between the turquoise module and fibroblast infiltration, with genes in this module enriched in pathways such as cytokine-cytokine receptor interaction and TNF signaling. Machine learning models identified PHLDA1 and ANGPTL2 as potential biomarkers with high diagnostic accuracy (AUC 0.935 and 0.917, respectively). Furthermore, exprimental analyses confirmed that ANGPTL2 was significantly upregulated in fibroblasts from UC patients, serum ELISA experiments demonstrated that ANGPTL2 was also significantly elevated in the serum of UC patients, supporting its potential as a non-invasive diagnostic indicator. In vivo experiments confirmed ANGPTL2 upregulation in DSS-treated mice, reversed by GDC-0152. Spatial transcriptomics partitioned UC tissue into 13 distinct regions, revealing prominent fibroblast distribution and markedly high ANGPTL2 expression with significant spatial colocalization with fibroblasts. Fibroblasts are central to UC pathogenesis, contributing to inflammation and fibrosis. ANGPTL2 is a promising diagnostic biomarker and potential therapeutic target in UC.

Objectives: This Mendelian randomization study aimed to systematically investigate the causal associations of 2,821 plasma protein ratios with UC susceptibility and validate potential biomarkers through multi-omics approaches. Methods: This study employed a two-sample Mendelian randomization (MR) approach using publicly available genetic data from genome-wide association studies (GWAS), with single nucleotide polymorphisms (SNPs) serving as instruments for exposures and outcome variables. Using the two-sample MR approach, we assessed the associations between 2,821 plasma protein ratios and UC and performed a series of sensitivity analyses to enhance the robustness of our findings. Additionally, single-cell sequencing was used to validate and explore the MR results. And ELISA assays were carried to validate the expression of certain protein ratios. Results: The inverse-variance weighted method identified significant relationships between 165 plasma protein ratios and UC (FDR<0.05). UC susceptibility, per one standard deviation increase in genetically predicted protein ratios, ranged from 0.539 (DCTN1/IKBKG, 95 % CI: 0.408–0.712) to 2.078 (CCT5/DCTN1, 95 % CI: 1.607–2.686). Various sensitivity analyses further confirmed the robustness of these causal relationships. Single-cell sequencing further revealed significant differences in DLL1/TGFBR2 ratios between UC and healthy controls (p<0.0001), with a moderate yet significant elevation in CCT5/DCTN1 ratios (p<0.01) and no notable difference in BCR/DCTN1 ratios. Validation using ELISA in 26 pairs of UC patients and healthy controls showed a significantly elevated DLL1/TGFBR2 ratio in the UC group (p<0.001), while CCT5/DCTN1 and BCR/DCTN1 ratios showed no differences. Conclusions: The findings reveal a robust causal relationship between the DLL1/TGFBR2 plasma protein ratio and UC, offering novel insights into the diagnosis and treatment of the disease.