Overexpression of MCL1 attenuates irritable bowel syndrome by regulating cuproptosis: Screening and validation

Irritable bowel syndrome (IBS) is a type of chronic bowel disorder with a poorly understood pathophysiology. Recently, the imbalance of copper has been reported to influence the progression of IBS, suggesting cuproptosis, a new type of copper-induced cell death, may play a role in IBS. This study found 17 cuproptosis-related differentially expressed genes in IBS through bioinformatic analysis. Six hub genes were identified after the protein-protein interaction network analysis, namely myeloid cell leukemia 1 (MCL1), epidermal growth factor receptor 2, cadherin-associated protein beta 1, solute carrier family 25 members 37, solute carrier family 39 members 14, and six transmembrane epithelial antigens of the prostate 3. We selected MCL1 for further verification. Human normal colon epithelial cell line (NCM460) was used to construct models of IBS or cuproptosis in vitro by lipopolysaccharide (LPS) or LPS combined with copper (II) chloride (CuCl₂). We observed that overexpression of MCL1 promoted cell viability and proliferation ability, and inhibited the secretion of inflammatory factors and expression of Bax and caspase-3 of NCM460 cells treated with LPS or LPS combined with CuCl₂. In addition, up-regulated MCL1 significantly suppressed the protein levels of ferredoxin 1 and lipoyl synthase, two key regulators of cuproptosis. In conclusion, our study demonstrates that cuproptosis is involved in IBS and identifies a cuproptosis-related gene, MCL1, that helps alleviate IBS by promoting cell growth, reducing inflammation, and suppressing cuproptosis, making it a promising therapeutic target in IBS.