Focusing on non-responders to infliximab with ulcerative colitis, what can we do first and next?

• Published in: International immunopharmacology 2024-11, Vol.141, p.112943, Article 112943
• Main Authors: Pu, Dan, Wang, Pengfei, Wang, Xiang, Tian, Yonggang, Gong, Hang, Ma, Xueni, Li, Muyang, Zhang, Dekui
• Format: Article
• Language: English
• Subjects: Colitis, Ulcerative - drug therapy; Colitis, Ulcerative - genetics; Colitis, Ulcerative - immunology; Gastrointestinal Agents - therapeutic use; Gene Expression Profiling; Homology Modeling; Humans; Infliximab; Infliximab - therapeutic use; Molecular Docking; Molecular Docking Simulation; Prediction model; Ulcerative Colitis
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2024.112943

•For the first time, we developed a novel prediction model to pre-assess the efficacy of IFX in patients with ulcerative colitis as the first step towards personalized treatment.•Next-step therapeutic targets, including drugs and non-coding RNAs, were provided for those predicted non-responders to IFX by the novel prediction model.•Deferasirox, an iron chelator targeting the key model-gene CYP24A1, was identified as the most promising adjuvant or alternative for IFX through Homology Modeling, Molecular Docking and cellular validation. Ulcerative colitis (UC) is a chronic immune-mediated inflammation of the colorectum, for which infliximab (IFX) is currently the mainstay of treatment. However, one-third of patients with UC still fail to benefit from the IFX therapy, and early exposure to IFX impairs the efficacy of other subsequent biologics. Therefore, personalized therapeutic system is urgently needed to assist in clinical decision-making and precision treatment. Four microarray datasets of colonic biopsies from UC patients treated with IFX were obtained from the GEO database to form the Training Cohort and Validation Cohort. Differentially expressed genes (DEGs) in Training Cohort were identified and enriched for GO, KEGG and immune cell infiltration analysis. A prediction model for IFX efficacy was developed based on the LASSO and Logistic regression. The predictive accuracy of the model was verified by the Validation Cohort, and the model-genes/proteins were validated by immunohistochemistry. Gene-drug, gene-ncRNA interaction analysis were performed to identify drugs or non-coding RNAs (ncRNAs) that potentially interacted with the model-genes. Homology Modeling and Molecular Docking were conducted to filter the optimal candidate as the subsequent adjuvant or alternative for IFX in predicted non-responders. At last, the down-regulation of the key model-gene/protein CYP24A1 by the drug candidate Deferasirox was verified by Western Blot and qRT-PCR Assay based on cellular experiments. A total of 113 DEGs were identified in the Training Cohort, mainly enriched in inflammatory cell chemotaxis, migration, and response to molecules derived from intestinal microbiota. Activated pro-inflammatory innate immune cells, including neutrophils, M1 macrophages, activated dendritic cells and mast cells, were significantly enriched in colons of non-responders. The prediction model based on three model-genes (IFI44L, CYP24A1, and RGS1) exhibited strong predictive efficac