Ilomastat

This study aimed to investigate the molecular mechanisms underlying ulcerative colitis (UC)-associated colorectal cancer (CRC) development and identify potential therapeutic targets through integrated multi-omics analysis. Mendelian randomization (MR) analysis, combined with bioinformatics approaches including differential gene expression analysis, protein-protein interaction network construction, gene set enrichment analysis, and single-cell RNA sequencing, was employed. Data were obtained from GEO, TCGA, and genome-wide association study (GWAS) databases. Drug prediction and molecular docking were performed using DSigDB and AutoDockTools. A total of 48 shared genes were identified between UC and CRC, with MMP1 emerging as a significant protective factor (OR = 0.766; 95% CI = 0.593-0.989, P = 0.041). MMP1 demonstrated strong diagnostic potential (AUC = 0.927, 95% CI = 0.895-0.959) and was functionally associated with immune regulation and metabolic pathways. Single-cell analysis revealed predominant MMP1 expression in fibroblasts and immune cells, while immune infiltration analysis showed significant correlations with CD8⁺ T cells and NK cells. Mediation MR analysis indicated that 63.33% of MMP1's protective effect was mediated through naive-mature B cells. Drug prediction identified ilomastat as a potential MMP1 inhibitor with strong binding affinity (binding energy = -7.17 kcal/mol). These findings provide evidence for MMP1's protective role in UC-associated CRC through immune microenvironment modulation, highlighting its potential as a diagnostic biomarker and therapeutic target. The identification of ilomastat as a potential MMP1 inhibitor offers new avenues for targeted therapy in inflammation-associated cancers.

Aberrant BMPR2 (bone morphogenetic protein receptor 2) signaling is associated with the pathogenesis of pulmonary hypertension. SMAD4 (mothers against decapentaplegic homolog 4) is an essential downstream effector of BMPR2 signaling, but whether and how it participates in pulmonary hypertension are unclear.

Globally and vascular cell-specifically inducible knockout mouse models were used to examine the role of SMAD4 deficiency in differential cell compartments in the development of pulmonary hypertension. Single-cell transcriptomic analysis in combination with in vitro cell function measurements was conducted to provide mechanistic insights into pulmonary hypertension pathogenesis.

Adult mice with Smad4 global deletion or endothelial cell-specific deletion spontaneously developed pulmonary hypertension manifestations, characterized by elevated right ventricle systolic pressure and excessive muscularization in pulmonary distal vessels, which were accompanied by other cardiovascular abnormalities. By contrast, mice with smooth muscle cell-specific Smad4 deletion had no pulmonary hypertension but rather displayed evident aortic aneurysm and dissection. At the cellular level, SMAD4 deficiency led to impairment of both endothelial cell-cell and cell-matrix adhesions and disorganized ECM (extracellular matrix), resulting in increased vascular leak and weakened endothelium-matrix attachment. Notably, endothelial Itgb1 deletion mimicked the impact of endothelial Smad4 loss on pulmonary hypertension. Finally, enhancing endothelial cell adhesion and ECM assembly by administrating an MMP (matrix metallopeptidase) inhibitor ilomastat could alleviate the pulmonary hypertension manifestations caused by endothelial SMAD4 deficiency.

SMAD4 deficiency in endothelial cells, but not smooth muscle cells, plays a pathogenic role in pulmonary hypertension, via dampening endothelial cell-cell and cell-matrix adhesions and ECM organization.