MicroRNA Enrichment and Docking-Based Evaluation of Ilomastat Targeting of MMP-2 in Esophageal Squamous Cell Carcinoma: Insights from a South African Cohort

<b>Introduction:</b> MicroRNAs (miRNAs) play central roles in cancer pathogenesis by modulating oncogenic and tumor-suppressive pathways. The microRNA-29 (miR-29) family, known to inhibit matrix metalloproteinase-2 (MMP-2), represents a key regulatory axis in tumor invasion. This study analyzed miRNA pathway enrichment derived from tumor-normal mRNA differential expression in esophageal squamous cell carcinoma (ESCC) patients and investigated whether Ilomastat, a known MMP inhibitor, could plausibly bind the catalytic site of MMP-2. <b>Methods:</b> Thirty-eight patients with suspected esophageal cancer were recruited from an Academic Hospital in 2024. Twenty-nine ESCC patients were finally included. Paired tumor/adjacent-normal tissues were collected using endoscopic biopsies. Total RNA was extracted, sequenced, and bioinformatics conducted using the nf-core/rnaseq pipeline, with pathway enrichment analysis completed using g:Profiler2. Additional computational docking studies were performed to assess whether Ilomastat tautomers could plausibly bind the catalytic site of MMP-2. <b>Results and Discussion:</b> Pathway enrichment analysis identified several miRNAs implicated in ESCC pathogenesis, including the miR-29 family. Transcriptome analysis revealed overexpression of LINC00392 and FABP4 (fatty acid-binding protein 4) among the differentially expressed genes. FABP4 drives lipid metabolic reprogramming and tumor microenvironments that support cancer cell proliferation and metastatic potential. Computational docking suggested that the neutral tautomer of Ilomastat favorably occupies the catalytic site of MMP-2, providing a hypothesis-generating structural rationale for downstream pharmacologic inhibition of MMP-2. <b>Conclusion:</b> This study integrates pathway-based miRNA enrichment and computational docking to highlight the miR-29-MMP-2 axis as a potential regulatory pathway in ESCC. Collectively, our findings provide hypothesis-generating support for miRNA-guided MMP-2 inhibitor design that bridges transcriptomic discovery with pharmacologic modeling.