Integrative bioinformatics and molecular simulations identify HMGB3 as a key immune modulator in triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer is an aggressive and its diverse subtype that lacks targeted treatment options and often shows resistance to immune-based therapies. This study aimed to identify immune-related regulatory axes within BLIA and MLIA subtypes by integrating ceRNA network of ncRNAs and mRNAs, and to evaluate HMGB3 as a potential therapeutic target. METHODS: Transcriptomic datasets from GEO and TCGA were analyzed to identify DE-mRNAs. Network analysis was performed using STRING, CytoHubba, CytoNCA, and MCODE in Cytoscape. HMGB3-associated ncRNAs were examined for functional relevance. Molecular docking, ADMET evaluation, and molecular dynamics (MD) simulations were conducted to assess ligand binding and complex stability. RESULTS: HMGB3 showed strong association with poor prognosis in MLIA subtype. The HMGB3-miR-214-3p-let-7f-5p-NEAT1 axis emerged as a potential immune-modulatory pathway. Docking revealed high affinity for Pimicotinib (- 8.0 kcal/mol), CID17584963 (7.0 kcal/mol), and CID1763476 (kcal/mol). MD simulations confirmed the stability of these complexes, reflected by lower RMSD, reduced residue fluctuations, compact conformations, and decreased solvent exposure. CONCLUSION: This work identifies HMGB3 as a promising immunotherapeutic target in the MLIA subtype of TNBC and highlights Pimicotinib, CID17584963, and CID1763476 as potential HMGB3 inhibitors for drug repurposing strategies.