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

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.

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.

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.

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.