Machine Learning and Molecular Modeling Reveal HDAC6 As a Key Target of Tanshinone IIA in Multiple Myeloma

Multiple myeloma (MM) is a malignant blood cancer marked by severe bone destruction and immune microenvironment disruption. Yet relapse and drug resistance remain major clinical challenges. Tanshinone IIA (TIIA) exhibits potent antitumor activity, but its molecular targets and mechanisms in MM remain unclear. Here, we systematically elucidate TIIA's pharmacological mechanisms in MM using network pharmacology, transcriptomics, molecular docking, molecular dynamics (MD) simulations, and in vitro cellular experiments. Histone deacetylase 6 (HDAC6) was identified as a key prognostic target in MM via integrative bioinformatics─combining cross-database analysis, machine learning (LASSO, SVM-RFE, random forest), and survival validation in the MMRF-CoMMpass cohort. Molecular docking and MD simulations showed stable binding of TIIA to HDAC6. In vitro, TIIA directly inhibited HDAC6 enzymatic activity and selectively killed U266 and RPMI 8226 myeloma cells in a dose-dependent manner, with minimal toxicity to normal cells. Additionally, gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) immune profiling using the LM22 signature suggested that HDAC6 participates in microenvironmental remodeling by modulating cell adhesion-mediated resistance and orchestrating an immunosuppressive niche characterized by monocyte depletion. This study highlights for the first time the critical role of HDAC6 in TIIA-mediated antimyeloma activity and provides novel mechanistic insights and potential targeted therapeutic strategies for the treatment of MM.