miR-106b-5p as a Central Regulator of Cancer Progression and Chemotherapy-Induced Cardiotoxicity: From Molecular...

MicroRNAs (miRNAs) are critical regulators of gene expression in cancer biology and cardiovascular disease. miR-106b-5p, a member of the miR-106b-25 cluster, has been widely studied for its oncogenic activity in various malignancies. However, its role as a direct molecular driver of anthracycline-induced cardiotoxicity has only recently been uncovered. This finding highlights new therapeutic possibilities at the intersection of oncology and cardiovascular medicine. This review outlines the dual role of miR-106b-5p as a key modulator in both tumor progression and chemotherapy-induced cardiac dysfunction. miR-106b-5p is upregulated in numerous cancers-including breast, prostate, lung, gastric, colorectal, hepatocellular, and esophageal-and promotes tumorigenesis via suppression of tumor suppressors such as PTEN, BTG3, p21, and SMAD7, leading to activation of oncogenic pathways like PI3K/AKT and TGF-β. Importantly, we present the first evidence that miR-106b-5p is significantly upregulated in the myocardium in response to doxorubicin treatment, where it drives left ventricular dysfunction by targeting PR55α, a key regulator of PP2A activity. This pathway results in cytoplasmic HDAC4 accumulation, aberrant activation of the YY1 transcription factor, and upregulation of sST2, a biomarker linked to adverse cardiac remodeling and poor prognosis. In response, we developed AM106, a novel locked nucleic acid antagomir that silences miR-106 b-5p. Preclinical studies demonstrate that AM106 restores PR55α/PP2A activity, reduces sST2 expression, and prevents structural and functional cardiac damage without compromising anti-tumor efficacy. In parallel, artificial intelligence (AI) tools could be leveraged in the future-based on established AI applications in miRNA cancer research-to accelerate the identification of miR-106b-5p-related biomarkers and guide personalized therapy selection. Our findings position miR-106b-5p as a previously unrecognized molecular bridge between cancer and doxorubicin-induced cardiotoxicity. The development of the AM106 antagomir represents a promising approach with potential clinical applicability in cardio-oncology, offering dual benefits: tumor control and cardioprotection. Coupling this innovation with AI-driven analysis of patient data may enable precision risk stratification, early intervention, and improved outcomes. miR-106b-5p thus emerges as a central therapeutic target and biomarker candidate for transforming the clinical management of cancer patients at risk for heart failure.