Berberine in breast cancer, a multi-targeted therapeutic agent from mechanisms to clinical translation.

Breast cancer remains a highly heterogeneous malignancy in which metastasis and therapeutic resistance represent the primary drivers of patient mortality. Berberine (BBR), a natural isoquinoline alkaloid, has emerged as a promising pleiotropic agent capable of simultaneously targeting multiple oncogenic vulnerabilities. In this Review, we systematically outline the multifaceted molecular mechanisms underlying the anti-tumor efficacy of BBR in breast cancer. We detail how BBR disrupts core intracellular signaling networks-specifically the PI3K/AKT/mTOR, MAPK/ERK, and Wnt/β-catenin pathways-and modulates the m6A RNA epitranscriptome via the METTL3/IGF2BP3 axis to induce apoptosis, enforce cell cycle arrest, and suppress the epithelial-mesenchymal transition (EMT). Beyond direct cytotoxicity, we highlight BBR's capacity to remodel the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAFs) and tumor angiogenesis, while simultaneously targeting treatment-resistant cancer stem cells (CSCs) through the epigenetic restoration of tumor-suppressive microRNAs. Furthermore, we discuss the role of BBR as a potent chemosensitizer capable of reversing multidrug resistance to augment conventional chemotherapeutic and endocrine regimens. Finally, we address the inherent pharmacokinetic bottlenecks that limit BBR's clinical translation and examine how cutting-edge nanomedicine platforms can circumvent these barriers, offering a comprehensive translational roadmap for integrating BBR into next-generation oncology therapeutics.