The multifaceted role of bile acids in breast cancer: pathogenesis, therapeutic potential, and drug delivery

Background Bile acids (BAs), once often considered tumor-promoting, are now recognized for their complex roles in breast cancer. Their effects are influenced by the gut microbiota and may vary across cancer subtypes and exposure contexts. Objectives This systematic review aims to summarize the current evidence on the clinical relevance, molecular mechanisms, and therapeutic applications of BAs in breast cancer. Methods We performed a systematic literature search of four international (PubMed, Web of Science, Embase, Cochrane Library) and two Chinese (China National Knowledge Infrastructure, Wanfang) databases, along with clinical trial registries, from inception to February 8, 2026. Study selection adhered to PRISMA guidelines, and we focused on original studies investigating the role of BAs in breast cancer pathogenesis, therapy, or drug development. Results Evidence mapping across clinical profiling, receptor biology, direct BA interventions, and translational applications indicates that human BA measurements do not converge on a stable systemic “BA signature”. Our qualitative heterogeneity assessment indicates that the apparent contradictions are largely driven by differences in exposure compartment, comparator definition, analytical platform and BA speciation/coverage, and variable control of clinical confounders and subtype/stage or treatment background. When these sources of heterogeneity are considered, more coherent patterns emerge: receptor studies support context-dependent outputs across tumor subtypes and microenvironmental states, while direct BA interventions report both anti-tumor and pro-tumor phenotypes that depend strongly on BA species/form and concentration, with many in vitro experiments using pharmacologic or supraphysiologic exposures. In translational research, BAs have been explored as active derivatives targeting defined pathways and as enabling components in drug delivery systems. In the latter setting, BAs mainly serve as biocompatible scaffolds to improve delivery of established chemotherapeutics in preclinical models. Conclusion The BA system represents a promising but challenging therapeutic target for breast cancer. However, its clinical translation requires carefully designed strategies to overcome major hurdles. The inherent lack of tissue specificity poses risks for systemic toxicity. Future efforts must focus on developing tumor-targeted approaches, understanding the gut-microbiome-liver-breast axis, and performing subtype-stratified (especially estrogen receptor status-stratified) research to establish robust patient stratification biomarkers and safely realize the potential of BA-based therapies.