Gut microbiota-mediated dietary lignans metabolism drives accumulation of N,N-dimethylsphingosine and sensitizes triple-negative breast cancer to paclitaxel.

Abstract

For triple-negative breast cancer (TNBC), which lacks specific therapeutic targets, paclitaxel (PTX) chemotherapy remains the first-line clinical treatment. However, the widespread issue of treatment resistance severely limits its effectiveness, making it urgent to explore safer and more effective chemosensitization strategies. Dietary lignans (DL), bioactive compounds abundant in plants, require transformation by the gut microbiota to exert many of their effects and have shown potential antitumor activity. However, their impact on paclitaxel chemotherapy remains insufficiently understood. In this study, we show that DL enhance PTX efficacy in TNBC while attenuating PTX-induced gut microbial dysbiosis. Using antibiotic-induced microbiota depletion and fecal microbiota transplantation, we establish that the gut microbiota is essential for DL-mediated sensitization to PTX. Metabolomic profiling reveals that DL treatment markedly elevates the levels of the metabolite N,N-dimethylsphingosine (DMS). Importantly, DMS suppresses breast cancer cell proliferation and enhances PTX sensitivity even in the absence of gut microbiota, identifying DMS as a key functional metabolite of DL. Mechanistically, DMS downregulates PDGFRA and thereby modulates the PI3K-AKT signaling pathway. Together, these results indicate that DL potentiate PTX efficacy in TNBC, at least in part, through microbiota-dependent accumulation of DMS, offering a rationale for microbiota-informed strategies to optimize chemotherapy in TNBC.