10-gingerol potentiates paclitaxel efficacy in triple-negative breast cancer by remodeling gut microbiota and suppressing PI3K/AKT/mTOR signaling pathway.

Abstract

Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and chemoresistance, particularly to first-line agents such as paclitaxel (PTX). 10-Gingerol (10-G), the main pungent constituent of ginger, has been shown to possess anti-tumor and chemosensitizing properties. However, the mechanisms by which it potentiates PTX efficacy in TNBC remain incompletely understood. We established a 4 T1 TNBC-bearing BALB/c mouse model to assess the in vivo therapeutic effect of 10-G combined with PTX. Multi-omics analyses integrating 16S rRNA gene sequencing and transcriptome sequencing were performed to characterize gut microbial remodeling and tumor transcriptomic alterations. Results showed that combination therapy significantly inhibited tumor growth and cell proliferation with favorable safety and remodeled the gut microbiota by enriching beneficial genera (Limosilactobacillus, Lactobacillus) and reducing potentially pathogenic genera (Enterocloster, Mucispirillum). Transcriptomic profiling revealed that the PI3K/AKT/mTOR signaling pathway in tumor tissues following combination treatment was markedly suppressed. Mechanistic validation through molecular docking, molecular dynamics simulations, and Western blotting confirmed that 10-G directly binds to PI3K, AKT, and mTOR, and that combination therapy significantly suppressed phosphorylation of PI3K, AKT, and mTOR in tumor tissues. Collectively, this study demonstrates that 10-G augments the anti-tumor efficacy of PTX in TNBC, and this potentiation is mechanistically linked to favorable gut microbiota remodeling and targeted inhibition of the PI3K/AKT/mTOR signaling axis, thereby positioning 10-G as a promising chemosensitizing adjuvant for TNBC therapy.