Emodin inhibits breast tumorigenesis in the comorbidity of hyperlipidemia and associated with IL-17 suppression

This study explored the interaction between breast cancer and the hyperlipidemia microenvironment, and assessed the anti-tumorigenic effects of the natural compound Emodin. The human cancer atlas and gene expression databases were used to identify links between breast cancer and hyperlipidemia. Oxidized LDL (oxLDL) stimulation in vitro and high-fat diet (HFD) feeding in vivo were used to simulate hyperlipidemia. Quantitative PCR, flow cytometry, IF/IHC staining, FPLC and biological experiments were conducted to evaluate Emodin's efficacy. Molecular docking simulation and molecular dynamic analysis were used to identify potential targets of Emodin. Lipid metabolism mediators CD36 and IL-17 activation were associated with breast cancer development. Bioinformatics identified IL-17 priming cytokines, and in vitro experiments confirmed Emodin inhibited Th17-priming cytokines after oxLDL stimulation. Emodin modulated tumorigenic genes especially apoptosis, inhibited breast cancer cell stemness and migration, and reduced tumor growth in HFD-feeding wild-type (WT) mice. Emodin reduced macrophage infiltration, angiogenesis, and IL-17 expression in tumors. Molecular docking and dynamic analysis suggested potential targets (IL17RA and TNFR1) for Emodin in modulating breast cancer development in hyperlipidemia microenvironment. Emodin effectively reduced tumorigenesis in HFD mice, accompanied with inhibited IL-17 expression and suppressed macrophage infiltration. This result provided evidence for the pro-tumorigenic role of hyperlipidemia in breast cancer development, and support the natural compound Emodin as a promising anti-tumor agent with targeting IL-17 signaling molecules. • Bioinformatics and experimental evidence demonstrate that hyperlipidemia-related IL-17 signaling activation promote breast cancer progression. • Emodin inhibits breast cancer cell stemness, migration, and in vivo tumor growth under hyperlipidemic conditions by suppressing IL-17 signaling and macrophage infiltration. • Molecular docking identifies IL17RA and TNFR1 as potential targets of Emodin, supporting its candidacy as a natural anti-tumor agent targeting the hyperlipidemia-breast cancer crosstalk.