Quercetin Alleviates Breast Cancer‐Related Depression by Inhibiting Neutrophil Extracellular Traps via Inhibition of Sphingosine 1‐Phosphate/Sphingosine 1‐Phosphate Receptor Axis

ABSTRACT Breast cancer is associated with a higher incidence of depression and decreased quality of life. Previous studies have indicated that quercetin can mitigate the advancement of breast cancer‐related depression (BCRD); however, the specific mechanism by which quercetin affects BCRD is yet to be determined. In this study, we aimed to examine the effect of quercetin on BCRD and explore the underlying mechanisms. We established a mouse model of BCRD and administered quercetin. LC–MS was used to analyze and determine distinct alterations in metabolites in mouse tumor samples. Polymorphonuclear neutrophils (PMNs) were extracted from mouse femurs and treated with PMA and quercetin/Sphingosine 1‐phosphate (S1P). Mouse breast cancer cells 4 T1 were treated with lipopolysaccharides (LPS), neutrophil extracellular traps (NETs) and S1P. Neuronal cells were treated with LPS, NETs, S1P, and Corticosterone. Pearson's correlation coefficient was used to evaluate the relationship between differential metabolites and NETs. Quercetin inhibited NET formation in BCRD mice. In vitro, quercetin reversed NET‐induced 4 T1 cell proliferation, migration, and ROS production. Quercetin also reversed the effects of NET‐induced 4 T1 cells on neuronal cells. LC–MS analysis demonstrated that quercetin ameliorated the metabolic abnormalities in the tumors of BCRD mice. Pearson's correlation analysis showed that S1P, Oleoyl glycine, N‐Arachidonoylglycine, 2, 3‐butanediol apiosylglucoside, and tetracosatetraenoyl carnitine levels positively correlated with MPO DNA levels. Furthermore, in vitro, S1P enhanced NET‐induced 4 T1 cell proliferation, migration, and ROS production, as well as enhanced NET‐induced 4 T1 cell damage to neuronal cells. Quercetin alleviated BCRD by inhibiting NETs via inhibition of the S1P/S1PR axis.