Chronic Psychological Stress Activates TRP/TAM/CXCL1 Signaling to Promote Breast Cancer Adipocyte Lipolysis via KEAP1 m(6)A Demethylation.

Chronic unpredicted mild stress (CUMS) and obesity are well-known risk factors for breast cancer (BC). However, their underlying correlation and potential mechanisms remain unknown. Herein, CUMS was found to promote BC growth and metastasis with increased adipocyte lipolysis, reactive oxygen species (ROS) burst, and mitochondrial fission. Metabolomic analysis identified tryptophan (TRP) as the main responding metabolite, which markedly induced macrophage M2 polarization and CXCL1 expression, and in turn promoted adipocyte lipolysis. Molecular investigation showed that CXCL1 triggered KEAP1 m(6)A demethylation via FTO (fat mass and obesity-associated protein) up-regulation, subsequently reducing NRF2 expression to exacerbate ROS burst and mitochondrial fission. Furthermore, either siCXCL1 or FTO inhibition markedly inhibited CUMS-induced BC progression, accompanied by suppression of adipocyte lipolysis, ROS production, and mitochondrial fission, as well as KEAP1 m(6)A demethylation. Our findings highlight the novel signaling of TRP/TAM/CXCL1 in mediating adipocyte lipolysis underlying CUMS-induced BC progression, and KEAP1 m(6)A demethylation presents a promising therapeutic target.