Non-alcoholic fatty liver disease promotes breast cancer progression through upregulated hepatic fibroblast growth factor 21

Abstract Non-alcoholic fatty liver disease influences breast cancer progression, however, the mechanisms remain unclear. Here, we found promoted breast cancer tumor growth and cell viability in NAFLD models and screened out the possible mediator hepatic fibroblast growth factor 21. Both peritumoral and systemic FGF21 administration facilitated breast cancer tumor growth, whereas FGF21 knockout diminished the tumor-promoting effects of the high-fat diet. Mechanically, exogenous FGF21 treatment enhanced the anti-apoptotic ability of breast cancer cells via STAT3 and Akt/FoXO1 signaling pathways and mitigated doxorubicin-induced cell death. Furthermore, overexpressed FGF21 was observed in tumor tissues from breast cancer patients and associated with poor prognosis. Taken together, our findings support a new role of FGF21 as a mediator upregulated in the NAFLD context that promotes breast cancer development, serving as a promising cancer therapeutic target.