Circulating FABP4 promotes obesity-associated breast cancer lung metastasis through PIP2

Obesity is a well-established risk factor for increased incidence and mortality in multiple cancers, including breast cancer. However, the key molecular mechanisms linking obesity to breast cancer progression remain incompletely understood. In this study, using several high-fat diet-induced obesity models, we demonstrate that obesity promotes breast cancer lung metastasis through elevated levels of adipocyte-derived circulating FABP4. Mechanistically, circulating FABP4 directly binds to a subset of breast cancer cells via the membrane lipid PIP2. This FABP4/PIP2 interaction activates PKC signaling and enhances mitochondrial ROS production, driving cancer cell migration. Genetic deletion of FABP4, either globally or specifically in adipocytes, markedly reduces obesity-associated metastasis. Moreover, therapeutic targeting of circulating FABP4 using a distinctive neutralizing monoclonal antibody significantly suppresses breast cancer metastasis in multiple preclinical models. Together, these findings identify the FABP4/PIP2 axis as a key mechanism underlying obesity-driven breast cancer and highlight it as a promising therapeutic target for treating metastatic breast cancer.