Significance It is still a great challenge to identify novel therapeutic strategies for breast cancer, especially for those with treatment resistance. It was demonstrated here that nuclear receptor Nur77 was an effective drug target for breast cancer and compound Csn-B was clinically relevant by binding to Nur77 to prevent peroxisome proliferator-activated receptor-γ (PPARγ) targeting by steric hindrance, thereby inhibiting fatty acid uptake in cells and mouse models. Clinical sample analysis further supported the opposing roles of Nur77 and PPARγ in the patient prognosis of breast cancer. This study not only reveals a inhibitory function of Nur77 on fatty acid uptake for impeding tumor growth, but also identifies Csn-B as an effective therapeutic lead compound for breast cancer.