This study demonstrates that a slow metabolism‐driven amplification of hepatic PPARγ agonism mediates BBR‐induced obesity‐specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre‐existing NAFLD in both clinical practice and drug discovery processes. The gene discussed is PPARG; the disease is obesity due to melanocortin 4 receptor deficiency.