Uncoupler therapy for NAFLD: is flushing a possible harbinger of a safety concern?

Mitochondrial uncouplers such as 2,4-dinitrophenol (DNP) promote both weight loss and heat generation.1 HU6 is a prodrug, metabolised in the liver to produce DNP. Mazen Noureddin and colleagues2 reported a phase 2a clinical trial in people with non-alcoholic fatty liver disease (NAFLD) and high BMI, showing that HU6 decreased mean liver fat content by 26·8–35·6% and bodyweight by 0·52–2·75 kg. Because HU6 is activated in the liver, it offers hope of mitigating DNP's serious safety issues (eg, hyperthermia) by minimising extrahepatic exposure.