Mitochondrial uncoupler <scp>BAM15</scp> ameliorates liver lipid metabolism disorders by activating the <scp>AMPK</scp> pathway

N⁵,N⁶-bis(2-Fluorophenyl)-[1,2,5]oxadiazolo[3,4-b]pyrazine-5,6-diamine (BAM15) is a recently identified mitochondrial uncoupler with antitumor, anti-inflammatory, antioxidant and antiobesity properties. Although it has been shown that BAM15 has a high targeting ability to the liver, its capacity to improve liver metabolic disorders and the underlying mechanisms are not well understood. This study examined how BAM15 works in high-fat-diet (HFD) induced obese mice. Our results showed that compared with 2,4-Dinitrophenol (DNP) and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), BAM15 has a higher binding capacity and stronger activity in mediating proton uncoupling, and effectively promoted mitochondrial fusion, division, autophagy, and the tricarboxylic acid cycle. BAM15 improved hepatic lipid metabolism disorders by enhancing mitochondrial autophagy through activation of the 5'-AMP-activated protein kinase (AMPK) pathway. This indicates that BAM15 could be used to treat liver lipid metabolism issues and offers a solid theoretical foundation for managing lipid-related diseases.