ABSTRACT Alcohol-associated liver disease (ALD) is a major health problem and can lead to liver failure, liver cancer, and death, incurring enormous healthcare expenditures annually in the US. Few specific treatments are available for patients with ALD. Abstinence is difficult to achieve in many patients and cannot prevent the progression at later stages of ALD. Deciphering molecular mechanisms and identifying novel markers of ALD can lead to new therapeutic avenues and is of substantial interest to public health and welfare. Mitochondria, the central location for alcohol-metabolizing enzymes, are active mediators in response to alcohol toxicity. Mitochondrial alterations induced by alcohol are a hallmark of ALD, which have profound impacts on cell metabolism and associate with activation of inflammation, underlying the pathogenesis of ALD. Pyruvate dehydrogenase kinase 4 (PDK4) inactivates pyruvate dehydrogenase complex (PDC) in the mitochondrial matrix, thus suppressing the conversion of pyruvate to acetyl-CoA. PDK4 maintains mitochondrial homeostasis and has been implicated in the development of non-alcoholic fatty liver disease and apoptotic liver injury. However, little is known about the role of PDK4 in ALD. This proposal is to reveal how PDK4 coordinates mitochondrial dysfunction with activation of inflammation in the face of ethanol-induced liver injury. Our central hypothesis is that loss of PDK4 function impairs alcohol metabolism/detoxification and enhances pro-inflammatory response to promote the development of ALD. We aim to: (1) define the role PDK4 in liver injury in mouse models of ethanol feeding; (2) unravel the molecular mechanisms of PDK4 in ethanol-induced liver injury. Our proposed studies will conceptually and mechanistically reveal the connection between mitochondrial ethanol metabolism and inflammasome activation, which helps to open novel therapeutic avenues for the treatment of ALD. This K01 application will allow the applicant to acquire advanced knowledge and research skills in ALD by integrating interdisciplinary resources. The applicant has assembled an advisory committee composed of outstanding members, including Drs. Laura Nagy (mentor), Srinivasan Dasarathy, and Xiaoxia Li, who are renowned hepatologists or well-recognized scientists in fields of alcohol metabolism, inflammation, mitochondrial biology, gene expression and regulation, immunology, etc., with a formidable record of training junior scientists to be independent and successful in academia. They will direct the applicant's academic career development and provide full support to the implementation of proposed experiments.