Non-alcoholic steatohepatitis: emerging molecular targets and therapeutic strategies

Key Points Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, encompasses a histological spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), the latter of which has varying degrees of fibrosis. NASH can progress to cirrhosis and is projected to be the leading cause of liver transplantation by 2020. There is no approved therapy for NASH. Several pharmacological strategies for NASH treatment, reflecting putative pathogenic mechanisms, are at the preclinical or early clinical stages of development, and include the modulation of nuclear transcription factors, reversal of lipotoxicity and oxidative stress, and modulation of cellular energy homeostasis and metabolism. In parallel to these metabolic approaches, there is increasing evidence that numerous noxae that initiate liver disease converge to common, stereotyped patterns of injury, inflammation and fibrogenesis in NASH. Molecular mechanisms mediating cell injury and inflammation are also targeted by experimental therapies, including modulation of the inflammasome, chemokines and eicosanoids. An important advance in our knowledge of liver diseases is the understanding that the most advanced stages of fibrosis (and even cirrhosis itself) are part of a dynamic process that may regress if the underlying fibrogenic stimuli are corrected. On this basis, several therapeutic strategies targeting key pathogenic mechanisms involved in fibrogenesis are being evaluated, including inhibitors of galectin 3, leukotrienes, caspases, Hedgehog signalling and lysyl oxidase-like 2 (LOXL2). Collectively, these promising pharmacological strategies may become the armamentarium for an individualized treatment of NASH, targeting the predominant pathogenic mechanisms that operate in each patient and at each stage of disease. Future randomized trials — of adequate power and duration, and with appropriate clinical outcomes — are needed to assess the long-term effectiveness and safety of each pharmacological option. Non-alcoholic steatohepatitis (NASH) is increasing in prevalence, partially because of the pervasiveness of obesity. In this Review, Musso and colleagues discuss potential future approaches to treat this disease, including those that target causes, such as inflammation and aberrant metabolism, as well as those that target fibrosis, one of the key features of patients with NASH. Non-alcoholic fatty liver disease — the most common chronic liver disease — encompasses a