Obesity is a chronic disease characterized by the abnormal or excessive accumulation of body fat, affecting more than 1 billion people worldwide. Obesity is commonly associated with other metabolic disorders, such as type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular diseases, chronic kidney disease, and cancers. Factors such as a sedentary lifestyle, overnutrition, socioeconomic status, and other environmental and genetic conditions can cause obesity. Many molecules and signaling pathways are involved in the pathogenesis of obesity, such as nuclear factor (NF)-κB, Toll-like receptors (TLRs), adhesion molecules, G protein-coupled receptors (GPCRs), programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), and sirtuin 1 (SIRT1). Commonly used strategies of obesity management and treatment include exercise and dietary change or restriction for the early stage of obesity, bariatric surgery for server obesity, and Food and Drug Administration (FDA)-approved medicines such as semaglutide and liraglutide that can be used as monotherapy or as a synergistic treatment. In addition, psychological management, especially for patients with obesity and distress, is a good option. Gut microbiota plays an important role in obesity and its comorbidities, and gut microbial reprogramming by fecal microbiota transplantation (FMT), probiotics, prebiotics, or synbiotics shows promising potential in obesity and metabolic syndrome. Many clinical trials are ongoing to evaluate the therapeutic effects of different treatments. Currently, prevention and early treatment of obesity are the best options to prevent its progression to many comorbidities.

Non-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease with many metabolic comorbidities, such as obesity, diabetes, and cardiovascular diseases. Non-alcoholic steatohepatitis (NASH), an advanced form of NAFLD, accompanies the progression of hepatic steatosis, inflammation, cell death, and varying degree of liver fibrosis. Interferons (IFNs) have been shown to play important roles in the pathogenesis of NAFLD and NASH. Their regulating transcriptional factors such as interferon regulatory factors (IRFs) can regulate IFN expression, as well as genes involved in macrophage polarization, which are implicated in the pathogenesis of NAFLD and advanced liver disease. In this review, the roles of IRF-involved signaling pathways in hepatic inflammation, insulin resistance, and immune cell activation are reviewed. IRFs such as IRF1 and IRF4 are also involved in the polarization of macrophages that contribute to critical roles in NAFLD or NASH pathogenesis. In addition, IRFs have been shown to be regulated by treatments including microRNAs, PPAR modulators, anti-inflammatory agents, and TLR agonists or antagonists. Modulating IRF-mediated factors through these treatments in chronic liver disease can ameliorate the progression of NAFLD to NASH. Furthermore, adenoviruses and CRISPR activation plasmids can also be applied to regulate IRF-mediated effects in chronic liver disease. Pre-clinical and clinical trials for evaluating IRF regulators in NAFLD treatment are essential in the future direction.