Nonalcoholic fatty liver disease (NAFLD) has emerged as the leading cause of chronic liver disease, and it is estimated to affect more than 25% of the global population. NAFLD contains a broad spectrum of disorders, from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), the latter of which may progress to liver fibrosis, liver cirrhosis, and even hepatocellular carcinoma (HCC). NAFLD is strongly associated with obesity, metabolic syndrome, diabetes mellitus, and hypertension. A two-hit hypothesis was initially proposed to explain the progression from NAFLD to NASH: the first hit is hepatic triglyceride accumulation and insulin resistance, and the second hit includes adipokines, inflammatory cytokines, oxidative stress, and mitochondrial dysfunction. Although numerous studies have supported this hypothesis, a multiple-hit model, which better explains NASH development, has become the most widely accepted theory.

Previous studies have shown that genetic, epigenetic, environmental, metabolic, and gut microbial factors may all contribute to the progression of fibrosis in NAFLD. It has been reported that the prevalence of NAFLD can vary between populations, being most common in Latin America and the Middle East, as well as being more prevalent in males. These differences may be due to the interplay between genetic, environmental, and behavioral factors. Genome-wide association studies (GWAS) have provided an approach for identifying genetic susceptibility to NAFLD. Variation in some genes, including patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, apolipoprotein B (APOB), and glucokinase regulator (GCKR) rs1260326 has been found to increase the risk of NAFLD. Non-coding RNAs, DNA methylation, and chromatin remodeling are also involved in the development of NAFLD. However, the molecular mechanisms are not fully understood. Liver biopsy is considered as the gold standard for the diagnosis and evaluation of liver fibrosis in NAFLD, but it may result in severe complications. Noninvasive methods, including aspartate transaminase (AST)/alanine transaminase (ALT) ratio, AST/platelet ratio index (APRI), fibrosis-4 index (FIB-4), NAFLD fibrosis score (NFS), BARD score, and elastography have been proposed for evaluating liver fibrosis, the strongest histological predictor of liver-related prognosis and mortality in NAFLD. However, the effectiveness of these noninvasive methods needs to be further explored.

The aim of this Special Issue is to invite authors to submit original research, clinical studies, and reviews regarding the pathogenesis of NAFLD, and on the development of noninvasive methods for assessing NAFLD.

Potential topics include but are not limited to the following:

• The epidemiology and health burden of patients with NAFLD
• Molecular mechanisms of NAFLD
• Noninvasive tools, including serum biomarkers, and techniques for the diagnosis and evaluation of NAFLD
• Assessment of obesity, metabolic syndrome, diabetes mellitus, and hypertension in NAFLD