Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally, affecting up to 25% of the population. It is characterized by hepatic steatosis, which results from an imbalance between lipid uptake and disposal. The liver regulates lipid homeostasis through four major pathways: fatty acid uptake, de novo lipogenesis (DNL), fatty acid oxidation (FAO), and lipid export. In NAFLD, increased lipid uptake and DNL, combined with insufficient FAO and lipid export, lead to lipid accumulation and progression to non-alcoholic steatohepatitis (NASH), which involves inflammation, hepatocyte damage, and fibrosis. The disease is associated with increased mortality and is linked to various lifestyle-related diseases. Lipid accumulation in NAFLD is influenced by factors such as fatty acid transporters (e.g., FATP2, FATP5, CD36), which facilitate lipid uptake. Increased expression of these proteins is associated with NAFLD, while genetic variations may contribute to disease progression. DNL is enhanced in NAFLD, contributing to lipid accumulation, and is regulated by transcription factors such as SREBP1c and ChREBP. However, impaired FAO and lipid export, along with mitochondrial dysfunction, lead to oxidative stress and further liver damage. Lipid export is crucial for maintaining lipid homeostasis, but it plateaus or decreases in NAFLD, exacerbating lipid accumulation. The liver's ability to export lipids is mediated by VLDL particles, which are formed in the endoplasmic reticulum and require apoB100 and MTTP for secretion. Impaired lipid export in NAFLD is linked to reduced MTTP and apoB100 levels, contributing to disease progression. Current treatments for NAFLD are limited, and no approved pharmacological therapies exist. Pre-clinical models, such as dietary and genetic models, are used to study NAFLD, but they often fail to fully replicate human disease. Clinical trials have shown some efficacy of drugs like vitamin E, pioglitazone, and obeticholic acid in improving NASH and fibrosis, but adverse effects limit their use. Lifestyle interventions, including weight loss, are effective but challenging to maintain. In conclusion, NAFLD is a complex disease involving multiple pathways, and interventions targeting lipid metabolism, inflammation, or fibrosis may be beneficial. However, the heterogeneity of NAFLD and the interplay between different pathways make it challenging to develop effective treatments. Future research should focus on understanding the molecular mechanisms underlying NAFLD and developing targeted therapies.Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally, affecting up to 25% of the population. It is characterized by hepatic steatosis, which results from an imbalance between lipid uptake and disposal. The liver regulates lipid homeostasis through four major pathways: fatty acid uptake, de novo lipogenesis (DNL), fatty acid oxidation (FAO), and lipid export. In NAFLD, increased lipid uptake and DNL, combined with insufficient FAO and lipid export, lead to lipid accumulation and progression to non-alcoholic steatohepatitis (NASH), which involves inflammation, hepatocyte damage, and fibrosis. The disease is associated with increased mortality and is linked to various lifestyle-related diseases. Lipid accumulation in NAFLD is influenced by factors such as fatty acid transporters (e.g., FATP2, FATP5, CD36), which facilitate lipid uptake. Increased expression of these proteins is associated with NAFLD, while genetic variations may contribute to disease progression. DNL is enhanced in NAFLD, contributing to lipid accumulation, and is regulated by transcription factors such as SREBP1c and ChREBP. However, impaired FAO and lipid export, along with mitochondrial dysfunction, lead to oxidative stress and further liver damage. Lipid export is crucial for maintaining lipid homeostasis, but it plateaus or decreases in NAFLD, exacerbating lipid accumulation. The liver's ability to export lipids is mediated by VLDL particles, which are formed in the endoplasmic reticulum and require apoB100 and MTTP for secretion. Impaired lipid export in NAFLD is linked to reduced MTTP and apoB100 levels, contributing to disease progression. Current treatments for NAFLD are limited, and no approved pharmacological therapies exist. Pre-clinical models, such as dietary and genetic models, are used to study NAFLD, but they often fail to fully replicate human disease. Clinical trials have shown some efficacy of drugs like vitamin E, pioglitazone, and obeticholic acid in improving NASH and fibrosis, but adverse effects limit their use. Lifestyle interventions, including weight loss, are effective but challenging to maintain. In conclusion, NAFLD is a complex disease involving multiple pathways, and interventions targeting lipid metabolism, inflammation, or fibrosis may be beneficial. However, the heterogeneity of NAFLD and the interplay between different pathways make it challenging to develop effective treatments. Future research should focus on understanding the molecular mechanisms underlying NAFLD and developing targeted therapies.