The article "The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)" by Buzzetti, Pinzani, and Tsochatzis reviews the complex mechanisms underlying the development and progression of NAFLD. The authors argue that the traditional "two-hit" hypothesis, which posits a single insult leading to liver disease, is inadequate. Instead, they propose a "multiple hit" hypothesis, which considers multiple factors acting together on genetically predisposed individuals to induce NAFLD. Key factors contributing to NAFLD include insulin resistance, hormonal changes from adipose tissue, nutritional factors, gut microbiota, and genetic and epigenetic factors. Insulin resistance, a critical component of NAFLD, leads to increased hepatic de novo lipogenesis and impaired fat oxidation, resulting in increased triglyceride accumulation and lipotoxicity. This, in turn, triggers mitochondrial dysfunction, endoplasmic reticulum stress, and inflammatory responses, all of which contribute to liver inflammation and fibrosis. The gut microbiome plays a crucial role through the gut-liver axis, influencing energy homeostasis and systemic inflammation. Changes in gut microbiota, often seen in obesity and insulin resistance, can lead to increased intestinal permeability and bacterial overgrowth, further exacerbating NAFLD. Genetic variants, such as the PNPLA3 I148M polymorphism, and epigenetic modifications, including DNA methylation and histone modifications, also influence the development and progression of NAFLD. Dietary factors, particularly fructose and specific nutrients, can exacerbate the condition, while certain fats and moderate alcohol consumption may have protective effects. The authors conclude that the pathogenesis of NAFLD is a multifactorial process, and further research is needed to develop non-invasive markers and targeted treatments.The article "The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)" by Buzzetti, Pinzani, and Tsochatzis reviews the complex mechanisms underlying the development and progression of NAFLD. The authors argue that the traditional "two-hit" hypothesis, which posits a single insult leading to liver disease, is inadequate. Instead, they propose a "multiple hit" hypothesis, which considers multiple factors acting together on genetically predisposed individuals to induce NAFLD. Key factors contributing to NAFLD include insulin resistance, hormonal changes from adipose tissue, nutritional factors, gut microbiota, and genetic and epigenetic factors. Insulin resistance, a critical component of NAFLD, leads to increased hepatic de novo lipogenesis and impaired fat oxidation, resulting in increased triglyceride accumulation and lipotoxicity. This, in turn, triggers mitochondrial dysfunction, endoplasmic reticulum stress, and inflammatory responses, all of which contribute to liver inflammation and fibrosis. The gut microbiome plays a crucial role through the gut-liver axis, influencing energy homeostasis and systemic inflammation. Changes in gut microbiota, often seen in obesity and insulin resistance, can lead to increased intestinal permeability and bacterial overgrowth, further exacerbating NAFLD. Genetic variants, such as the PNPLA3 I148M polymorphism, and epigenetic modifications, including DNA methylation and histone modifications, also influence the development and progression of NAFLD. Dietary factors, particularly fructose and specific nutrients, can exacerbate the condition, while certain fats and moderate alcohol consumption may have protective effects. The authors conclude that the pathogenesis of NAFLD is a multifactorial process, and further research is needed to develop non-invasive markers and targeted treatments.