The article discusses the evolution of inflammation in nonalcoholic fatty liver disease (NAFLD), proposing a "multiple parallel hits" hypothesis. This hypothesis suggests that multiple factors, particularly from the gut and adipose tissue, can promote liver inflammation and the progression of NAFLD to nonalcoholic steatohepatitis (NASH). Inflammation can precede steatosis in NASH, and certain dietary factors, gut-derived signals, and adipose tissue-derived signals are highlighted as key contributors. The role of endoplasmic reticulum (ER) stress and the transcription factor XBP1 in regulating these processes is also explored. The article emphasizes the importance of understanding the complex interplay between various biological pathways and the potential for targeted therapies to address the disease.The article discusses the evolution of inflammation in nonalcoholic fatty liver disease (NAFLD), proposing a "multiple parallel hits" hypothesis. This hypothesis suggests that multiple factors, particularly from the gut and adipose tissue, can promote liver inflammation and the progression of NAFLD to nonalcoholic steatohepatitis (NASH). Inflammation can precede steatosis in NASH, and certain dietary factors, gut-derived signals, and adipose tissue-derived signals are highlighted as key contributors. The role of endoplasmic reticulum (ER) stress and the transcription factor XBP1 in regulating these processes is also explored. The article emphasizes the importance of understanding the complex interplay between various biological pathways and the potential for targeted therapies to address the disease.