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The spleen could be considered a neglected organ. To date, it has been deemed an ancillary organ in portal hypertension or an organ localization in lymphoproliferative diseases, even though it has had significant attention in infectious diseases for some time. Now, it is thought to be central in regulating the immune system, a metabolic asset and involved in endocrine function with regard to nonalcoholic fatty liver disease. The main mechanisms involved in this complex network will be critically discussed in this article.