Zayed, Ahmed Salem, Mohamed ANegm, Walaa AEzzat, Shahira M2023-05-262023-05-262023-05https://doi.org/10.1007/s43450-023-00403-9http://repository.msa.edu.eg/xmlui/handle/123456789/5584Fever is a complicated process that occurs in response to infection and infammatory diseases, stimulating the immune system that may cause severe biological changes in the human body. Hence, anti-pyretic agents are prescribed to reduce elevated body temperature in order to maintain thermal homeostasis and protect the brain from damage. Additionally, there is always a growing need for safe and efective anti-pyretic drugs derived from natural products, especially that anti-pyretic pathways have been investigated well in previous literature. Many animal models are established for assessing anti-pyretic candidates resulting in two types of anti-pyretics. They are the endogenous anti-pyretics that act as a defense mechanism for temperature regulation and the exogenous anti-pyretics. The current article discusses the main anti-pyretic pathways, models for assessing anti-pyretics, metabolomics applications in anti-pyretic assays, and screening of anti-pyretic and analgesic natural products. Screening of plant-derived natural products and active principles with anti-pyretic, anti-infammatory, and analgesic activities, in addition to their mechanism of action and validation methods, is described in the current article. Hence, this review could contribute to the introduction of a site-specifc and safe naturally derived anti-pyretic medications with potential therapeutic qualities compared to currently available synthetic anti-pyretics.en-USAnimal models ·Anti-pyretic pathways ·Fever ·Metabolomics ·Plant sources ·Active principles ·ValidationArticlehttps://doi.org/10.1007/s43450-023-00403-9