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The previous study demonstrates that benzbromarone (BBR), a commonly prescribed pharmaceutical agent for managing gout and hyperuricemia, exacerbates hepatic steatosis and liver injury specifically in obese individuals. However, the precise mechanism underpinning this adverse effect remains incompletely elucidated. Given the significance of BBR and its analogs in anti\u2010gout\/hyperuricemia drug discovery, elucidating the mechanism by which BBR exacerbates obesity\u2010specific DILI warrants further investigation. In this study, through a combined multi\u2010omics, pharmacological, and pharmacokinetic approaches, it is found that BBR\u2010induced obesity\u2010specific DILI is primarily through the potentiation of peroxisome proliferator\u2010activated receptor gamma (PPAR\u03b3) signaling pathways. Further in vivo and in vitro pharmacokinetic analyses reveal that obese db\/db mice exhibited a diminished capacity to metabolize BBR in their livers. 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This study demonstrates that a slow metabolism\u2010driven amplification of hepatic PPAR\u03b3 agonism mediates BBR\u2010induced obesity\u2010specific hepatic steatosis and subsequent DILI, which also emphasizes the importance of the reduced hepatic drug metabolism capacity in patients with obesity or pre\u2010existing NAFLD in both clinical practice and drug discovery processes.<\/jats:p>","DOI":"10.1002\/advs.202409126","type":"journal-article","created":{"date-parts":[[2024,11,29]],"date-time":"2024-11-29T06:42:08Z","timestamp":1732862528000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Slow Metabolism\u2013Driven Amplification of Hepatic PPAR\u03b3 Agonism Mediates Benzbromarone\u2010Induced Obesity\u2010Specific Liver Injury"],"prefix":"10.1002","volume":"12","author":[{"given":"Guanting","family":"Li","sequence":"first","affiliation":[{"name":"The Affiliated Wuxi People's Hospital of Nanjing Medical 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