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This narrative review employs a methodological approach utilizing literature searches of PubMed data up to March 2024. The search term criteria encompasses keywords related to the role, mechanism, challenges, and current and future treatments of pancreatic lipase in obesity with an overall references is 106. This paper offers a comprehensive explanation of the role of PL, underlining its significance in the digestive process and lipid imbalances that contribute to obesity and by extension, its impact on obesity development and progression. Additionally, it delves into the dual functionality of the pancreas, emphasizing its impact on metabolism and energy utilization which, when dysregulated, promotes obesity. A focal point of this review is the investigation into the efficacy, challenges, and adverse effects of current pancreatic lipase inhibitors, with orlistat being highlighted as a primary current drug delivery. By discussing advanced obesity treatments, including the exploration of novel anti-obesity medications that target specific biological pathways, this review underscores the complexity of obesity treatment and the necessity for a multifaceted approach. In conclusion, this paper emphasizing the importance of understanding the role of enzymes like pancreatic lipase mechanistic and adopting a multidisciplinary approach to treatment and side effects of current obesity drugs and explore new emerging therapeutic strategies for more effective obesity management.<\/jats:p>","DOI":"10.1038\/s41366-025-01729-1","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T07:52:28Z","timestamp":1740729148000},"page":"492-506","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Role of pancreatic lipase inhibition in obesity treatment: mechanisms and challenges towards current insights and future directions"],"prefix":"10.1038","volume":"49","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9629-9494","authenticated-orcid":false,"given":"Vetriselvan","family":"Subramaniyan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5320-5443","authenticated-orcid":false,"given":"Yusoff Umul","family":"Hanim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"1729_CR1","doi-asserted-by":"publisher","first-page":"615375.","DOI":"10.3389\/fonc.2020.615375","volume":"10","author":"T Scully","year":"2021","unstructured":"Scully T, Ettela A, LeRoith D, Gallagher EJ. 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