Inhibitors of pancreatic lipase have garnered significant interest as promising therapeutic agent candidates for addressing metabolic diseases, especially obesity, type 2 diabetes mellitus, and dyslipidemia. Pancreatic lipase, the principal primary enzyme responsible for triglyceride hydrolysis, is crucial for lipid absorption; hence, its inhibition can noticeably reduce calorie consumption. Despite the clinical efficacy of traditional medications, such as orlistat, their wide use is often restricted due to gastrointestinal side effects. Recent research focusing on natural compounds and synthetic analogues, as well as interconnecting biotechnological approaches such as gene silencing, precise CRISPR-based editing, and beneficial probiotic introducing, is positioned at the forefront of therapeutic innovation. However, clinical translation remains limited by safety concerns, delivery challenges, and variability in patient response. The gut microbiome has been recognized as a significant player in the regulation of pancreatic lipase activity and fat absorption, offering new avenues for developing microbiome-targeted treatments. This review illuminates the physiological function of pancreatic lipase, the clinical significance of its inhibition, and the impact of molecular biology, biotechnology, and microbiome research on the development of targeted emerging therapies for the treatment of metabolic disorders.
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