Orlistat: a comprehensive review of a lipase inhibitor from obesity management to emerging oncological applications.

Orlistat, a potent inhibitor of gastric and pancreatic lipases, has been a cornerstone of pharmacological obesity management for over 2 decades. By reducing dietary fat absorption, it facilitates modest but clinically significant weight loss and helps prevent weight regain when combined with lifestyle interventions. Its use is associated with improvements in a range of obesity-related comorbidities, including enhanced glycemic control, reduced risk of type 2 diabetes progression, and favorable modifications of cardiovascular risk factors such as dyslipidemia. However, its clinical utility is often limited by predictable gastrointestinal adverse effects, which can impact patient adherence. Beyond its established role in weight control, a growing body of preclinical evidence has unveiled Orlistat's off-target activity as an inhibitor of fatty acid synthase (FASN), a key enzyme in de novo lipogenesis that is frequently overexpressed in various cancers. This discovery has spurred investigation into its potential as an anti-neoplastic agent, with studies demonstrating its ability to induce apoptosis, arrest cell cycle progression, and synergize with immunotherapy in cancer models. This review provides a comprehensive analysis of Orlistat, covering its molecular mechanisms, clinical efficacy and safety in diverse populations, impact on metabolic health, and the exciting, yet nascent, evidence for its repurposing in oncology.