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Hypertriglyceridemia is characterized by elevated triglyceride levels in the blood, which increases the risk of cardiovascular disease and pancreatitis. This condition stems from multiple factors including lifestyle choices, genetics, and conditions such as diabetes and metabolic syndrome. Apolipoprotein C-III (APOC3), a protein for lipid metabolism, hinders enzymes necessary for breaking down triglycerides and thus plays a key role in hypertriglyceridemia. Variations in the APOC3 gene are associated with varying triglyceride levels among individuals. Recent genetic studies and clinical trials have shed light on the potential of targeting APOC3 as a potentially promising therapeutic modality of hypertriglyceridemia. Antisense oligonucleotides like volanesorsen have displayed effectiveness in lowering triglyceride levels in individuals with severe hypertriglyceridemia. This review article delves into how APOC3 influences triglyceride control and its potential use in targeting APOC3 to manage severe hypertriglyceridemia., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Shah et al.)