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We categorize fish oil formulations along a therapeutic gradient from nutritional maintenance to targeted intervention, with molecular structure stratification based on bioavailability and safety profiles. NFO retains natural triglyceride structures with superior absorption kinetics but lower \u03c9\u20103 polyunsaturated fatty acid (PUFA) purity, positioning it for maintenance nutritional supplementation. PFO, through advanced purification, achieves higher purity in ethyl esters (EEs), free fatty acids (FFAs), and re\u2010esterified triglycerides (rTG) forms. The rTG structure uniquely combines high purity with enhanced bioavailability, bridging the gap between NFO and conventional PFO. Within the PFO category, our framework distinguishes eicosapentaenoic acid ethyl ester (EPA\u2010EE) as the evidence\u2010based choice for atherosclerotic cardiovascular disease (ASCVD) risk reduction, combinations of EPA and docosahexaenoic acid (EPA\/DHA) as neutral for cardiovascular outcomes, and rTG as the bioavailable alternative for enteral therapeutic applications. For parenteral nutrition, PFO\u2010based lipid emulsions provide formulation and operational advantages. In summary, this framework identifies a fundamental trade\u2010off between natural matrix preservation (NFO) and purity\/bioavailability optimization (PFO). PFO, particularly high\u2010purity EPA\u2010EE formulations, demonstrates established efficacy in cardiovascular risk reduction, while rTG offers superior bioavailability with comparable clinical promise; both PFO formulations show advantages in parenteral nutrition. High\u2010dose \u03c9\u20103 formulations, regardless of EPA monotherapy or EPA\/DHA combination, carry a dose\u2010dependent atrial fibrillation risk that warrants age\u2010stratified assessment. NFO remains preferable for general nutritional supplementation given its favorable tolerability and preservation of natural antioxidants. Selection between NFO and PFO should be guided by clinical indication, required dosage, and arrhythmia risk stratification.<\/jats:p>","DOI":"10.1155\/jnme\/5029849","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:09:37Z","timestamp":1792069777000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Natural Fish Oil Versus Purified Fish Oil: Composition, Efficacy, and Applications"],"prefix":"10.1155","volume":"2026","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3237-2833","authenticated-orcid":false,"given":"Jingxu","family":"Nie","sequence":"first","affiliation":[{"name":"Department of Pharmacy Shanxi Province Cancer Hospital Shanxi Hospital Affiliated to Cancer Hospital Cancer Hospital Affiliated to Shanxi Medical University Chinese Academy of Medical Sciences  Taiyuan Shanxi China  cacms.ac.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9712-5657","authenticated-orcid":false,"given":"Linlin","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Cancer Center National Clinical Research Center for Cancer Cancer Hospital Peking Union Medical College Chinese Academy of Medical Sciences  Beijing China  cacms.ac.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4016-5894","authenticated-orcid":false,"given":"Juan","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanxi Province Cancer Hospital Shanxi Hospital Affiliated to Cancer Hospital Cancer Hospital Affiliated to Shanxi Medical University Chinese Academy of Medical Sciences  Taiyuan Shanxi China  cacms.ac.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8975-3919","authenticated-orcid":false,"given":"Weihua","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy National Cancer Center National Clinical Research Center for Cancer Cancer Hospital Peking Union Medical College Chinese Academy of Medical Sciences  Beijing China  cacms.ac.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5547-1083","authenticated-orcid":false,"given":"Jun","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanxi Province Cancer Hospital Shanxi Hospital Affiliated to Cancer Hospital Cancer Hospital Affiliated to Shanxi Medical University Chinese Academy of Medical Sciences  Taiyuan Shanxi China  cacms.ac.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2567-5552","authenticated-orcid":false,"given":"Lianzhen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Shanxi Province Cancer Hospital Shanxi Hospital Affiliated to Cancer Hospital Cancer Hospital Affiliated to Shanxi Medical University Chinese Academy of Medical Sciences  Taiyuan Shanxi China  cacms.ac.cn"},{"name":"Department of Pharmacy National Cancer Center National Clinical Research Center for Cancer Cancer Hospital Peking Union Medical College Chinese Academy of Medical Sciences  Beijing China  cacms.ac.cn"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,15]]},"reference":[{"key":"e_1_2_10_1_2","doi-asserted-by":"publisher","DOI":"10.5551\/jat.50658"},{"key":"e_1_2_10_2_2","doi-asserted-by":"crossref","DOI":"10.4010\/jln.28.25","article-title":"Omega-3 Polyunsaturated Fatty Acids in Prevention for Cardiovascular Disease: Its Molecular Mechanism and Recent Large-Scale Clinical Studies","author":"Tatsuno I.","year":"2019","journal-title":"Journal of Lipid Nutrition"},{"key":"e_1_2_10_3_2","doi-asserted-by":"publisher","DOI":"10.1080\/10408398.2018.1425978"},{"key":"e_1_2_10_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2014.04.007"},{"key":"e_1_2_10_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2021.130874"},{"key":"e_1_2_10_6_2","doi-asserted-by":"publisher","DOI":"10.5650\/jos1996.48.1017"},{"key":"e_1_2_10_7_2","first-page":"199","article-title":"Beneficial Effects of Fish Oil to Human Health: A Review","volume":"30","author":"Das S. 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