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However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid\u2014a monounsaturated fatty acid (MUFA) typically associated with good health\u2014markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFA) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA\/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA\/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential \u201cprecision nutrition\u201d strategies for PDAC prevention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>This study reveals that dietary unsaturated fatty acids divergently influence pancreatic cancer progression by incorporating into tissue phospholipids to modulate ferroptosis sensitivity. Dietary MUFAs promote tumorigenesis, whereas PUFAs confer protection. These findings suggest that alterations in dietary fat intake could affect cancer risk.<\/jats:p>\n                    <jats:p>See related commentary by Jeong and Lien, p. 1961<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0734","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T14:01:10Z","timestamp":1777471270000},"page":"2108-2129","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Diet-Induced Phospholipid Remodeling Dictates Ferroptosis Sensitivity and Tumorigenesis in the Pancreas"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1470-8061","authenticated-orcid":false,"given":"Christian Felipe","family":"Ruiz","sequence":"first","affiliation":[{"name":"1Department of Genetics, Yale University School of Medicine, New Haven, 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