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This study aims to explore the causal relationship between dietary preferences and NAFLD risk using multi\u2010omics analysis, and to comprehensively explore possible mediating factors and their underlying mechanisms. We analyzed data from genome\u2010wide association studies (GWAS) to assess the potential genetic links between various dietary preferences and NAFLD. A two\u2010step Mendelian randomization (MR) analysis was conducted to evaluate whether dietary preferences affect NAFLD risk by regulating inflammatory factors. Further, co\u2010localization analysis was used to identify gene loci driving the causal relationships between dietary preferences and NAFLD risk. Finally, clinical cross\u2010sectional data from the National Health and Nutrition Examination Survey (NHANES) and bioinformatics analysis were used to validate the findings.MR analysis revealed that a preference for a low\u2010calorie diet significantly reduces NAFLD risk by modulating DNER. Co\u2010localization analysis identified the FTO gene variant rs28429148 as a key driver of the causal relationship between soft cheese and fruit juice preferences, with soft cheese increasing and fruit juice reducing NAFLD risk. These findings were further validated by clinical cross\u2010sectional and bioinformatics analysis. This study, for the first time, comprehensively elucidates the causal relationship between dietary preferences and NAFLD risk from a multi\u2010omics perspective and identifies FTO and DNER as potential therapeutic targets. These findings provide new insights into the importance of personalized dietary interventions in the prevention of NAFLD and informs clinical treatment.<\/jats:p>","DOI":"10.1002\/fsn3.70446","type":"journal-article","created":{"date-parts":[[2025,6,23]],"date-time":"2025-06-23T03:30:22Z","timestamp":1750649422000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Multi\u2010Omics Analysis Reveals Causal Relationships and Potential Mediators Between Dietary Preferences and Risk of\n                    <scp>NAFLD<\/scp>"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7012-9540","authenticated-orcid":false,"given":"Qingan","family":"Fu","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, the Second Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang China"},{"name":"Cardiovascular Medicine Department The Second Affiliated 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Nanchang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3556-3511","authenticated-orcid":false,"given":"Huangxin","family":"Zhu","sequence":"additional","affiliation":[{"name":"Gastroenterology Department The Second Affiliated Hospital of Nanchang University  Nanchang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shisheng","family":"Wu","sequence":"additional","affiliation":[{"name":"Gastroenterology Department The Second Affiliated Hospital of Nanchang University  Nanchang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rixiang","family":"Liu","sequence":"additional","affiliation":[{"name":"Gastroenterology Department The Second Affiliated Hospital of Nanchang University  Nanchang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deju","family":"Zhang","sequence":"additional","affiliation":[{"name":"Food and Nutritional Sciences, School of Biological Sciences The University of Hong Kong  Pokfulam Hong Kong"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Sun Yat\u2010Sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoping","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Neurology Affiliated Hospital of Jiujiang University  Jiujiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0138-6845","authenticated-orcid":false,"given":"Jianping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, the Second Affiliated Hospital, Jiangxi Medical College Nanchang University  Nanchang 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