{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:25:37Z","timestamp":1792200337629,"version":"4.4.0"},"reference-count":130,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101086988"],"award-info":[{"award-number":["101086988"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101212897"],"award-info":[{"award-number":["101212897"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"award":["101086988"],"award-info":[{"award-number":["101086988"]}],"id":[{"id":"https:\/\/ror.org\/0472cxd90","id-type":"ROR","asserted-by":"publisher"}]},{"award":["101212897"],"award-info":[{"award-number":["101212897"]}],"id":[{"id":"https:\/\/ror.org\/0472cxd90","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In plants, miRNAs are involved in environmental responses and can be transferred to other species to mediate cross-kingdom regulation of gene expression. This mechanism has recently been proposed in mammals, yet evidence remains scarce and inconsistent. Multiple studies have shown that a fraction of plant-derived miRNAs (pmiRNAs) present in food resist processing, cooking, and digestion. Evidence suggests that dietary-derived pmiRNAs might be absorbed in the gastrointestinal tract and enter circulation, predominantly packaged in extracellular vesicles, and reach different tissues, where they might exert cross-kingdom gene expression regulation. Nonetheless, several attempts to reproduce or confirm the above results have failed, raising questions about the reliability of studies supporting the hypothesis of cross-kingdom gene regulation by pmiRNAs. In this review, we recapitulate the state-of-the-art knowledge in the field, addressing both supporting and opposing evidence, as well as the main analytical challenges that need to be taken into consideration, in an effort to provide a comprehensive framework on the controversial evidence collected so far and support the use of best practices for future research.<\/jats:p>","DOI":"10.3390\/ijms27104220","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:49:09Z","timestamp":1778572149000},"page":"4220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An Apple a Day? The Hypothesis of Cross-Kingdom Gene Regulation by Plant miRNAs in Mammals and Its Controversies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9625-1191","authenticated-orcid":false,"given":"Rachele","family":"Matsagani","sequence":"first","affiliation":[{"name":"\u2018LETE\u2019 Laboratory of Environmental and Translational Epigenetics, Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"},{"name":"\u2018INES\u2019 Initiative of Epigenetics for Smiles, University of Milan, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Monti","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, \u201cDipartimento di Eccellenza 2023\u20132027\u201d, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-4709","authenticated-orcid":false,"given":"Federica","family":"Rota","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, \u201cDipartimento di Eccellenza 2023\u20132027\u201d, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5675-3389","authenticated-orcid":false,"given":"Eva","family":"Dariol","sequence":"additional","affiliation":[{"name":"\u2018LETE\u2019 Laboratory of Environmental and Translational Epigenetics, Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"},{"name":"\u2018INES\u2019 Initiative of Epigenetics for Smiles, University of Milan, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1202-5873","authenticated-orcid":false,"given":"Elia Mario","family":"Biganzoli","sequence":"additional","affiliation":[{"name":"\u2018LETE\u2019 Laboratory of Environmental and Translational Epigenetics, Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"},{"name":"\u2018INES\u2019 Initiative of Epigenetics for Smiles, University of Milan, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0370-9598","authenticated-orcid":false,"given":"Valentina","family":"Bollati","sequence":"additional","affiliation":[{"name":"\u2018LETE\u2019 Laboratory of Environmental and Translational Epigenetics, Department of Biomedical and Clinical Sciences, University of Milan, 20157 Milan, Italy"},{"name":"\u2018INES\u2019 Initiative of Epigenetics for Smiles, University of Milan, 20157 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.1002\/jcp.27486","article-title":"An overview of microRNAs: Biology, functions, therapeutics, and analysis methods","volume":"234","author":"Saliminejad","year":"2019","journal-title":"J. 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