{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T18:12:41Z","timestamp":1788545561005,"version":"build-2803163510"},"reference-count":86,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Plant-derived bioactive peptides are widely investigated for their effects on intestinal epithelial function using Caco-2 cells, with reported antioxidant, anti-inflammatory, antihypertensive and antidiabetic activities. However, this literature remains heterogeneous and has rarely addressed whether the tested material corresponds to the actual bioactive species. This PRISMA-compliant systematic review searched PubMed and Scopus for studies on plant-derived peptides, hydrolysates or digests in Caco-2 cells, identifying 34 eligible studies. The material tested in each study was classified a priori as a purified or synthetic single peptide, an ultrafiltration or chromatographic fraction, a whole hydrolysate or gastrointestinal digest, or an intact parent protein used as a comparator, because these forms do not support equivalent structure\u2013activity inference. Risk of bias was assessed using the QUIN tool, adopted in the absence of an instrument validated for nutritional cell-culture research. For each study, metabolic characterisation of the tested peptide and the physiological relevance of the concentrations used were evaluated. Directionally consistent bioactivity, including antioxidant, anti-inflammatory, antihypertensive and antidiabetic effects, was observed across most functional domains, although effect magnitude and stress dependence varied considerably. Mass-based concentrations did not uniformly exceed a conservative exploratory luminal benchmark (0.1\u20131 mg\/mL), but upper-range experiments exceeded it by approximately 25-fold in the antioxidant domain, 50-fold in the anti-inflammatory and antidiabetic domains, and 500-fold in the viability domain; in vivo confirmation was available for a single identified metabolite (LTFPG). Because the primary studies did not report effect estimates with measures of precision, the synthesis is qualitative, based on vote counting by direction of effect, and no pooled effect sizes, heterogeneity statistics or certainty ratings were derived. Overall, plant-derived peptides show directionally consistent bioactivity in Caco-2 models, but the evidence rarely identifies the responsible molecular species or confirms physiological attainability. Future work should prioritise metabolic characterisation, exposure-justified concentrations, and multi-omics approaches to clarify underlying mechanisms.<\/jats:p>","DOI":"10.3390\/ijms27177905","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T17:25:56Z","timestamp":1788542756000},"page":"7905","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Biological Activity of Plant-Derived Peptides, Hydrolysates and Digests in the Caco-2 Intestinal Epithelial Model: A Systematic Critical Review"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2720-1473","authenticated-orcid":false,"given":"Simone","family":"Perna","sequence":"first","affiliation":[{"name":"Department of Food, Environmental and Nutritional Sciences (DeFENS), Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8219-0191","authenticated-orcid":false,"given":"Mattia","family":"Di Nunzio","sequence":"additional","affiliation":[{"name":"Department of Food, Environmental and Nutritional Sciences (DeFENS), Universit\u00e0 degli Studi di Milano, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"103403","DOI":"10.1016\/j.dsx.2026.103403","article-title":"Recent evidence on plant-based diets and risk of chronic noncommunicable diseases in adults: A systematic review and meta-analysis","volume":"20","author":"Moreira","year":"2026","journal-title":"Diabetes Metab. 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