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Pomegranate polysaccharides (PGPs) show promising anti-tumor activity but have limited bioavailability. Their stability and delivery can be improved using nanostructured systems, such as nanoemulsions (NEs). This study investigated the chemopreventive effect of PGPs and their nanoemulsion (PGPs-NE) against 1,2-dimethylhydrazine (DMH)-induced CRC in rats. Male Wistar rats received subcutaneous DMH injections (20\u00a0mg\/kg) and were orally administered PGPs and PGPs-NE at 200\u00a0mg\/kg body weight for 12 weeks. CRC progression was assessed by measuring tumor burden, mucosal plaque lesions, aberrant crypt foci (ACF), cecal short-chain fatty acids (SCFAs), oxidative stress markers, liver enzymes, inflammatory cytokine (IL-6), matrix metalloproteinase-9 (MMP-9), DNA fragmentation, histological changes, and PCNA expression. DMH significantly decreased antioxidant enzyme activities and SCFA levels while increasing tumor growth, inflammation, DNA damage, and cell proliferation. Both PGPs and PGPs-NE markedly improved these parameters, with PGPs-NE showing greater effectiveness in reducing tumor weight, restoring antioxidant levels, and inhibiting the expression of PCNA, MMP-9, and IL-6. Furthermore, PGPs-NE elevated SCFA levels and promoted goblet cell differentiation, indicating modulation of the microbiota. Molecular docking confirmed strong binding of pectin, the main component of PGPs, with key CRC-related kinases CDK1 and CDK2, suggesting interference with cell cycle regulation. These findings support PGPs-NE as a promising nano-formulated therapy for CRC prevention, targeting oxidative stress, inflammation, metastasis, and proliferation.<\/jats:p>","DOI":"10.1007\/s12032-025-03123-3","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T09:11:32Z","timestamp":1764234692000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nanoemulsion encapsulation enhanced the anti-tumor potency of pomegranate polysaccharides by suppressing oxidative stress, inflammation, and tumor metastasis induced by 1,2-dimethylhydrazine in rats"],"prefix":"10.1007","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4093-0627","authenticated-orcid":false,"given":"Shimaa A.","family":"Sadek","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samah S.","family":"Hoseny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed Mostafa","family":"Fahmy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara Bayoumi","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed A.","family":"Kotb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amel M.","family":"Soliman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohair R.","family":"Fahmy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"3123_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2021.101174","volume":"14","author":"Y Xi","year":"2021","unstructured":"Xi Y, Xu P. 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