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Silymarin exhibits hepatoprotective properties, but its utility is limited by poor bioavailability. This study evaluated a novel phytosomal silymarin formulation co-administered with piperine and lecithin, compared to fenofibrate, in an oxytetracycline-induced MASLD rat model. Twenty-five male Wistar rats were allocated into five groups: healthy control, MASLD control, fenofibrate (100\u00a0mg\/kg), silymarin (500\u00a0mg\/kg), or silymarin\u2013piperine\u2013lecithin phytocomplex (500\/100\/3\u00a0mg\/kg) for 90\u00a0days. Parameters evaluated included serum liver enzymes, lipid profiles, hepatic histology, and hepatic PPAR-\u03b1 expression. The phytocomplex formulation significantly reduced serum ALT, AST, ALP, and GGT, improved lipid profiles, and restored hepatic architecture, with MASLD-AS and PPAR-\u03b1 expression demonstrating a marked reduction in hepatic injury and oxidative stress. The phytocomplex outperformed both fenofibrate and silymarin alone, likely due to enhanced bioavailability and synergistic antioxidant action comparable to fenofibrate treatment. This study demonstrates the potential of a phytosomal silymarin\u2013piperine\u2013lecithin complex as a natural therapeutic avenue for MASLD, outperforming a conventional lipid-lowering agent in this animal model. Future clinical and pharmacokinetic studies are warranted.<\/jats:p>","DOI":"10.1007\/s00210-025-04752-1","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T04:16:50Z","timestamp":1762402610000},"page":"5559-5574","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting metabolic dysfunction-associated steatotic liver disease with phytosomal silymarin and piperine: A natural alternative to fenofibrate in a rat model"],"prefix":"10.1007","volume":"399","author":[{"given":"Magdy Fouad","family":"Tawfik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin Sayed","family":"Hussein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amany Helmy","family":"Hasanin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walaa","family":"Baher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6646-4674","authenticated-orcid":false,"given":"Nashwa","family":"El-Khazragy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farouk Guindi","family":"Moawad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mawada Abou","family":"El-Khair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwa M.","family":"El-Sayed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"4752_CR1","doi-asserted-by":"publisher","unstructured":"Aghemo A, AO P, Francesco A, BI G, BN V, Dmitry B, Ba O, Do M, Anton G, Ke M, Kn V, Ku A, Ll B, Lm A, Mi V, Ma I, Om F, Se I, Antonina S, Uy P, Ve V, Ye P, Yakovlev AA (2022) Role of silymarin as antioxidant in clinical management of chronic liver diseases: a narrative review. 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