{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T03:07:27Z","timestamp":1793156847720,"version":"4.5.0"},"reference-count":76,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Imam Mohammad ibn Saud Islamic University","award":["IMSIU-DDRSP2601"],"award-info":[{"award-number":["IMSIU-DDRSP2601"]}]},{"award":["IMSIU-DDRSP2601"],"award-info":[{"award-number":["IMSIU-DDRSP2601"]}],"id":[{"id":"https:\/\/ror.org\/05gxjyb39","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing global health burden, yet no approved pharmacological therapy currently exists. Purpose: The purpose of this study is to investigate the prophylactic and therapeutic potential of Rebamipide, a mucosal-protective and anti-inflammatory drug, in a high-fat diet (MHFD)-induced MASLD rat model, integrating quantitative liver proteomics, network analysis, and histopathology. Methods: Male Wistar rats were fed MHFD for 16 weeks and treated with Rebamipide either prophylactically (Reb T1, co-administered with diet) or therapeutically (Reb T2, administered post-NASH onset). Label-free LC-MS\/MS proteomics combined with principal component analysis (PCA), partial squares discriminant analysis (PLS-DA), and enrichment analyses (including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome via g: Profiler, network mapping, and Rat Genome Database (RGD) mining) revealed that MHFD had the following impacts: it induced the profound suppression of mitochondrial chaperones (Hspa9), microsomal triglyceride transfer protein (Mttp), and cytochrome P450 isoforms (Cyp2c6); it disrupted lipid trafficking, oxidative stress defense, and xenobiotic metabolism. Results: Rebamipide prophylaxis preserved lipid-handling proteins, prevented glycogen loss, and maintained antioxidant defenses. In contrast, therapeutic administration reversed established steatosis and remodeled metabolic pathways, enhancing fatty acid \u03b2-oxidation, detoxification, and mitochondrial protein import. Nine shared proteins across all comparisons, including MTTP and multiple Stress-70 mitochondrial isoforms, mapped to three core genes (Mttp, Cyp2c6, Hspa9) central to lipid transport, protein import, and metabolic stress adaptation. KEGG and Reactome analyses highlighted Rebamipide\u2019s modulation of bile acid synthesis, ceramide and phosphatidylcholine metabolism, lipoprotein remodeling, and MAPK signaling. Histopathological evaluation confirmed Rebamipide\u2019s efficacy, showing reduced steatosis and the normalization of the hepatocyte structure, with near-complete restoration in the therapeutic (Reb T2) group compared to partial protection in the Reb T1 group. Conclusions: These findings demonstrate Rebamipide\u2019s dual-phase, multi-targeted mechanism: early protection against diet-induced metabolic injury and robust reversal of established MASLD pathology. The identified protein triad (Mttp, Cyp2c6, Hspa9) and associated pathways provide novel biomarker candidates and mechanistic insight supporting Rebamipide\u2019s repurposing as a therapeutic for metabolic liver disease.<\/jats:p>","DOI":"10.3390\/ph19040559","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:26:12Z","timestamp":1775121972000},"page":"559","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rebamipide Reprograms Hepatic Networks to Prevent and Reverse Metabolic-Dysfunction-Associated Steatotic Liver Disease: Multi-Omics Insights and Histological Validation"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6754-5045","authenticated-orcid":false,"given":"Hebatallah H.","family":"Abo Nahas","sequence":"first","affiliation":[{"name":"Zoology Department, Faculty of Science, Port Said University, Port Said 42526, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3193-7328","authenticated-orcid":false,"given":"Abdullah","family":"Al-Dakhil","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doaa I.","family":"Mohamed","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3039-7646","authenticated-orcid":false,"given":"Tarek A.","family":"Yousef","sequence":"additional","affiliation":[{"name":"Chemistry Department, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9056-0228","authenticated-orcid":false,"given":"Ali H. Abu","family":"Almaaty","sequence":"additional","affiliation":[{"name":"Zoology Department, Faculty of Science, Port Said University, Port Said 42526, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibrahium M.","family":"El-Deen","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Port Said University, Port Said 42526, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0204-2696","authenticated-orcid":false,"given":"Hatem Adel M.","family":"Sembawa","sequence":"additional","affiliation":[{"name":"Department of General Surgery, Faculty of Medicine, Umm Al-Qura University, Makkah 24382, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7342-6200","authenticated-orcid":false,"given":"Essa M.","family":"Saied","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt"},{"name":"Institute for Chemistry, Humboldt Universit\u00e4t zu Berlin, 12489 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/s41598-024-84564-0","article-title":"Abnormal ac4C Modification in Metabolic Dysfunction Associated Steatotic Liver Cells","volume":"15","author":"Zhang","year":"2025","journal-title":"Sci. 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