{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:33:56Z","timestamp":1770816836896,"version":"3.50.1"},"reference-count":33,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Cholestatic liver injury (CLI) is characterized by complex pathogenesis; however, oxidative stress-mediated inflammatory response due to bile acid accumulation in the liver is considered a primary cause. Cynarin (CN), an artichoke phytochemical, has demonstrated different biological activities, including antioxidant and anti-inflammatory ones. The current study aimed to explore the potential hepatoprotective effect of CN on CLI induced by alpha-naphthyl isothiocyanate (ANIT) in mice and investigate the possible involved mechanisms. Methods: Mice received CN (25 and 50 mg\/kg) for four consecutive days and were challenged with ANIT (75 mg\/kg) once on the second day. Liver injury was examined through biochemical determination of liver injury biomarkers and confirmed by histopathological evaluation. Oxidative stress biomarkers and pro-inflammatory cytokines were detected in the hepatic tissue. RT-PCR, Western blotting, and ELISA were applied to address gene and protein expression of potential underlying molecular targets, including thioredoxin-interacting protein (TXNIP), NLR family pyrin domain-containing 3 (NLRP3) inflammasome, and high-mobility group box 1 (HMGB1). Moreover, nuclear factor kappa-B (NF-\u03baB) activation was determined by immunohistochemical analysis. Results: Our findings revealed that CN remarkably ameliorated ANIT-induced hepatic necro-inflammatory changes and biliary duct injury and restored redox balance in the liver. Mechanistically, CN markedly decreased the expression of TXNIP, NLRP3, active caspase-1, gasdermin D N-terminal (GSDMD-N), interleukin (IL)-1\u03b2, and IL-18, which were elevated upon ANIT administration. Moreover, CN suppressed ANIT-induced expression of HMGB1 and NF-\u03baB. Conclusions: Our findings suggest that CN has a protective effect against ANIT-induced CLI in mice that is associated with modulation of the TXNIP\/NLRP3 and HMGB1\/NF-\u03baB signaling cascades.<\/jats:p>","DOI":"10.3390\/ph19020280","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:41:02Z","timestamp":1770630062000},"page":"280","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatoprotective Effect of Cynarin on Alpha-Naphthyl Isothiocyanate-Induced Cholestatic Liver Injury: Associated Modulation of TXNIP\/NLRP3 and HMGB1\/NF-\u03baB Signaling Cascades"],"prefix":"10.3390","volume":"19","author":[{"given":"Hani M.","family":"Alrawili","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9528-7483","authenticated-orcid":false,"given":"Mahmoud","family":"Elshal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-5378","authenticated-orcid":false,"given":"Marwa S.","family":"Serrya","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7545-6235","authenticated-orcid":false,"given":"Dina S.","family":"El-Agamy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1002\/j.2040-4603.2013.tb00519.x","article-title":"Bile formation and secretion","volume":"3","author":"Boyer","year":"2013","journal-title":"Compr. 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