{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T01:02:40Z","timestamp":1784509360164,"version":"3.55.0"},"reference-count":44,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"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: Acute liver injury (ALI) is commonly caused by acetaminophen (APAP) overdose, which drives oxidative stress alongside activation of innate immune signaling. Casticin, a naturally occurring flavonoid, has anti-inflammatory and antioxidant properties. Focusing on the toll-like receptor 4 (TLR4)\/myeloid differentiation primary response 88 (MyD88)\/tumor necrosis factor receptor-associated factor 6 (TRAF6)\/nuclear factor kappa B (NF-\u03baB) pathway, this study assessed casticin\u2019s ability to protect mice from APAP-induced hepatotoxicity. Methods: APAP-induced ALI was established in mice randomly assigned to the following six groups: normal control, casticin control, APAP, APAP plus N-acetylcysteine (NAC), APAP plus low-dose casticin, and APAP plus high-dose casticin. Casticin was administered for three consecutive days before APAP to evaluate its preventive rather than therapeutic potential. Biochemical and histological analyses were performed, with molecular assessments using Western blotting, ELISA, quantitative real-time PCR (qPCR), and immunohistochemistry. Results: APAP significantly elevated serum ALT, AST, and ALP and markedly deteriorated hepatic architecture, confirming hepatotoxicity. APAP also induced lipid peroxidation and depleted antioxidant defenses. Hepatic TNF-\u03b1 and IL-6 increased, IL-10 decreased, and the abundance of TLR4, MyD88, TRAF6, and NF-\u03baB p65 was elevated. Casticin reduced these pathway components, lowered TNF-\u03b1 and IL-6, and increased IL-10 dose-dependently, with effects approaching those of NAC. Conclusions: Casticin protected the liver against APAP toxicity, restraining oxidative injury while damping TLR4\/MyD88\/TRAF6\/NF-\u03baB signaling.<\/jats:p>","DOI":"10.3390\/ph19071111","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:47:32Z","timestamp":1784508452000},"page":"1111","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Casticin Alleviates Acetaminophen-Induced Acute Liver Injury by Modulating the TLR4\/MyD88\/TRAF6\/NF-\u03baB Signaling Pathway"],"prefix":"10.3390","volume":"19","author":[{"given":"Salman H.","family":"Alotaibi","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud M.","family":"Samaha","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manar G.","family":"Helal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.4103\/jpbs.jpbs_568_25","article-title":"Drug-Induced Liver Injury: Mechanisms, Diagnosis, and Management: A Review","volume":"17","author":"Keshari","year":"2025","journal-title":"J. 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