{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T13:14:41Z","timestamp":1786713281996,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2024,5,26]],"date-time":"2024-05-26T00:00:00Z","timestamp":1716681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006261","name":"Taif University","doi-asserted-by":"publisher","award":["TU-DSPP-2024-116"],"award-info":[{"award-number":["TU-DSPP-2024-116"]}],"id":[{"id":"10.13039\/501100006261","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Despite being an effective chemotherapeutic agent, the clinical use of doxorubicin (DOX) is limited by several organ toxicities including hepatic injury. Pentoxifylline (PTX) is a methylxanthine derivative with marked anti-inflammatory and anti-apoptotic features. It is unknown, however, whether PTX can mitigate DOX-evoked hepatotoxicity. This study aims to explore the potential hepatoprotective impact of PTX in DOX-induced hepatic injury and the underlying molecular mechanisms. Histopathology, immunohistochemistry, and ELISA were used to examine liver tissues. The current findings revealed that PTX administration to DOX-intoxicated rats mitigated the pathological manifestations of hepatic injury, reduced microscopical damage scores, and improved serum ALT and AST markers, revealing restored hepatic cellular integrity. These favorable effects were attributed to PTX\u2019s ability to mitigate inflammation by reducing hepatic IL-1\u03b2 and TNF-\u03b1 levels and suppressing the pro-inflammatory HMGB1\/TLR4\/NF-\u03baB axis. Moreover, PTX curtailed the hepatic apoptotic abnormalities by suppressing caspase 3 activity and lowering the Bax\/Bcl-2 ratio. In tandem, PTX improved the defective autophagy events by lowering hepatic SQSTM-1\/p62 accumulation and enhancing the AMPK\/mTOR pathway, favoring autophagy and hepatic cell preservation. Together, for the first time, our findings demonstrate the ameliorative effect of PTX against DOX-evoked hepatotoxicity by dampening the hepatic HMGB1\/TLR4\/NF-\u03baB pro-inflammatory axis and augmenting hepatic AMPK\/mTOR-driven autophagy. Thus, PTX could be utilized as an adjunct agent with DOX regimens to mitigate DOX-induced hepatic injury.<\/jats:p>","DOI":"10.3390\/ph17060681","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:14:07Z","timestamp":1716804847000},"page":"681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Activation of AMPK\/mTOR-Driven Autophagy and Suppression of the HMGB1\/TLR4 Pathway with Pentoxifylline Attenuates Doxorubicin-Induced Hepatic Injury in Rats"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4195-6901","authenticated-orcid":false,"given":"Hany H.","family":"Arab","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed H.","family":"Eid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5567-6169","authenticated-orcid":false,"given":"Shuruq E.","family":"Alsufyani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2118-0499","authenticated-orcid":false,"given":"Ahmed M.","family":"Ashour","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alwaleed M.","family":"Alnefaie","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasser M.","family":"Alsharif","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdullah M.","family":"Alshehri","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulmajeed A.","family":"Almalawi","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulmajeed A.","family":"Alsowat","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hayat A.","family":"Abd El Aal","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman S. G.","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wessam H.","family":"Elesawy","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, Giza 12568, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alzahraa A.","family":"Elhemiely","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Egyptian Drug Authority (EDA)\u2014Formerly NODCAR, Giza 12654, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110834","DOI":"10.1016\/j.fct.2019.110834","article-title":"An update on the mechanisms related to cell death and toxicity of doxorubicin and the protective role of nutrients","volume":"134","author":"Battino","year":"2019","journal-title":"Food Chem. 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