{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T02:03:08Z","timestamp":1784167388975,"version":"3.55.0"},"reference-count":30,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources","award":["2060302"],"award-info":[{"award-number":["2060302"]}]},{"name":"Tongren Hospital, Shanghai Jiao Tong University School of Medicine","award":["TR2024RC11"],"award-info":[{"award-number":["TR2024RC11"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objectives: Triptolide (TP), a bioactive diterpenoid from Tripterygium wilfordii Hook. f., has pharmacological activity, but repeated exposure is limited by hepatotoxicity. CYP2E1 is a hepatic metabolic-redox enzyme linked to oxidative liver injury. This study evaluated whether liver-directed Cyp2e1 RNA interference mitigates TP-induced subacute hepatotoxicity without evidence of a marked reduction in short-term systemic TP exposure. Methods:\u00a0Cyp2e1-targeting siRNA was encapsulated in lipid nanoparticles (si-Cyp2e1 LNPs) and validated for hepatic CYP2E1 protein knockdown in female C57BL\/6J mice. Subacute liver injury was induced by oral TP at 800 \u03bcg\/kg\/day for 7 days. Prophylactic and concurrent si-Cyp2e1 regimens were evaluated using serum transaminases, gross liver morphology, H&amp;E histopathology with blinded semi-quantitative scoring, oxidative-stress indices, RNA-seq, RT-qPCR, Western blotting, and exploratory LC-MS\/MS pharmacokinetic analysis. Results: si-Cyp2e1 LNPs showed favorable nanoscale properties and robust hepatic CYP2E1 protein knockdown. Both regimens reduced ALT\/AST elevations, improved gross liver appearance and histological injury scores, decreased hepatic ROS and malondialdehyde, and restored glutathione and superoxide dismutase. Transcriptomic and molecular analyses indicated TP-associated PI3K\/AKT activation and reduced PI3K\/AKT phosphorylation after si-Cyp2e1 treatment. Exploratory pharmacokinetic profiling showed a lower early plasma TP peak, whereas AUC0\u2013t and AUC0\u2013\u221e appeared broadly comparable within the 0\u20133 h observation window. Conclusions: Liver-directed Cyp2e1 silencing provided proof-of-concept hepatoprotection against repeated TP exposure, accompanied by redox recovery and attenuated stress-associated PI3K\/AKT activation. Because CYP2E1 enzymatic activity, TP-derived reactive metabolites, and pathway causality were not directly tested, these findings should be interpreted as pathway-associated evidence requiring further validation.<\/jats:p>","DOI":"10.3390\/ph19071087","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:05:07Z","timestamp":1784163907000},"page":"1087","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Liver-Directed Cyp2e1 RNA Interference Attenuates Hepatotoxicity Induced by Triptolide, a Bioactive Diterpenoid from Tripterygium wilfordii Hook. f."],"prefix":"10.3390","volume":"19","author":[{"given":"Zijin","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Pharmacy, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhao","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyao","family":"Sang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Ouyang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8912-0118","authenticated-orcid":false,"given":"Qian","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia Rd, Shanghai 200336, China"},{"name":"Haihe Laboratory of Cell Ecosystem, 10 Yuexin Rd, Tianjin 300400, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Jiangsu University, Zhenjiang 212013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110651","DOI":"10.1016\/j.cbi.2023.110651","article-title":"Recent advances in the pharmacological applications and liver toxicity of triptolide","volume":"382","author":"Cui","year":"2023","journal-title":"Chem. 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