{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:51:49Z","timestamp":1787791909856,"version":"build-2784847793"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Shenzhen Science and Technology Research and Development Foundation of China","award":["JCYJ20220530154015035"],"award-info":[{"award-number":["JCYJ20220530154015035"]}]},{"name":"Project of Traditional Chinese Medicine Bureau of Guangdong Province","award":["20241217"],"award-info":[{"award-number":["20241217"]}]},{"name":"Bao\u2019an District Medical and Health Research Projects","award":["2022JD049"],"award-info":[{"award-number":["2022JD049"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Chronic kidney disease (CKD) is a progressive medical condition marked by a gradual decline in kidney function, leading to an accumulation of waste products and fluids in the body. Drug-induced liver injury (DILI) poses a significant clinical challenge in CKD management, with paracetamol being a commonly used medication. Advanced oxidation protein products (AOPPs) are biomarkers of CKD progression and contributors to DILI. However, the mechanisms behind the increased incidence of DILI in CKD remain unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We developed an adenine-induced CKD mice model, a paracetamol-induced DILI mice model, and an AOPPs-loaded mice model using intraperitoneal injections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key findings<\/jats:title>\n                    <jats:p>Declining renal function in the CKD model was associated with a significant weight loss and increased the concentration of serum creatinine and blood urea nitrogen. Following paracetamol administration, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), and N-acetyl-p-benzoquinoneimine and liver tissue necrosis increased significantly in CKD groups. In addition, the expression of cytochrome P450 2E1 (CYP2E1) and thrombospondin receptor (CD36) were upregulated, while the adenylate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway showed significant changes in protein expression and phosphorylation. In AOPPs-loaded model, AOPPs upregulated AMPK and Akt protein expression, along with reduced mTOR levels. In HepG2 and L0-2 cell lines, AOPPs and paracetamol significantly increased the protein expression and phosphorylation of AMPK and Akt, alongside a decreased mTOR expression and phosphorylation. AOPPs and paracetamol significantly induced the apoptosis in HepG2 and L0-2 cells. Notably, the expression of CYP2E1 induced by AOPPs and paracetamol was inhibited by dorsomorphin and corynoxine B.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that the AMPK-mTOR signaling pathway mediates the worsening of paracetamol-induced liver injury in CKD, with AOPPs potentially serving as key endogenous factors. This study lays the groundwork for identifying crucial molecules involved in exacerbated paracetamol-induced liver injury in CKD, which may serve as new drug targets and improve the safety profile of paracetamol in patients with CKD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jpp\/rgaf069","type":"journal-article","created":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T12:02:46Z","timestamp":1754049766000},"page":"1663-1675","source":"Crossref","is-referenced-by-count":1,"title":["Advanced oxidation protein products accelerates paracetamol-induced liver injury through AMPK-mTOR signaling pathway in chronic kidney disease"],"prefix":"10.1093","volume":"77","author":[{"given":"Sui","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Pharmacy, Shenzhen Hospital, Southern Medical University , Shenzhen 518101 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Southern Medical University , Shenzhen 518101 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixing","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Neurology, Shenzhen Institute of Translational Medicine, Shenzhen Second People\u2019s Hospital (The First Affiliated Hospital of Shenzhen University) , Shenzhen 518035 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaokang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Longhua District Central Hospital , Shenzhen 518000 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingqian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Shenzhen Hospital, Southern Medical University , Shenzhen 518101 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