TY - JOUR
T1 - Hyperuricemia exacerbates acetaminophen hepatotoxicity via JNK activation and mitophagy reduction
AU - Liu, Yan
AU - Peng, Baizhao
AU - Li, Dexian
AU - Chen, Jie
AU - Lai, Yigui
AU - You, Yanting
AU - Jiang, Zihao
AU - Zhou, Xinghong
AU - Wu, Chuanghai
AU - Chen, Liqian
AU - Kwan, Hiu Yee
AU - Yu, Lin
AU - Zuo, Daming
AU - Zhao, Xiaoshan
N1 - This work was supported by the Joint Funds of National Natural Science Foundation of China (U22A20365), the Key Project of National Natural Science Foundation of China (81830117), the Natural Science Foundation of Guangdong Province, China (2023A1515012429), the Guangzhou Science and Technology Fund (2024B03J1343, 2025A03J3427), the Major scientific and technological project of Guangzhou Municipal Health Commission (20252D003), the Scientific Research Fund of Yangjiang People's Hospital, China (2021002), the Youth Science and Technology Talent Program of the Affiliated Traditional Chinese Medicine Hospital, Guangzhou Medical University (2024SZYRC08).
Publisher Copyright:
© 2025 Elsevier Inc.
PY - 2026/1
Y1 - 2026/1
N2 - Acetaminophen (APAP) induced hepatotoxicity represents a classic form of drug-related liver injury and ranks among the most prevalent causes of acute liver failure globally. Underlying diseases can increase the risk factor of liver injury induced by APAP overdose. Hyperuricemia (HUA), a condition defined by an abnormally high serum uric acid (UA) concentration, is a recognized risk factor for various health conditions, such as gout, cardiovascular disease, metabolic syndrome, and chronic kidney disease. Additionally, HUA is also associated with liver disease, such as non-alcoholic fatty liver and hepatocellular carcinoma. However, the safe dosage of APAP for patients with HUA and the role of HUA in APAP-induced hepatotoxicity remain unclear. This study of a cohort derived from the UK Biobank showed that participants with long-term APAP intake had a 1.26(1.02–1.58) higher odds of developing liver failure than the control group. Importantly, people with HUA had a 1.44(1.12–1.84) higher odds, and those with HUA at baseline had a 1.66(1.06–2.61) higher odds of progressing to liver failure than those with normal UA. Furthermore, our data showed that HUA rats showed more severe hepatic necrosis and liver dysfunction than control rats following APAP injection. Mechanistic investigations revealed that HUA activated c-Jun N-terminal kinase (JNK) and reduced mitophagy to aggravate APAP-induced hepatocyte death. Taken together, this study indicates that HUA is a potential risk factor for APAP-induced hepatic injury, exacerbating hepatic cell death through JNK pathway activation and the suppression of mitophagy. These findings offer important insights for guiding APAP administration in patients with HUA.
AB - Acetaminophen (APAP) induced hepatotoxicity represents a classic form of drug-related liver injury and ranks among the most prevalent causes of acute liver failure globally. Underlying diseases can increase the risk factor of liver injury induced by APAP overdose. Hyperuricemia (HUA), a condition defined by an abnormally high serum uric acid (UA) concentration, is a recognized risk factor for various health conditions, such as gout, cardiovascular disease, metabolic syndrome, and chronic kidney disease. Additionally, HUA is also associated with liver disease, such as non-alcoholic fatty liver and hepatocellular carcinoma. However, the safe dosage of APAP for patients with HUA and the role of HUA in APAP-induced hepatotoxicity remain unclear. This study of a cohort derived from the UK Biobank showed that participants with long-term APAP intake had a 1.26(1.02–1.58) higher odds of developing liver failure than the control group. Importantly, people with HUA had a 1.44(1.12–1.84) higher odds, and those with HUA at baseline had a 1.66(1.06–2.61) higher odds of progressing to liver failure than those with normal UA. Furthermore, our data showed that HUA rats showed more severe hepatic necrosis and liver dysfunction than control rats following APAP injection. Mechanistic investigations revealed that HUA activated c-Jun N-terminal kinase (JNK) and reduced mitophagy to aggravate APAP-induced hepatocyte death. Taken together, this study indicates that HUA is a potential risk factor for APAP-induced hepatic injury, exacerbating hepatic cell death through JNK pathway activation and the suppression of mitophagy. These findings offer important insights for guiding APAP administration in patients with HUA.
KW - Acetaminophen-induced hepatotoxicity
KW - C-Jun N-terminal kinase
KW - Hyperuricemia
KW - Mitophagy
KW - Reactive oxygen species
UR - https://www.scopus.com/pages/publications/105020766857
U2 - 10.1016/j.bcp.2025.117487
DO - 10.1016/j.bcp.2025.117487
M3 - Journal article
C2 - 41173055
AN - SCOPUS:105020766857
SN - 0006-2952
VL - 243, Part 1
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
M1 - 117487
ER -
