| Title: | Hyperuricemia exacerbates acetaminophen hepatotoxicity via JNK activation and mitophagy reduction |
| Journal: | Biochemical Pharmacology |
| Published: | 30 Oct 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41173055/ |
| DOI: | https://doi.org/10.1016/j.bcp.2025.117487 |
Publication 19116
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Abstract
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.</p>
16 Keywords
- Acetaminophen
- Aged
- Analgesics, Non-Narcotic
- Animals
- Chemical and Drug Induced Liver Injury
- Cohort Studies
- Enzyme Activation
- Female
- Humans
- Hyperuricemia
- JNK Mitogen-Activated Protein Kinases
- MAP Kinase Kinase 4
- Male
- Middle Aged
- Mitophagy
- Rats
14 Authors
- Yan Liu
- Baizhao Peng
- Dexian Li
- Jie Chen
- Yigui Lai
- Yanting You
- Zihao Jiang
- Xinghong Zhou
- Chuanghai Wu
- Liqian Chen
- Hiu Yee Kwan
- Lin Yu
- Daming Zuo
- Xiaoshan Zhao
1 Application
| Application ID | Title |
|---|---|
| 90369 | Analysis of the Dynamic Characteristics of Aging-related Serum Uric Acid in Nervous and Digestive System Disorders with Machine Learning Methods |
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