Abstract
Acetaminophen (APAP) overdose is a leading cause of acute liver injury (AILI). While Prostaglandin E2 (PGE2) protects against various forms of acute hepatitis, its underlying mechanisms and the role of circRNA-mediated regulatory networks in AILI remain to be elucidated. AILI was induced in mice by administration of 500 mg/kg APAP, with or without 16,16-dimethyl PGE2 (dmPGE2) pretreatment. Hepatic transcriptomic landscapes (circRNA, miRNA, and mRNA) were characterized by high-throughput sequencing. The circLima1/miR-486/Ddit4 axis was validated using dual-luciferase assays and hepatocyte-specific AAV8-mediated knockdown. Autophagic flux was monitored via mRFP-EGFP-LC3 tandem reporting, and the functional necessity of autophagy was confirmed using the inhibitor 3-methyladenine (3-MA). dmPGE2 treatment reduced serum transaminases and suppressed hepatic p-JNK activation in APAP-challenged mice. Transcriptomic profiling and qPCR identified Ddit4 as a key responder, which was confirmed in primary hepatocytes. Mechanistically, dmPGE2-induced circLima1 sponges miR-486a/b-3p to upregulate DDIT4, leading to inhibited mTOR phosphorylation and enhanced autophagic flux. AAV-mediated knockdown of circLima1 or Ddit4, as well as pharmacological inhibition of autophagy with 3-MA, abolished the hepatoprotective effects of dmPGE2. dmPGE2 alleviates AILI by activating the circLima1/miR-486/DDIT4 axis to promote protective autophagy. These findings identify the circLima1/DDIT4 pathway as a potential therapeutic target for drug-induced liver injury.
Funding
This work was financially supported by Science and Technology Major Projects of Zhejiang Province (NO. 2018C04016) and National Science and Technology Major Project of China (NO. 2018ZX10302206).
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The animal experiments were approved by the Animal Care and Use Committee of the First Affiliated Hospital of Zhejiang University. The animal studies were conducted according to the ARRIVE guidelines 2.0 (Animal Research: Reporting of In Vivo Experiments). All methods were carried out in accordance with relevant guidelines and regulations. The authors declare that they have not use AI-generated work in this manuscript.
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Chen, C., Guan, J., Wu, S. et al. Prostaglandin E2 alleviates acetaminophen-induced liver injury through DDIT4-enhanced autophagy regulated by circLima1/miR-486. Sci Rep (2026). https://doi.org/10.1038/s41598-026-52049-x
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DOI: https://doi.org/10.1038/s41598-026-52049-x
