Scholarlink

<p>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&#xa0;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 <i>circLima1</i>/<i>miR-486</i>/<i>Ddit4</i> 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 <i>Ddit4</i> 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 <i>circLima1</i> or <i>Ddit4</i>, as well as pharmacological inhibition of autophagy with 3-MA, abolished the hepatoprotective effects of dmPGE2. dmPGE2 alleviates AILI by activating the <i>circLima1</i>/<i>miR-486</i>/DDIT4 axis to promote protective autophagy. These findings identify the <i>circLima1</i>/DDIT4 pathway as a potential therapeutic target for drug-induced liver injury.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Prostaglandin E2 alleviates acetaminophen-induced liver injury through DDIT4-enhanced autophagy regulated by circLima1/miR-486

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月6日

查看全文
  • Chao Chen,
  • Jun Guan,
  • Shanshan Wu,
  • Meng Hong,
  • Yanli Ren,
  • Guodi Wu,
  • Jing Wang,
  • Xinyu Gu,
  • Zhi Chen,
  • Haihong Zhu

摘要

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.