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Oridonin ameliorates acetaminophen-induced acute liver injury through ATF4/PGC-1α pathway
Dongsheng Yu1, Jiye Li2,3, Yu Wang1
1Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Acetaminophen (APAP) overdose-induced acute liver injury (ALI) causes hepatocyte cell death, oxidative stress, and inflammation. Oridonin (Ori), a covalent NLRP3-inflammasome inhibitor, ameliorates APAP-induced ALI through an unclear molecular mechanism. This study found that Ori decreased hepatic cytochrome P450 2E1 level and increased glutathione content to prevent APAP metabolism, and then reduced the necrotic area, improved liver function, and inhibited APAP-induced proinflammatory cytokines and oxidative stress. Ori also decreased activating transcription factor 4 (ATF4) protein levels and increased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) to reduce APAP-induced endoplasmic reticulum stress activation and mitochondrial dysfunction. Furthermore, western blot and luciferase assay found that ATF4 inhibited transcription in the PGC-1α promoter -507 to -495 region to reduce PGC-1α levels, while ATF4 knockdown neutralized the hepatoprotective effect of Ori. Molecular docking showed that Ori bound to ATF4's amino acid residue glutamate 302 through 6, 7, and 18 hydroxyl bands. Our findings demonstrated that Ori prevented metabolic activation of APAP and further inhibited the ATF4/PGC-1α pathway to alleviate APAP overdose-induced hepatic toxicity, which illuminated its potential therapeutic effects on ALI.
Insights
Oridonin protects against acetaminophen overdose-induced liver injury by reducing toxic metabolism and inhibiting the ATF4/PGC-1α pathway. This study reveals a novel mechanism for treating acute liver injury (ALI).
Area of Science:
- Hepatology
- Toxicology
- Molecular Pharmacology
Background:
- Acetaminophen (APAP) overdose causes acute liver injury (ALI) via hepatocyte death, oxidative stress, and inflammation.
- Oridonin (Ori), an NLRP3-inflammasome inhibitor, shows promise in ameliorating APAP-induced ALI, but its molecular mechanisms are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Oridonin (Ori) protects against acetaminophen (APAP)-induced acute liver injury (ALI).
Main Methods:
- Investigated Ori's effects on APAP metabolism, oxidative stress, inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction in APAP-induced ALI models.
- Utilized western blot and luciferase assays to analyze the ATF4/PGC-1α pathway.
- Performed molecular docking to identify the binding interaction between Ori and ATF4.
Main Results:
- Ori decreased hepatic cytochrome P450 2E1, increased glutathione, and reduced APAP metabolism.
- Ori ameliorated liver damage, improved liver function, and reduced oxidative stress and inflammation.
- Ori inhibited the ATF4/PGC-1α pathway by decreasing ATF4 protein levels and enhancing PGC-1α expression, thereby reducing endoplasmic reticulum stress and mitochondrial dysfunction.
- Molecular docking revealed Ori binds to ATF4 at glutamate 302.
Conclusions:
- Oridonin (Ori) exerts hepatoprotective effects against APAP overdose by preventing metabolic activation of APAP and inhibiting the ATF4/PGC-1α pathway.
- Ori's inhibition of the ATF4/PGC-1α pathway alleviates APAP-induced hepatic toxicity, highlighting its therapeutic potential for ALI.
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