Oridonin ameliorates acetaminophen‐induced acute liver injury through ATF4/PGC‐1α pathway

Abstract

Acetaminophen (APAP) overdose-induced acute liver injury (ALI) causes hepatocyte cell death, oxidative stress, and inflammation. Oridonin (Ori), a covalent NLRP3inflammasome 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.

Integrating Epigenetics, Proteomics, and Metabolomics to Reveal the Involvement of Wnt/β-Catenin Signaling Pathway in Oridonin-Induced Reproductive Toxicity

“…Oridonin has been found to exert effects across multiple cellular levels [43,53,54]. Numerous investigations have associated oridonin toxicity with the modification of essential biomolecule structure and function through involvement in ROS generation [43,44,55].…”

Crosstalk between Endoplasmic Reticulum Stress and Ferroptosis in Liver Diseases

“…APAP is catalyzed by cytochrome P450 2E1 (CYP2E1) to produce Nacetyl-p-benzoquinoneimine (NAPQI), which is a highly toxic product. An excessive concentration of APAP in vivo increases GSH consumption and NAPQ and ROS levels, and this process leads to ferroptosis and ERS, ultimately leading to hepatocyte death [78,79]. ERS is involved in drug-induced liver damage, and Galpha12 (Gα12) is associated with cell activity.…”