Salvianolic Acid C against Acetaminophen-Induced Acute Liver Injury by Attenuating Inflammation, Oxidative Stress, and Apoptosis through Inhibition of the Keap1/Nrf2/HO-1 Signaling

Oxid Med Cell Longev. 2019 May 12:2019:9056845. doi: 10.1155/2019/9056845. eCollection 2019.


Acetaminophen (APAP) overdose is one of the most common causes of drug-induced acute liver failure in humans. To investigate the hepatoprotective effect of salvianolic acid C (SAC) on APAP-induced hepatic damage, SAC was administered by daily intraperitoneal (i.p.) injection for 6 days before the APAP administration in mice. SAC prevented the elevation of serum biochemical parameters and lipid profile including aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (T-Bil), total cholesterol (TC), and triacylglycerol (TG) against acute liver failure. Additionally, SAC reduced the content of malondialdehyde (MDA), the cytochrome P450 2E1 (CYP2E1), and the histopathological alterations and inhibited the production of proinflammatory cytokines in APAP-induced hepatotoxicity. Importantly, SAC effectively diminished APAP-induced liver injury by inhibiting nuclear factor-kappa B (NF-κB), toll-like receptor 4 (TLR4), and mitogen-activated protein kinases (MAPKs) activation signaling pathway. Moreover, SAC enhanced the levels of hepatic activities of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase, and Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in APAP-induced mice. SAC mainly inhibited the activation of apoptotic pathways by reduction of cytochrome c, Bax, and caspase-3 protein expression. Taken together, we provide the molecular evidence that SAC protected the hepatocytes from APAP-induced damage by mitigating mitochondrial oxidative stress, inflammatory response, and caspase-mediated antiapoptotic effect through inhibition of the Keap1/Nrf2/HO-1 signaling axis.

MeSH terms

  • Acetaminophen
  • Alkenes / therapeutic use*
  • Animals
  • Anti-Inflammatory Agents / therapeutic use*
  • Apoptosis
  • Chemical and Drug Induced Liver Injury / drug therapy*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Inflammation / drug therapy*
  • Inflammation Mediators / metabolism
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred ICR
  • NF-E2-Related Factor 2 / metabolism
  • Oxidative Stress
  • Polyphenols / therapeutic use*
  • Salvia miltiorrhiza*
  • Signal Transduction


  • Alkenes
  • Anti-Inflammatory Agents
  • Cytokines
  • Inflammation Mediators
  • Kelch-Like ECH-Associated Protein 1
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Polyphenols
  • Acetaminophen
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • salvianolic acid C