Gambogic acid ameliorates hepatocellular carcinoma by inhibiting oxidative stress via Nrf2-pSmad2C/2L pathway

Gambogic acid (GA), a natural active ingredient extracted from gamboge resin, has traditionally been utilized for liver-related diseases. Prior investigations have confirmed that GA holds remarkable efficacy in mitigating inflammatory response through the Nrf2 signaling pathway; also, Nrf2 acts synergistically with TGF-β₁/Smad2 in hepatocarcinogenesis. However, scientific evidence concerning how GA modulates the TGF-β₁/Smad2 and Nrf2/HO-1 signaling pathways and even Nrf2 inhibition on Smad2C/2L phosphorylation relates to the hepatoprotective ability of GA on oxidative stress remains opaque. Nowadays, DEN/CCl₄/C₂H₅OH (DCC) induced HCC in mice, and TGF-β₁ and/or Nrf2 inhibitor stimulated HepG2 cells were generated to settle the above questions. As it turns out, GA significantly inhibited the occurrence and progression of liver cancer, as reflected by amelioration in liver biopsies, liver function, and histopathology; while also markedly reducing tumor incidence and multiplicity. It had a notable effect on the activation of Nrf2/AREs-related proteins and inhibition on pSmad2C/2L expression. Cell experiments further confirmed that Nrf2 and pSmad2C/2L may simultaneously participate in the anti-HCC effect of GA, and the Nrf2 inhibitor ML385 could abate GA's anti-HCC effect on proliferation, migration, and invasion, with Nrf2 and pSmad2C/2L expression levels showing a contrary tendency. These studies highlighted that GA may inhibit oxidative stress to ameliorate hepatocellular carcinoma via the Nrf2-pSmad2C/2L pathway. However, the specific interaction regulatory mechanism deserves further exploration.