Cr(VI) induced hepatocyte apoptosis through the CTH/H₂S/Drp1 signaling pathway

Hexavalent chromium [Cr(VI)] is a highly hazardous heavy metal with multiple toxic effects. Occupational studies indicate that its accumulation in humans can lead to liver damage. However, the exact mechanism underlying Cr(VI)-induced hepatotoxicity remains unknown. In this study, we explored the role of CTH/H₂S/Drp1 pathway in Cr(VI)-induced oxidative stress, mitochondrial dysfunction, apoptosis, and liver injury. Our data showed that Cr(VI) triggered apoptosis, accompanied by H₂S reduction, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction in both AML12 cells and mouse livers. Moreover, Cr(VI) reduced cystathionine γ-lyase (CTH) and dynamin related protein 1 (Drp1) S-sulfhydration levels, and elevated Drp1 phosphorylation levels at Serine 616, which promoted Drp1 mitochondrial translocation and Drp1-voltage-dependent anion channel 1 (VDAC1) interactions, ultimately leading to mitochondria-dependent apoptosis. Elevated hydrogen sulfide (H₂S) levels eliminated Drp1 phosphorylation at Serine 616 by increasing Drp1 S-sulfhydration, thereby preventing Cr(VI)-induced Drp1-VDAC1 interaction and hepatotoxicity. These findings indicated that Cr(VI) induced mitochondrial apoptosis and hepatotoxicity by inhibiting CTH/H₂S/Drp1 pathway and that targeting either CTH/H₂S pathway or Drp1 S-sulfhydration could serve as a potential therapy for Cr(VI)-induced liver injury.