ERS-Mediated Metabolic Toxicity: The IRE1α/XBP1s Pathway as a Critical Driver of Cr(VI)-Induced Disruption in Glucose and Lipid Metabolism.

Hexavalent chromium (Cr(VI)), a widely prevalent environmental contaminant, has been demonstrated to interfere with hepatic glucose and lipid metabolism, however, its precise molecular mechanisms remain unclear. This study systematically evaluated the effects of Cr(VI) on glucose metabolism and lipid homeostasis both in vivo and in vitro. The results showed that Cr(VI) downregulated the expression of the glucose transporter GLUT2 while simultaneously upregulating the key gluconeogenic enzymes G6Pase and PCK1, leading to elevated intracellular glucose levels. Additionally, Cr(VI) upregulated the lipid synthesis regulatory factors SREBP1, ACC1, and FASN, which manifested as lipid droplet aggregation and dyslipidemia, including elevated levels of TG, TC, LDL-C, as well as reduced HDL-C. These effects were mediated by excessive production of intracellular ROS, which triggered the endoplasmic reticulum stress (ERS) and subsequently activated the IRE1α/XBP1s axis. Downregulation of IRE1α not only suppressed the ERS response but also significantly reversed the expression of GLUT2, PCK1, SREBP1, ACC1, and FASN, thereby alleviating the Cr(VI)-induced abnormalities in glucose and lipid levels. In summary, our study suggests that the ERS/IRE1α/XBP1s signaling pathway plays a pivotal regulatory role in Cr(VI)-induced glucose and lipid metabolic disorders, offering new insights into the toxic mechanisms of Cr(VI).