ATF6α mediates Cr(VI)-induced acute hepatotoxicity via GRP78-dependent mitochondrial dysfunction under oxidative stress.

Acute exposure to the common environmental toxin, hexavalent chromium (Cr(VI)), can cause severe chemical hepatotoxicity. Although endoplasmic reticulum (ER) stress is closely associated with Cr(VI)-induced liver damage, the underlying mechanism requires further investigation. In this study, mice and hepatocytes exposed to Cr(VI) were used to analyze the effects of reactive oxygen species (ROS)-mediated ER stress on acute liver injury, with a particular focus on the activating transcription factor 6 (ATF6) branch. It was found that Cr(VI) stimulated the expression and cleavage of ATF6α, while the level of ATF6β was decreased. Pharmacological inhibition and gene knockdown of ATF6α alleviated liver damage caused by Cr(VI). Mechanistically, cleaved ATF6α translocated to the nucleus and directly bound to the promoter of HSPA5 to induce GRP78 transcription, which was closely related to mitochondrial impairment. HSPA5 interference in Cr(VI)-exposed hepatocytes partially improved mitochondrial homeostasis and mitochondria-dependent apoptosis. Interestingly, suppression of ATF6β increased site 1 protease (S1P) but not site 2 protease (S2P), promoting ATF6α cleavage in the Golgi apparatus. Overall, these findings establish ATF6α as a key regulator of Cr(VI)-induced hepatotoxicity via GRP78-mediated mitochondrial dysfunction under oxidative ER stress, suggesting the therapeutic potential of targeting the ATF6 pathway in xenobiotic-induced hepatic injury.