PRDX1 Suppression Drives Chromium-Induced Hepatotoxicity via Calcium-Mediated Mitochondrial-ER Dysfunction and Ferroptosis

Hexavalent chromium (Cr[VI]) is a significant environmental contaminant that poses substantial risks to agricultural safety and public health. Although Cr(VI)-induced hepatic injury is associated with oxidative stress and organelle dysfunction, the crosstalk between ionic homeostasis disruption and organelle-specific pathophysiology remains incompletely elucidated. Herein, we identified significant suppression of peroxiredoxin 1 (PRDX1) following Cr(VI) exposure, concomitant with intracellular calcium depletion, mitochondrial lipid peroxidation, endoplasmic reticulum (ER) stress, and ferroptosis. Mechanistically, Cr(VI)-driven PRDX1 deficiency initiates calcium-mediated mitochondrial oxidative damage and ER stress, synergistically triggering the ferroptosis cascade that culminates in hepatic injury. These findings establish PRDX1 as the master regulator of Cr(VI) hepatotoxicity and uncover a novel calcium-dependent axis that converges mitochondrial redox imbalance with ER proteotoxic stress to drive ferroptotic cell death. This study provides fundamental insights into the toxicological role of PRDX1 in Cr(VI) exposure and advances theoretical frameworks for understanding chromium-associated pathophysiological mechanisms.