6PPD-quinone disrupts the MARCHF2-EXOC7 ubiquitin axis to drive ferroptosis and redox imbalance in podocytes

Abstract

levels, downregulation of GPX4, and accumulation of lipid peroxidation. A genome-wide CRISPR/Cas9 knockout screen identified EXOC7 as a critical mediator of 6PPD-Q-induced podocyte injury. Mechanistically, 6PPD-Q disrupted the E3 ubiquitin ligase activity of MARCHF2, leading to reduced ubiquitination of EXOC7, subsequent attenuation of its proteasomal degradation, and consequent accumulation of EXOC7 protein, which ultimately promoted ferroptosis. Limited proteolysis-mass spectrometry (LIP-MS) further revealed that 6PPD-Q directly bound to EXOC7, interfering with its recognition and ubiquitination by MARCHF. Importantly, inhibition of EXOC7 or ferroptosis alleviated chronic 6PPD-Q-induced oxidative stress and podocyte injury in vivo. Together, these findings identify a previously unknown molecular mechanism for 6PPD-Q-induced nephrotoxicity and establish EXOC7-mediated ferroptosis as a sensitive mechanistic endpoint for assessing environmental 6PPD-Q exposure.