NOX4-related ROS couples PET micro- and nanoplastic exposure to JAK2/STAT3 activation in clear cell renal cell...

The potential influence of polyethylene terephthalate micro- and nanoplastics (PET-MNPs) on the progression of clear cell renal cell carcinoma (ccRCC) remains insufficiently defined. In this study, environmentally derived PET-MNPs promoted ccRCC cell growth, clonogenic capacity, migration, and invasion, and also accelerated tumor development in subcutaneous and orthotopic models. PET-MNP exposure markedly elevated intracellular ROS and H₂O₂ and preferentially increased NOX4 among the NOX family members examined. Silencing NOX4 attenuated ROS and H₂O₂ accumulation and weakened the associated malignant phenotypes both in vitro and in vivo. Functional rescue further showed that wild-type NOX4, but not the catalytically impaired NOX4-P437H mutant, reinstated oxidative signaling and JAK2/STAT3 activation after NOX4 depletion. Transcriptomic analysis of PET-MNP-responsive genes reversed by NOX4 knockdown highlighted JAK-STAT signaling, which was subsequently narrowed to the JAK2/STAT3 branch by protein screening. JAK2 depletion impaired STAT3 Tyr705 phosphorylation, nuclear localization, and transcriptional activity, whereas STAT3 silencing suppressed PET-MNP-induced tumor-promoting phenotypes. Conversely, constitutively active STAT3 partially restored the effects lost after NOX4 depletion. These results define a NOX4-related ROS-JAK2/STAT3 signaling cascade that contributes to PET-MNP-driven ccRCC progression.