A PARK7–PINK1 axis coordinates redox balance and metabolic remodeling during somatic cell reprogramming

Induced pluripotent stem cells (iPSCs) are widely used in regenerative medicine, yet the mechanisms that coordinate redox regulation with transcriptional and metabolic remodeling during pluripotency induction remain incompletely understood. PARK7 (DJ-1) is a multifunctional redox-sensitive protein implicated in oxidative stress regulation and transcriptional control, and has been reported to associate with the Nanog promoter and suppress reprogramming efficiency. Here, we demonstrate that PARK7 acts as a regulator during somatic cell reprogramming. Park7 knockdown in mouse embryonic fibroblasts enhances Nanog -positive colony formation, particularly during early reprogramming phases. Using paused iPSCs to dissect the underlying mechanisms, we show that Park7 depletion increases mitochondrial and cytosolic reactive oxygen species (ROS), stabilizes HIF-1α, promotes glycolytic gene expression, and upregulates pluripotency markers. Antioxidant treatment substantially reduced these effects, indicating that ROS-mediated metabolic remodeling drives the enhanced reprogramming phenotype. Elevated ROS also activates NRF2-dependent antioxidant transcriptional programs, revealing a compensatory redox response. We further identify PINK1 as the essential downstream mediator of PARK7 in this cascade; Park7 depletion reduces Pink1 expression, and Pink1 knockdown phenocopies Park7 loss, whereas restoration of wild-type PINK1 reverses the increase in pluripotency markers. These findings demonstrate that PARK7 regulates pluripotency primarily through a PARK7–PINK1 axis that coordinates ROS suppression, glycolytic metabolic remodeling, and pluripotency gene expression during reprogramming.