Redox-dependent mitochondrial dynamics: PLK1 couples glutathione metabolism to ROS-driven JNK and DUSP6 pathways in colorectal cancer.

Polo-like protein kinase 1 (PLK1) is aberrantly overexpressed in colorectal cancer (CRC) and promotes malignant progression. However, whether PLK1 contributes to redox adaptation remains unclear. Here, we identify PLK1 as a critical hub that integrates glutathione (GSH) metabolism with mitochondrial dynamics to sustain redox homeostasis in CRC cells. Mechanistically, PLK1 drives STAT3-dependent SLC1A1 transcription to fuel GSH synthesis, thereby keeping reactive oxygen species (ROS) at a non-toxic level. When PLK1 is inhibited, GSH depletion triggers a burst of ROS, which acts as a signaling switch to disrupt mitochondrial homeostasis. Accumulated ROS drive two parallel pathways: (i) ROS promote proteasomal degradation of DUSP6, leading to sustained DRP1-Ser616 phosphorylation and excessive mitochondrial fission; (ii) ROS activate JNK, which translocates to mitochondria, binds MFN2, and promotes its ubiquitin-dependent degradation, thereby blocking mitochondrial fusion. This ROS-dependent collapse of mitochondrial dynamics results in cytochrome c release and intrinsic apoptosis. Our findings reveal that PLK1 sustains CRC survival by coupling GSH metabolism with redox-sensitive control of mitochondrial dynamics. These findings identify the ROS-mediated metabolic-mitochondrial axis as a potential therapeutic vulnerability in CRC.