ATF5 promotes redox homeostasis and cancer progression through nuclear-mitochondrial collaboration in pancreatic cancer

Abstract Mitochondrial dysfunction has a dual impact on the progression of pancreatic cancer (PC). While moderate impairment of mitochondrial function supports tumor growth and adaptation, severe mitochondrial damage accompanied by excessive reactive oxygen species accumulation induces mitochondria-mediated apoptosis, posing a critical threat to cancer cell survival. Consequently, PC cells must tightly regulate mitochondrial homeostasis and redox balance; however, the underlying mechanisms remain largely unknown. This study aimed to evaluate the role of activating transcription factor 5 (ATF5) in PC progression and its underlying molecular mechanisms. Our study indicates that ATF5 is overexpressed in PC and correlates with unfavorable prognosis. Functional assays revealed that ATF5 silencing results in decreased proliferation, migration, and invasion capabilities of PC cells. Mechanistically, we proved that ATF5-dependent mitochondrial unfolded protein response (UPR mt ) is essential for maintaining mitochondrial stress adaptation. Furthermore, we showed that mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), a mitochondrially encoded peptide, binds directly to the nuclear factor erythroid 2-related factor 2 (NRF2) promoter region, thereby promoting its transcription under conditions of mitochondrial stress. ATF5 depletion reduced MOTS-c nuclear translocation and exacerbated reactive oxygen species accumulation, whereas exogenous MOTS-c supplementation alleviated mitochondrial injury and reversed the aggressive phenotype induced by ATF5 loss. Collectively, these findings reveal that ATF5 promotes PC progression by orchestrating mitochondrial quality control and antioxidant defense through activation of the UPR mt pathway and the MOTS-c–NRF2 signaling axis.