GDH1 suppresses ferroptosis and promotes immune evasion in pancreatic ductal adenocarcinoma by liberating NRF2 from KEAP1 [scRNA-seq]

In this study, we demonstrated that GDH1 depletion enhanced tumour sensitivity to RT and drove CD8a cell infiltration in genetically engineered mouse models (GEMMs) harbouring mutant KRAS (mKRAS). Mechanistically, in mKRAS PDAC cells receiving RT, cytosolic GDH1 accumulates and competes for binding to KEAP1 via the GDH1 ETGE motif, thereby freeing NRF2 from the KEAP1/NRF2 complex independent of GDH1 activity. Liberated NRF2 is stabilized, accumulated, and shuffled into the nucleus, where it drives the expression of target genes, such as FTH1, SLC7A11 and CXCL5. Upon RT, these upregulated genes not only support the survival of PDAC cells via the antiferroptotic pathway but also reprogram the tumour immune microenvironment, favouring tumour evasion and consequent liver metastasis. Importantly, NRF2 inhibitor and CXCL5 depletion profoundly improved the efficacy of RT in KPC-generated GEMMs. Hence, to increase the effectiveness of RT, we developed a combination therapy for preventing PDAC-liver metastasis by blocking NRF2 activity and CXCL5 secretion in PDAC tumours. Moreover, GDH1/NRF2 axis has been clinically characterized in mKRAS patients, and may be utilized as a biomarker for predicting the prognosis of PDAC patients receiving RT. Here we employed the single-cell RNA sequencing to reveal that RT drove granulocyte enrichment but induced dramatic loss of infiltration of T cells in KPC tumours.