DPP9 Overexpression in Clear Cell Renal Cell Carcinoma Causes Ferroptosis Suppression and Sorafenib Resistance Through the KEAP1–NRF2 Pathway

Abstract The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-like 2 (NRF2) axis is the principal regulator of cellular responses against oxidative and electrophilic stressors. NRF2 hyperactivation, which is frequently observed in many types of cancers, promotes cancer initiation, progression, metastasis, and resistance to various therapies. Here, we determined that dipeptidyl peptidase 9 (DPP9) was markedly overexpressed at the mRNA and protein levels in clear cell renal cell carcinoma (ccRCC), and its overexpression was correlated with advanced tumour stage and poor prognosis in ccRCC patients. We searched for functional partners of DPP9 using protein affinity purification and determined that DPP9 interacts with KEAP1 via a conserved ESGE motif. The KEAP-NRF2 interaction was disrupted by DPP9, which competed with NRF2 for binding to KEAP1, independent of DPP9’s enzymatic function. Overexpression of DPP9 stabilized the NRF2 protein, drove NRF2-dependent transcription, and reduced cellular relative oxygen species (ROS) levels. Moreover, DPP9 overexpression suppressed ferroptosis and caused resistance to sorafenib in ccRCC cells, which was largely dependent on the NRF2 transcriptional target-SLC7A11. Collectively, our findings indicated that the pathological process associated with the accumulation of DPP9 results in hyperactivation of the NRF2 pathway, which contributes to tumorigenesis and intrinsic drug resistance in ccRCC.