KEAP1-NRF2轴是细胞对氧化性和电泳性压力的主要调节因子。NRF2的高活化在许多类型的癌症中经常观察到，并促进了癌症的发生、进展、转移和对各种疗法的抵抗。我们在这里确定二肽酶9（DPP9）是清除型肾细胞癌（ccRCC）中KEAP1-NRF2通路的调节因子。在ccRCC中，DPP9的mRNA和蛋白水平明显过表达，并且高DPP9表达水平与ccRCC患者的肿瘤进展和不良预后相关。蛋白亲和纯化以识别DPP9的功能伙伴，揭示了其通过保守的ESGE基序与KEAP1结合。DPP9通过竞争与NRF2与KEAP1结合，以一种与酶无关的方式破坏了KEAP1-NRF2结合。DPP9的上调导致了NRF2的稳定，驱动NRF2依赖性转录，从而降低细胞活性氧（ROS）水平。此外，DPP9的过表达抑制了ccRCC细胞的铁死亡，并诱导了对索拉非尼的耐药性，这在很大程度上依赖于NRF2转录靶点SLC7A11。总的来说，这些发现表明DPP9的累积导致了NRF2通路的高活化，从而促进了ccRCC的肿瘤发生和内在的耐药性。

The KEAP1-NRF2 axis is the principal regulator of cellular responses to oxidative and electrophilic stressors. NRF2 hyperactivation is frequently observed in many types of cancer and promotes cancer initiation, progression, metastasis, and resistance to various therapies. Here, we determined that dipeptidyl peptidase 9 (DPP9) is a regulator of the KEAP1-NRF2 pathway in clear cell renal cell carcinoma (ccRCC). DPP9 was markedly overexpressed at the mRNA and protein levels in ccRCC, and high DPP9 expression levels correlated with advanced tumor stage and poor prognosis in ccRCC patients. Protein affinity purification to identify functional partners of DPP9 revealed that it bound to KEAP1 via a conserved ESGE motif. DPP9 disrupted KEAP1-NRF2 binding by competing with NRF2 for binding to KEAP1 in an enzyme-independent manner. Upregulation of DPP9 led to stabilization of NRF2, driving NRF2-dependent transcription and thereby decreasing cellular reactive oxygen species (ROS) levels. Moreover, DPP9 overexpression suppressed ferroptosis and induced resistance to sorafenib in ccRCC cells, which was largely dependent on the NRF2 transcriptional target SLC7A11. Collectively, these findings indicate that the accumulation of DPP9 results in hyperactivation of the NRF2 pathway to promote tumorigenesis and intrinsic drug resistance in ccRCC.