Dpp9, short for dipeptidyl peptidase 9, is a member of the dipeptidyl peptidase IV family. It has emerged as a regulator in multiple key pathways. Dpp9 directly inhibits NLRP1 and is involved in regulating the KEAP1-NRF2 axis. The KEAP1-NRF2 pathway is crucial for cellular responses to oxidative and electrophilic stressors, and Dpp9's role in these pathways has significant implications for various biological processes and disease conditions [1,2,3,4].

In a mouse model, Dpp9 deficiency led to immune-associated defects, poor growth, pancytopenia, and skin pigmentation abnormalities. These phenotypes were driven by the aberrant activation of the canonical NLRP1 inflammasome and IL-1β signaling, as removing a single copy of Nlrp1a/b/c, Asc, Gsdmd, or Il-1r rescued the lethality of Dpp9 mutant neonates [2]. In clear cell renal cell carcinoma (ccRCC), Dpp9 overexpression was observed. It bound to KEAP1, disrupted KEAP1-NRF2 binding, stabilized NRF2, suppressed ferroptosis, and induced sorafenib resistance [1]. In liver cancer cells, Dpp9 promoted resistance to chemotherapy by up-regulating NQO1 and inhibiting intracellular ROS levels through the Dpp9-KEAP1-NRF2 axis [3].

In conclusion, Dpp9 plays essential roles in regulating inflammasome activation, oxidative stress responses, and drug resistance in various diseases. The gene knockout mouse models have been instrumental in revealing its role in disease-related biological processes such as immune-related defects and tumorigenesis, highlighting its potential as a therapeutic target for diseases including certain cancers and inflammasomopathies.