DPP9 is a serine protease that cleaves N-terminal dipeptides from proteins with Pro or Ala at position 2. Its primary role is as a key inhibitor of inflammasome activation, specifically suppressing NLRP1 and CARD8 inflammasomes in resting cells by sequestering their active C-terminal fragments and preventing oligomerization 1. This inhibitory function operates through both its catalytic activity and protein–protein interactions with the FIIND domain, independent of direct substrate cleavage of NLRP1 or CARD8 themselves. Biallelic DPP9 loss-of-function variants cause an inflammasomopathy characterized by immune defects, growth failure, pancytopenia, and pigmentation abnormalities; disease severity correlates with aberrant NLRP1 inflammasome activation and IL-1β signaling 2. In infectious disease, DPP9 variants associate with critical COVID-19 illness, implicating the gene in host antiviral defense 3. In cancer, DPP9 overexpression promotes therapeutic resistance through distinct mechanisms: in clear cell renal carcinoma, DPP9 stabilizes NRF2 by competing with KEAP1 in an enzyme-independent manner, suppressing ferroptosis and inducing sorafenib resistance 4. Similarly, in hepatocellular carcinoma, DPP9 upregulates NQO1 and inhibits ROS through the NRF2 pathway to promote chemoresistance 5. DPP9 inhibitors with drugs such as Val-boroPro show promise in enhancing both anti-HIV and chemotherapy efficacy 6.