DPP9 is a dipeptidyl peptidase that cleaves N-terminal dipeptides from proteins with Pro or Ala at position 2 1. Its primary function is inhibiting caspase-1-dependent pyroptosis by suppressing NLRP1 and CARD8 inflammasome activation 23. DPP9 sequesters cleaved C-terminal fragments of NLRP1 and CARD8 in ternary complexes, preventing their oligomerization 4. Interestingly, this inhibitory activity requires DPP9's dipeptidyl peptidase activity, though NLRP1 and CARD8 are not direct substrates 4. Beyond inflammasome regulation, DPP9 has emerged as a key regulator of cellular stress responses and cancer biology. DPP9 stabilizes NRF2 by competing with NRF2 for KEAP1 binding in an enzyme-independent manner, suppressing ferroptosis and promoting sorafenib resistance in renal cell carcinoma 5. Similarly, DPP9 regulates NQO1 and ROS levels to enhance chemotherapy resistance in liver cancer 6. Additional substrates include Syk, AK2, and BRCA2, whose N-terminal processing triggers proteasomal degradation 7. Clinically, DPP9 dysfunction causes Hatipoglu immunodeficiency syndrome, with DPP9 deficiency resulting in excessive NLRP1-driven inflammation 8. Genetic variants in DPP9 associate with severe COVID-19, implicating it in antiviral defense 9.