Dipeptidyl peptidase 8 (DPP8) (DPP8)

Dipeptidyl peptidase 8 (DPP8) is an intracellular serine protease belonging to the S9B family, which also includes DPP4, DPP9, and fibroblast activation protein (FAP) [3, 8]. Unlike the membrane-bound DPP4, DPP8 is primarily localized in the cytosol and is ubiquitously expressed across various tissues [6, 12]. It functions by cleaving N-terminal dipeptides from substrates with a proline or alanine at the penultimate position, thereby regulating the activity of signaling molecules and metabolic enzymes such as adenylate kinase 2 (AK2) [9, 15]. DPP8 plays a critical role in the innate immune system as a negative regulator of the NLRP1 and CARD8 inflammasomes; its inhibition or degradation triggers pro-caspase-1-dependent pyroptosis, particularly in myeloid cells [3, 10]. This unique mechanism has positioned DPP8 as a promising therapeutic target for hematological malignancies, including acute myeloid leukemia (AML) [5, 6]. However, DPP8 is also considered an "anti-target" in the development of DPP4 inhibitors for type 2 diabetes, as its off-target inhibition was historically associated with toxicities such as alopecia, thrombocytopenia, and multi-organ failure in preclinical models [1, 10].

Other names

DP8DPRP1MSTP141MST097MSTP097MSTP135DPRP-1Dipeptidyl peptidase IV-related protein 1

Inhibition of the enzyme's catalytic activity prevents the degradation of intracellular substrates and disrupts its interaction with inflammasome sensors like NLRP1 and CARD8, leading to their activation and subsequent pyroptosis [3, 10, 11].