Aljumaah_2025_Sci.Adv_11_eads5721

Human dipeptidyl peptidase 4 (hDPP-4) has been a pharmacological target for metabolic diseases, particularly diabetes, since the early 2000s. As a ubiquitous enzyme found in both prokaryotic and eukaryotic organisms, hDPP-4 plays crucial roles in host homeostasis and disease progression. While many studies have explored hDPP-4's properties, research on gut microbially derived DPP-4 (mDPP-4) remains limited. This review discusses the significance of mDPP-4 and its health implications, analyzing crystal structures of mDPP-4 in comparison to human counterparts. We examine how hDPP-4 inhibitors could influence gut microbiome composition and mDPP-4 activity. Additionally, this review connects ongoing discussions regarding DPP-4 substrate specificity and potential access routes for mDPP-4, emphasizing the urgent need for further research on mDPP-4's role in health and improve the precision of DPP-4 inhibitor therapies.