Dipeptidyl peptidase IV (DPP-IV), an important member of the serine hydrolase family, plays a core regulatory role in various physiological and pathological processes because of its unique broad-spectrum substrate specificity. DPP-IV-mediated proteolytic processing of endogenous peptide substrates serves as a fundamental regulatory mechanism governing physiological processes. An in-depth exploration of the enzymatic characteristics and mechanisms regulating DPP-IV activity will not only provide a theoretical basis for revealing the molecular pathogenesis of related diseases but also contribute to the construction of a complete disease regulatory network map. Furthermore, the development of specific DPP-IV inhibitors constitutes a key strategy for innovative therapy, holding significant promise for clinical translation. This review provides a comprehensive comparison of the applications, merits, and limitations of DPP-IV detection at the messenger RNA (mRNA), protein, and functional levels, along with an in-depth analysis of how DPP-IV enzymatic activity assessment profoundly impacts disease pathogenesis, progression, and therapeutic interventions. Particular emphasis is placed on the superior performance of probes based on drugs and optical substrates (e.g., for fluorescence and bioluminescence) in the functional determination of DPP-IV. Through metabolic phenotyping, we further summarize drug screening systems that target DPP-IV across multiple biological levels, including recombinant proteins (e.g., proteins derived from humans, animals, and gut bacteria), tissues, cells, human organ-on-a-chip models, and whole-animal studies. Furthermore, this review comprehensively evaluates both synthetic and natural DPP-IV inhibitors. Additionally, systematic investigations of their structure‒activity relationships (SARs) provide a rational foundation for developing novel inhibitors with enhanced efficacy and safety.

Chronic kidney disease (CKD) is a significant contributor to the global morbidity of non-communicable diseases and is predicted to become the fifth leading cause of death worldwide. However, effective treatments that directly target the underlying causes of CKD remain limited due to its complicated pathogenesis. Recent research has increasingly focused on elucidating the molecular mechanisms and identifying new therapeutic targets of CKD. In recent years, regulated cell death (RCD) has been highlighted as a central mechanism in the development and progression of CKD, suggesting that targeting specific RCD signaling pathways may offer effective strategies for CKD. Emerging research reveals that small molecules can effectively target different types of RCD in the context of CKD, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis and necroptosis. In this review, we summarize current understanding of the mechanism of RCD in CKD. Importantly, we emphasize the regulatory mechanism of small molecules on disturbed RCD to alleviate CKD. Taken together, this review enhances the comprehension of small molecules as modulators of RCD against CKD, which will provide new insights and potential avenues for CKD therapy.