How DPP-4 Research Becomes the National Natural Science Foundation’s "Golden Track" Connecting Multiple Disciplines

Breaking Boundaries and Integration: How DPP-4 Research Becomes the National Natural Science Foundation’s "Golden Track" Connecting Multiple Disciplines

 
In the funding landscape of the National Natural Science Foundation of China (NSFC), metabolic diseases, immune regulation, and tumorigenesis have long been enduring focal areas. One molecule, situated at the intersection of these hot fields, has attracted widespread attention from researchers due to its diverse biological functions—dipeptidyl peptidase-4 (DPP-4), more commonly known as intestinal enzyme. Although renowned for its role as a therapeutic target in diabetes, the biological functions of DPP-4 extend far beyond "glucose-lowering." It acts as an active "molecular switch," participating extensively in immune regulation, inflammatory responses, cell signaling, and even tumor progression by cleaving various substrates. Currently, in-depth research on DPP-4 is becoming a highly innovative and popular direction in NSFC applications. This article will explore several key hot topics in NSFC research from the perspective of its multiple biological functions and look forward future research trends.

Hot Question: How Does DPP-4 Play the Dual Role of an "Immune System Regulator"?

DPP-4 was initially identified by immunologists as CD26, an important marker for T-cell activation. Its role in the immune system is far more complex than that of a simple surface protein. Its "dual nature" is reflected in its ability to both promote immune responses and exert immunosuppressive effects, with the mystery lying primarily in the substrate selectivity of its enzymatic activity.

On one hand, DPP-4 acts as a "booster" for immune responses. When T cells are activated by antigens, the expression of CD26 on their surface significantly increases. DPP-4 can co-stimulate T cells by interacting with various molecules (such as adenosine deaminase ADA and extracellular matrix proteins), promoting their proliferation, activation, and cytokine production. Additionally, it can cleave certain chemokines, such as CXCL10, CXCL11, and CXCL12 (SDF-1α). After cleavage, the removal of two N-terminal amino acids transforms these chemokines from agonists to antagonists while maintaining their receptor-binding ability, thereby finely regulating the migration and positioning of immune cells. For example, the intact form of CXCL12 effectively recruits hematopoietic stem cells and lymphocytes, while the DPP-4-cleaved form blocks this process, preventing excessive infiltration of immune cells.

On the other hand, DPP-4 also serves as a "guardian" of immune tolerance. This inhibitory effect is largely achieved through its regulation of various immunosuppressive cytokines. DPP-4 efficiently degrades glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), two incretins critical for maintaining glucose homeostasis. In the tumor microenvironment, high expression of DPP-4 may indirectly promote immune escape by suppressing local T-cell activity. Interestingly, DPP-4 inhibitors (gliptins) have been observed in clinical practice to potentially offer anti-inflammatory and immunomodulatory benefits, suggesting that targeting DPP-4 to regulate the immune system could provide new avenues for treating autoimmune diseases (such as rheumatoid arthritis and multiple sclerosis).

NSFC Research Perspective: Applications in this direction could delve into the specific functions of DPP-4 in different immune cell subsets (e.g., regulatory T cells Treg, Th17 cells, cytotoxic T cells); elucidate how it precisely regulates immune balance by cleaving different substrates in specific autoimmune disease or chronic infection models; and explore tissue-specific DPP-4 modulation strategies to achieve immune regulation without affecting systemic glucose levels.
 
Hot Question: How Does DPP-4 Become a Key Hub Connecting the "Gut-Brain-Metabolism" Axis?

The "gut-brain axis" is one of the most concepts in life sciences in recent years, revealing the complex bidirectional communication network between the gastrointestinal tract and the central nervous system. As an enzyme highly expressed in the gut, DPP-4 is undoubtedly a core "messenger" and "mediator" in this communication network.

First, DPP-4 is the "primary regulator" of gut hormones. It rapidly inactivates GLP-1 and GIP, directly determining the duration and intensity of incretin effects. GLP-1 not only stimulates insulin secretion and inhibits glucagon release but also delays gastric emptying and acts on the hypothalamus to induce satiety. Thus, DPP-4 activity directly affects appetite, energy intake, and the body’s overall metabolic state. The success of DPP-4 inhibitors is built on enhancing the "gut-islet" axis signaling.

Beyond glucose-lowering, DPP-4 is closely related to neurological functions. DPP-4 can cross the blood-brain barrier and is also expressed in the central nervous system. Some of its neuropeptide substrates, such as neuropeptide Y (NPY), peptide YY (PYY), and substance P (SP), are involved in regulating mood, stress, pain, and cognitive functions. By cleaving these neuropeptides, DPP-4 may indirectly affect neuronal activity and plasticity. Growing evidence suggests that DPP-4 inhibitors may have beneficial effects on neurodegenerative diseases such as Alzheimer’s and Parkinson’s, as well as depression and anxiety, providing new insights into the comorbidity mechanisms of metabolic and neuropsychiatric disorders.

NSFC Research Perspective: Innovative research in this direction could focus on:

1) Cell-specific studies: Using intestinal cell- or neuron-specific knockout mouse models to investigate the relative contributions of DPP-4 from different sources (gut vs. circulation vs. brain) in metabolic and neural regulation.
2) Mechanistic exploration: Studying how DPP-4 indirectly regulates the "gut-brain axis" by influencing gut microbiota and their metabolites (e.g., short-chain fatty acids). 3) Disease association: Deeply exploring the specific mechanisms of DPP-4 in metabolism-related brain disorders (e.g., diabetic cognitive dysfunction) and evaluating its potential as a therapeutic target.
 
Hot Question: Is DPP-4 a "Friend" or "Foe" of Tumors? What Explains Its Contradictory Roles in Cancer?

The role of DPP-4 in tumor initiation, development, and metastasis exhibits remarkable complexity and contradiction. It can act as either a tumor suppressor or a promoter, making it a focal point in oncology research and an innovative direction for NSFC applications.

Its tumor-suppressing functions may include:

1) Inhibiting tumor invasion and metastasis: DPP-4 can interact with extracellular matrix proteins such as collagen and fibronectin, affecting tumor cell adhesion, migration, and invasion. Some studies have shown that upregulation of DPP-4 expression can inhibit the invasive phenotype of various cancer cells (e.g., thyroid cancer, melanoma).
2) Serving as an immune regulatory node: As mentioned earlier, DPP-4’s immunomodulatory functions also apply to the tumor microenvironment, where its activity may influence the strength of anti-tumor immune surveillance.

However, more evidence supports its tumor-promoting functions:

1) Promoting epithelial-mesenchymal transition (EMT): In various malignancies such as liver cancer, colorectal cancer, and lung cancer, high expression of DPP-4 is significantly associated with advanced tumor stages, metastasis, and poor prognosis. It may drive the EMT process by activating signaling pathways such as TGF-β and Wnt/β-catenin, enhancing cancer stem cell properties and drug resistance.
2) Regulating the tumor microenvironment: By cleaving chemokines (e.g., CXCL12), DPP-4 alters the recruitment of immune cells to tumor tissues, potentially creating an immunosuppressive microenvironment conducive to tumor growth. 3) Affecting cell

proliferation and apoptosis: DPP-4 can interfere with key cell survival and proliferation signaling pathways through enzyme-dependent or independent mechanisms.

NSFC Research Perspective: Resolving the contradictory roles of DPP-4 in cancer is key. Future research needs to:

1) Conduct context-dependent studies: Clarify why the same gene exerts opposite effects in different cancer types or even at different stages. This may be related to the genetic background of tumor cells, the cytokine profile in the microenvironment, and its interacting protein networks.
2) Perform substrate-specific studies: Use proteomics technologies to systematically identify the main substrates of DPP-4 in specific tumor environments, thereby explaining its specific mechanisms of action.
3) Explore targeted therapies: Investigate the synergistic anti-tumor effects of combining DPP-4 inhibitors with immune checkpoint inhibitors, targeted drugs, or chemotherapy, while carefully assessing their potential impact on glucose metabolism.
 
Hot Question: Beyond Traditional Inhibitors: What Are the Emerging Directions and Intervention Strategies in DPP-4 Research?

Although small-molecule DPP-4 inhibitors have become first-line drugs for type 2 diabetes, a deeper understanding of their biological functions is promote a series of emerging research directions and innovative intervention strategies beyond glucose-lowering.

Precise modulation targeting specific substrates: Traditional inhibitors broadly suppress DPP-4’s enzymatic activity against all substrates, which may lead to unpredictable side effects (e.g., joint pain, controversial pancreatitis risk). A future direction is to develop substrate-selective inhibitors or allosteric modulators that only interfere with DPP-4’s cleavage of specific types or individual substrates (e.g., chemokines vs. incretins), enabling more precise immune or neural regulation while avoiding systemic metabolic effects.

Exploring non-enzymatic function regulation: Many functions of DPP-4, particularly its role as a cell surface auxiliary protein (e.g., CD26), do not depend on its enzymatic activity. It participates in intracellular signaling through interactions with proteins such as ADA and CAV-1 (Caveolin-1). Therefore, developing small molecules or peptide inhibitors that specifically block these protein-protein interactions is a novel and highly promising therapeutic strategy, especially applicable to cancer and autoimmune diseases.

Tissue-specific delivery systems: To minimize off-target effects caused by systemic administration, developing delivery systems that can specifically deliver DPP-4 inhibitors or modulators to inflammatory sites, tumor tissues, or the brain using nanotechnology or antibody-drug conjugate (ADC) strategies is an important direction in translational medicine research.

Role as a disease biomarker: The level of soluble DPP-4 (sDPP-4) in serum is associated with various disease states. In-depth research on the source, regulation, and value of sDPP-4 as a non-invasive biomarker for predicting disease risk, prognosis, or treatment response has significant clinical implications.

NSFC Research Perspective: Applications in this direction should emphasize interdisciplinary and cutting-edge technologies. For example, combining structural biology (resolving the complex structures of DPP-4 with different substrates or interacting proteins), chemical biology (developing novel probes and inhibitors), nanomedicine (designing targeted delivery systems), and clinical big data analysis (mining clinical correlations of sDPP-4) to advance DPP-4 research from basic mechanisms to precision medicine.
 
Conclusion
In summary, intestinal enzyme (DPP-4) is an incredibly diverse molecular platform whose research has far exceeded the scope of diabetes, penetrating core areas of modern biomedicine such as immunology, neuroscience, and oncology. Its "dual" or "multifaceted" nature—acting as both an immune booster and suppressor, a metabolic hub and neural regulator, a tumor suppressor and promoter—is precisely its scientific allure and provides rich innovative entry points for NSFC applications. Future research needs to more finely analyze the context dependence of its mechanisms of action, develop more selective regulatory tools, and actively explore its new applications in the prevention and treatment of major chronic diseases. Continued in-depth exploration of DPP-4 will undoubtedly bring new dawn and breakthroughs to humanity’s understanding and treatment of complex diseases.
 
Click on the product catalog numbers below to access detailed information on our official website.
 
Product Information

S0B6008	DPP4 Recombinant Rabbit mAb (S-1631-130)	Host : Rabbit Conjugation : Unconjugated
UA010210	DPP4/CD26 Fc Chimera Protein, Human	Host : Human Expression System : HEK293 Conjugation : Unconjugated
UA010221	DPP4/CD26 Protein, Human	Host : Human Expression System : HEK293 Conjugation : Unconjugated
UA010162	DPP4/CD26 His Tag Protein, Human	Host : Human Expression System : HEK293 Conjugation : Unconjugated
UA010343	DPP4/CD26 His Tag Protein, Cynomolgus	Host : Cynomolgus Expression System : HEK293 Conjugation : Unconjugated
UA010674	Biotinylated DPP4/CD26 His&Avi Tag Protein, Human	Host : Human Expression System : HEK293 Conjugation : Biotin

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