The enzymatic activity of CD26/DPP4 (dipeptidyl peptidase 4/DPP4) is highlighted in multiple studies to play a vital role in glucose metabolism by cleaving and inactivating the incretins glucagon-like peptide-1 (GLP) and gastric inhibitory protein (GIP). A large number of studies demonstrate that CD26 also plays an integral role in the immune system, particularly in T cell activation. CD26 is extensively expressed in immune cells, such as T cells, B cells, NK cells, dendritic cells, and macrophages. The enzymatic activity of CD26 cleaves and regulates numerous chomokines and cytokines. CD26 inhibitors have been widely used for the treatment of diabetes mellitus, while it is still under investigation as a therapy for immune-mediated diseases. In addition, CD26’s involvement in cancer immunology was also described. The review aims to summarize the therapeutic effects of CD26 inhibitors on immune-mediated diseases, as well as the mechanisms that underpin them.

This review summarizes recent findings on the role of M2 tumor-associated macrophages (TAMs) and their exosome-derived non-coding RNAs (ncRNAs) in cancer cell resistance to therapeutics. M2 TAMs promote angiogenesis, suppress immune responses, and facilitate metastasis, thereby creating a tumor-supporting microenvironment. A range of antitumor drugs, including 5-FU, cisplatin, and gemcitabine, are mediated by M2 exosomes, each with distinct mechanisms of action. M2 exosomes transfer drug resistance capabilities via extracellular vesicles, especially exosomes containing miRNAs, lncRNAs, and circRNAs. These exosome mediate the development of tumor drug resistance by regulating signaling pathways such as PI3K/AKT, MAPK/ERK, Wnt/β-catenin M2 exosomes can regulate cellular responses by delivering bioactive molecules, including proteins, lipids, and ncRNA, which can also modulate cellular reactions to ionizing radiation, ultraviolet light, and chemotherapeutic agents. Targeting M2 TAMs and their exosome-mediated ncRNAs may offer new strategies to overcome drug resistance in cancer.

In this paper, two new iridium (III) complexes, [Ir(ppy)₂(ipbp)](PF₆) (Ir1) (ppy = 2-phenylpyridine, ipbp = 3-(1H-imidazo[4,5-f][1,10]phenanthrolin-2yl)-4H-chromen-4-one) and [Ir(bzq)₂(ipbp)](PF₆) (Ir2) (bzq = benzo[h]quinolone), were synthesized and characterized. The cytotoxicity of the complexes against human colon cancer HCT116 and normal LO2 cells was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. The complexes Ir1 and Ir2 show high cytotoxic efficacy toward HCT116 cells with a low IC₅₀ value of 1.75 ± 0.10 and 6.12 ± 0.2 µM. Interestingly, Ir1 only kills cancer cells, not normal LO2 cells (IC₅₀ > 200 µM). The inhibition of cell proliferation and migration were investigated by multiple tumor spheroid (3D) and wound healing experiments. The cellular uptake was explored under a fluorescence microscope. The intracellular reactive oxygen species (ROS), change of mitochondrial membrane potential, glutathione (GSH) and adenine nucleoside triphosphate (ATP) were studied. Apoptosis and cell cycle arrest were performed by flow cytometry. The results show that the complexes induce early apoptosis and inhibit the cell proliferation at the G0/G1 phase. Additionally, the apoptotic mechanism was researched by Western blot analysis. The results obtained demonstrate that the complexes cause apoptosis in HCT116 cells through ROS-mediated mitochondrial dysfunction and the inhibition of PI3K/AKT signaling pathways.

This study aimed to decipher the interaction between CD26 and caveolin-1, key proteins involved in cell signaling and linked to various diseases. Using computational methods, we predicted their binding conformations and assessed stability through 100 ns molecular dynamics (MD) simulations. We identified two distinct binding conformations (con1 and con4), with con1 exhibiting superior stability. In con1, specific amino acids in CD26, namely GLU237, TYR241, TYR248, and ARG147, were observed to engage in interactions with the F-J chain of Caveolin-1, establishing hydrogen bonds and cation or π–π interactions. Meanwhile, in con4, CD26 amino acids ARG253, LYS250, and TYR248 interacted with the J chain of Caveolin-1 via hydrogen bonds, cation–π interactions, and π–π interactions. Virtual screening also revealed potential small-molecule modulators, including Crocin, Poliumoside, and Canagliflozin, that could impact this interaction. Additionally, predictive analyses were conducted on the potential bioactivity, drug-likeness, and ADMET properties of these three compounds. These findings offer valuable insights into the binding mechanism, paving the way for new therapeutic strategies. However, further validation is required before clinical application. In summary, we provide a detailed understanding of the CD26 and caveolin-1 interaction, identifying key amino acids and potential modulators, essential for developing targeted therapies.

The frequent mutations and emerging drug resistance of Influenza A virus (IAV) pose a persistent global health challenge. The identification of host restriction factors that can inhibit viral infection is crucial for the development of novel antiviral therapies. CD26 acts as a host restriction factor in inhibiting H1N1 infection and the underlying mechanisms remain unclear. Our findings collectively demonstrate that CD26 inhibits H1N1 infection. In vitro, soluble CD26 (2.5 μg/ml) reduces H1N1 titers, specifically suppresses IL-6 upregulation in H1N1-infected A549 cells via NF-κB/IRF3/STAT1 signaling, and dose-dependently inhibits viral hemagglutinin (HA) expression. Surface Plasmon Resonance (SPR) assays confirm direct binding between sCD26 and H1N1 HA with a dissociation constant of 616 nM, while confocal microscopy demonstrates their colocalization, supporting the interaction. As compared with H1N1-infected Wild-Type mice, H1N1-infected CD26 knockout mice showed uncontrolled viral spread, more severe lung pathology, altered lung immune cell proportions, and elevated CXCL2/IL-1β/IL-6 levels in bronchoalveolar lavage fluid (BALF). Overall, this study identifies CD26 as a host restriction factor against H1N1, thereby providing a potential therapeutic avenue for managing influenza-induced lung complications.