(R)-STU104 and Brefeldin-A Synergistically Enhance the Therapeutic Effect On IBD By Inhibiting the TAK1-MKK3-P38 Signaling Pathway.

Introduction: Inflammatory Bowel Disease (IBD) imposes a huge burden on both patients and the society. Standard treatments are often ineffective and can lead to adverse effects. Biological Tumor Necrosis Factor (TNF-α) inhibitors, though effective, have issues with immunogenicity and high costs. Our study investigates the potential of Brefeldin A (BFA) and (R)-STU104 in treating IBD by targeting the Transforming Growth Factor-β-Activated Kinase 1 (TAK1) - Mitogen-Activated Protein Kinase Kinase 3 (MKK3)-p38 pathway.

Methods: RAW264.7 cells (Murine Leukemia macrophage cell line) were treated with (R)-STU104 and BFA to evaluate their impact on the TAK1-MKK3- p38 pathway using Western blotting and RT-qPCR. In vivo, C57BL/6 mice were given Dextran Sulfate Sodium (DSS) to induce IBD, and the effects of BFA and (R)-STU104 were assessed by monitoring Disease Activity Index (DAI), colon length, and cytokine levels.

Results: Both compounds inhibited the MKK3-p38 pathway and reduced TNF-α mRNA expression levels in a dose-dependent manner. Combination therapy showed an enhanced inhibitory effect, reducing mRNA levels of TNF-α, Interleukin (IL)-1β, and IL-6. In the DSS-induced IBD model, this combination alleviated symptoms, improved DAI scores, increased colon length, and reduced inflammatory cell infiltration.

Discussion: This study delved into the synergistic effect of BFA combined with (R)-STU104 on IBD treatment, and revealed that this combination can more effectively inhibit inflammatory responses, as well as enhance disease condition improvement. (R)-STU104selectively suppresses TNF-α production by targeting the p38 signaling pathway, and this suppressive effect is further strengthened when used in tandem with BFA. While,the combination therapy shows potential as an effective IBD treatment strategy,additional research is necessary to confirm its clinical applicability.

Conclusion: BFA and (R)-STU104 exert synergistic anti-inflammatory effects by inhibiting the TAK1-MKK3-p38 pathway, suggesting a new therapeutic approach for IBD. Further studies are required to determine the clinical potential of this combination therapy.