AP-1-Targeting Decoy Oligonucleotides: Mechanisms and Therapeutic Potential as Modulators of Inflammatory Pathways

Numerous cellular functions, such as apoptosis, proliferation, differentiation, survival, transformation and cell migration, are regulated by a crucial transcription factor called activator protein 1 (AP-1). Growing evidence indicates that AP-1 is involved in severe conditions like fibrosis, cancer, and organ damage, as well as inflammatory diseases, including rheumatoid arthritis, psoriasis, and asthma. In recent years, AP-1 has become a significant focus in drug research. The activation of AP-1 by TNF is crucial for essential components of the inflammatory reaction, including the expression of tissue remodelling proteases such as collagenase, as well as pro-inflammatory cell adhesion molecules like E-selectin. This transcription factor is formed by the assembly of jun-jun homodimers, jun-fos heterodimers, and jun-ATF (Activating Transcription Factor) heterodimers. As a member of the basic leucine zipper (bZIP) class, AP-1 regulates target genes by binding to their promoters in a sequence-specific way. New research suggests that reducing AP-1 function could improve various disease outcomes and treatments. Transfection of decoy oligonucleotides (ODNs) offers an innovative approach to gene therapy by targeting specific gene regulatory elements. Transcription factor decoys mimic the sites where transcription factors bind, competing with promoter regions within the cell nucleus. These molecules can regulate interactions between DNA sequences and transcription factors, which play a role in altering gene activation during both normal and disease-related cellular processes. This review aims to summarize the effects of AP-1-targeted decoys on various conditions. The studies demonstrated the great promising role of AP-1 decoys as therapeutics for various diseases, especially cardiovascular diseases and cancers. Moreover, it was shown that modifications of AP-1 (circular and hairpin as well as phosphorothioate backbones structures) decoys made them more stable and effective.