Interrupting The TRB3/MDM2 Interaction Destabilizes Transcriptional Factor SLUG As A Therapeutic Strategy For Pulmonary Fibrosis

The lung injury-induced epithelial to mesenchymal transition(EMT) causes myofibroblast activation, extraceHular matrix deposition,pulmonary fibrosis and,ultimately, lung dysfunction. Although recent studies provide great mechanistic insights,therapeutic agents for pulmonary fibrosis remain a significant clinical unmet need. Here we report that the stress-enhanced TRB3 caused EMT by interacting with E3 ubiquitin ligase MDM2 and interferes with its function that suppresses degradation of EMT-inducing transcriptional factor SLUG in the alveolar epithelial cells. SLUG accumulation promotes these cells acquiring a mesenchymal phenotype and activating myofibroblasts by releasing many pro-fibrotic cytokines, which can be attenuated by silencing TRB3 or interruipting the TRB3/MDM2 interaction. To translate this concept into erapeutic strategy,we generated a stapled peptide MRS that attenuates EMT,suppresses myofibroblast activation, and produces a potent therapeutic efficacy against acute and chronic pulmonary fibrosis via blocking the TRB3/MDM2interaction.Our studies provide a promising lead compound with novel mechanism for developing therapeutics against pulmonary fibrosis and fibroproliferative lung diseases.