TRIB3‒GSK-3 interaction promotes lung fibrosis and serves as a potential therapeutic target.

Pulmonary fibrosis (PF) is a chronic, progressive, fatal interstitial lung disease with limited available therapeutic strategies. We recently reported that the protein kinase glycogen synthase kinase-3 (GSK-3) interacts with and inactivates the ubiquitin-editing enzyme A20 to suppress the degradation of the transcription factor CCAAT/enhancer-binding protein beta (C/EBP) in alveolar macrophages (AMs), resulting in a profibrotic phenotype of AMs and promoting the development of PF. Here, we showed that chronic lung injury upregulated the stress response protein tribbles homolog 3 (TRIB3), which interacted with GSK-3 and stabilized GSK-3 from ubiquitination and degradation. Elevated GSK-3 expression phosphorylated A20 to inhibit its ubiquitin-editing activity, causing the accumulation of C/EBP and the production of several profibrotic factors in AMs and promoting PF development. Activated C/EBP, in turn, increased the transcription of TRIB3 and GSK-3, thereby establishing a positive feedback loop in AMs. The knockdown of expression or the pharmacologic disruption of the TRIB3‒GSK-3 interaction was an effective PF treatment. Our study reveals an intact profibrotic axis of TRIB3‒GSK-3‒A20‒C/EBP in AMs, which represents a target that may provide a promising treatment strategy for PF.