USP25 stabilizes STAT6 to promote IL-4-induced macrophage M2 polarization and fibrosis

As a leading cause of morbidity and mortality, fibrosis is the common pathway of various chronic inflammatory diseases in organs and causes death in a large number of patients. It can destroy the structure and function of organs and ultimately lead to organ failure, which is a major cause of disability and death in many diseases. However, the regulatory mechanism of organ fibrosis is not well clear and the lack of effective drugs and treatments, which seriously endangers human health and safety. In this study, we found that ubiquitin specific peptidases 25 (USP25) deficiency could protect mice from bleomycin (BLM)-induced pulmonary fibrosis and bile duct ligation (BDL)-induced liver fibrosis. Mechanistically, USP25 deficiency reduced the infiltration of M2 macrophages in the lungs and livers. USP25 inhibits signal transducer and activator of transcription 6 / peroxisome proliferator-activated receptor gamma (STAT6/PPAR-gamma) signaling by reducing the K48 specific ubiquitination of STAT6, thereby promoting IL-4-induced M2 macrophages. Overall, our findings support that USP25 promotes the development of fibrosis by facilitating macrophage M2 polarization.