TRIM36 inhibits lung fibroblast activation and pulmonary fibrosis through the degradation of phospho-AKT1

The ubiquitin-proteasome system (UPS) critically regulates protein stability and function. E3 ligase dysregulation plays a crucial role in idiopathic pulmonary fibrosis (IPF). TRIM36, a RING-finger E3 ligase with emerging tumor-suppressive roles in various cancers, remains poorly characterized in IPF. In this study, we found that TRIM36 is significantly upregulated in IPF patients, and its expression is negatively associated with the disease severity. TRIM36 inhibits lung fibroblast proliferation, migration, and differentiation into myofibroblast <i>in vitro</i>. Mechanistically, TRIM36 mediates K48-linked polyubiquitination of phospho-AKT1 (T308/S473), leading to its proteasomal degradation and consequent inhibition of AKT signaling. Overexpression of TRIM36 markedly ameliorates bleomycin (BLM)-induced mouse pulmonary fibrosis. Taken together, these findings demonstrate that TRIM36 inhibits pulmonary fibrosis by degrading phospho-AKT1 (T308/S473) to inhibit AKT1 signaling, offering valuable insights for IPF treatment.