Knockdown of CDC20 attenuates pulmonary fibrosis by repressing fibroblast activation via the TSC1-mediated mTOR pathway.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease of the fibrous lungs that is closely associated with fibroblast activation. Cell division cycle protein 20 homolog (CDC20) regulates cell cycle progression, yet its role in lung fibrosis remains unclear. This study aimed to explore the function of CDC20 in IPF and investigate the potential mechanism of CDC20 to influence the progression of pulmonary fibrosis. Here, we found that the expression levels of CDC20 were upregulated in the lung tissue of mice with bleomycin (BLM)-induced pulmonary fibrosis, as well as in activated fibroblasts. Knockdown of CDC20 suppressed the activation of MRC-5 triggered by TGF-β1 via enhancing autophagy. Nevertheless, chloroquine (CQ)-mediated inhibition of autophagy abolished this regulatory effect on fibroblast activation. CDC20 knockdown also inhibited TGF-β1-induced migration and contraction of fibroblasts. CDC20 silencing had a protective effect against BLM-induced lung injury in mice, and CDC20 knockdown inhibited fibrosis in lung tissue and promoted autophagy. The interacting protein TSC1 with CDC20 was screened by IP/LC-MS, and Co-IP analysis showed that TSC1 interacted with CDC20, and CDC20 promoted the ubiquitination degradation of TSC1. Mechanistically, CDC20 boosted the ubiquitination and degradation of TSC1, and the reduction of TSC1 promoted the activation of the mTOR pathway to inhibit fibroblast autophagy, thereby facilitating fibroblast activation. Overall, CDC20 exacerbated pulmonary fibrosis by inhibiting fibroblast autophagy via blocking the mTOR signaling pathway, which suggested that targeting CDC20 might hold putative therapeutic effect in IPF.