LKB1 depletion-mediated epithelial–mesenchymal transition induces fibroblast activation in lung fibrosis

• Published in: Genes & diseases Vol. 11; no. 3; p. 101065
• Main Authors: Xu, Zijian, Davies, Elizabeth R., Yao, Liudi, Zhou, Yilu, Li, Juanjuan, Alzetani, Aiman, Marshall, Ben G., Hancock, David, Wallis, Tim, Downward, Julian, Ewing, Rob M., Davies, Donna E., Jones, Mark G., Wang, Yihua
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2024; Chongqing Medical University; KeAi Communications Co., Ltd
• Subjects: CAB39L; Crosstalk; EMT; Full Length; LKB1; Pulmonary fibrosis; Pulmonary fibrosis; CAB39L; EMT; LKB1; Crosstalk
• ISSN: 2352-3042; 2352-4820; 2352-3042
• DOI: 10.1016/j.gendis.2023.06.034

The factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial–mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signaling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells inhibits autophagy and induces EMT as a consequence. In IPF lungs, this is caused by the down-regulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and MRC5 lung fibroblasts coupled with RNA sequencing (RNA-seq) confirmed that paracrine signaling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together, these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.