GOLM1 Promotes Pulmonary Fibrosis through Upregulation of NEAT1.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic methods. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2), was elevated in both lungs of patients with pulmonary fibrosis and bleomycin (BLM)-induced pulmonary fibrotic mice. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix (ECM) deposition of fibroblasts, while overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis post-BLM treatment were observed in GOLM1 knock-in (GOLM1 KI/KI ) mice, while BLM-treated GOLM1 knock-out (GOLM1 KO/KO ) mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA (lncRNA) NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and ECM production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent novel therapeutic strategies for treating pulmonary fibrosis.