Systemic miR-26a deficiency attenuates pulmonary fibrosis via PTEN upregulation and downstream TIMP-1 suppression

Several microRNAs (miRNAs) have been implicated in the pathophysiology of pulmonary fibrosis; however, the detailed mechanisms remain unclear. miR-26a has demonstrated antifibrotic effects, particularly when its expression is suppressed in the airways. However, the effects of systemic miR-26a deficiency on pulmonary fibrosis have not been investigated. We found that miR-26a knockout (KO) mice exhibited reduced pulmonary fibrosis compared with wild-type (WT) mice. Whole-lung RNA sequencing analysis indicated that the mammalian target of rapamycin complex 1 (MTORC1) signaling and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathways were elevated in the WT group compared with the KO group. Loss of miR-26a increases <i>PTEN</i> expression, a target gene of miR-26a, resulting in the reduction of <i>Timp1</i> levels downstream of the PI3K/Akt-mTOR pathway, thereby attenuating fibrosis. Transfection with miR-26a significantly suppressed <i>Pten</i> expression and increased <i>Timp1</i> and <i>Acta2</i> expression in primary lung fibroblasts <i>in vitro</i>. These results are consistent with the <i>in vivo</i> findings, which suggest that miR-26a promotes fibrosis, contrary to previous reports indicating an antifibrotic role for miR-26a. Our findings suggest that local and systemic inhibition of miR-26a may exert opposing effects, highlighting the importance of careful interpretation of miR-26a-targeted therapeutic strategies.