Targeting hypoxia-responsive miR-155-5p and miR-210-3p restores alveolar regeneration and reverses pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an age-associated degenerative disease largely driven by failure of alveolar epithelial regeneration, yet current therapies slow fibrosis progression without restoring epithelial repair. Building on our previous unbiased microRNA screen in primary murine alveolar type II (ATII) cells, we identified miR-155-5p and miR-210-3p as previously unrecognized mediators of alveolar epithelial regenerative failure. Both microRNAs were markedly upregulated in ATII cells from patients with IPF and enriched within KRT17+/KRT5- aberrant transitional epithelial cells. Their expression also increased spontaneously with ageing in ATII cells from uninjured mice, linking these microRNAs to the age-dependent loss of ATII to ATI transdifferentiation capacity. Furthermore, we found that hypoxia-induced HIF signalling drives the expression of these microRNAs in ATII cells, locking them in a dysfunctional transitional state characterized by a profibrotic secretome that promotes paracrine myofibroblasts activation. Antisense oligonucleotide (ASO) inhibition of selected miRNAs restored ATII-to-ATI differentiation, eliminated aberrant transitional states, normalized epithelial-mesenchymal communication, promoted de novo alveolar regeneration and reversed fibrosis, including in both young and aged mice. Together, these findings identify the hypoxia-responsive miRNAs miR-155-5p and miR-210-3p as therapeutically actionable regulators of alveolar regenerative failure and establish their inhibition as a strategy to restore endogenous lung repair while disrupting pathological epithelial-mesenchymal crosstalk in pulmonary fibrosis.