Blocking two microRNAs enabled aged mouse lungs to resolve fibrotic tissue: progenitor cells completed maturation after fibrosis had already formed
Blocking two microRNAs enabled aged mouse lungs to resolve fibrotic tissue: progenitor cells completed maturation after fibrosis had already formed
On September 16, 2026, biologists from the International Centre for Genetic Engineering and Biotechnology (ICGEB) in Trieste, working with colleagues from the United States, described two microRNAs, miR-155-5p and miR-210-3p, that block the maturation of progenitor cells and rise with age on their own, without injury. Suppressing either one restored alveolar regeneration even in aged mice with established fibrosis, and lineage tracing of labeled cells confirmed that the progenitors completed their maturation into functional cells.
Idiopathic pulmonary fibrosis is an age-related disease: over time the lung loses its capacity for self-repair and scarring accumulates because alveolar progenitor cells stop maturing into the gas-exchanging cells that line the air sacs. The approved drugs (pirfenidone, nintedanib, and nerandomilast, which was introduced in October 2025) only slow the scarring. In the pivotal trial of nerandomilast, the annual decline in forced vital capacity was merely attenuated, not halted.
Both microRNAs were identified by the ICGEB laboratory: out of 2042 microRNAs tested, only three simultaneously impaired progenitor maturation and induced senescence, and in the fibrosis model only miR-155-5p and miR-210-3p actually rose. Both are activated by oxygen deprivation, which creates a vicious cycle: damage reduces oxygen delivery, low oxygen activates both microRNAs, and they lock progenitors in an immature state while their secreted factors convert neighboring fibroblasts into scar-forming myofibroblasts.
The key experiment in the paper used aged animals: young mice recover on their own after injury, but old mice do not, mirroring the human disease. Therapy was administered to 20-month-old mice 10 days after injury, when fibrosis had already formed. A single dose of an antisense oligonucleotide (a short molecule that blocks its target RNA) against either microRNA reduced collagen content and lung weight and restored the proportion of mature alveolar cells. In a separate lineage-tracing experiment, the same therapy drove labeled progenitors to mature cells within nine days. Earlier this summer, a related challenge was addressed by an antibody that boosted an intercellular signal in the lung that weakens with age: it restored a youthful progenitor cell pool in aged mice, but neither the transition to mature cells nor the scar changed. In the present study, the block was lifted in the progenitors themselves, and the scar diminished.
Control experiments confirmed safety: healthy tissue and fibroblasts were unaffected, proliferation of A549 lung cancer cells did not accelerate (an important check, because suppressing microRNAs can potentially promote tumor growth), and the molecule persisted in the lung for up to 60 days without harming other organs.
In patients with idiopathic pulmonary fibrosis, both microRNAs are also elevated: miR-155-5p was found in 57.5% of progenitor cells compared with approximately 23% in healthy lungs. In cultured cells taken from these patients, suppressing either microRNA similarly reduced the fraction of arrested cells and increased the fraction of mature cells.
The same laboratory had previously delivered miR-124-3p by viral vector. For the new targets it chose antisense oligonucleotides, a class already tested in humans: a similar molecule, miravirsen, reached clinical trials against hepatitis C, and this class is easier to administer repeatedly than a virus.
Median survival after diagnosis of idiopathic pulmonary fibrosis is 3 to 5 years, and fewer than 15% of patients live longer than ten years, a prognosis worse than many cancers.