M10 is a ten-amino-acid peptide (TRPASFWETS) derived from the intracellular cytoplasmic tail of the mesenchymal-epithelial transition factor (c-MET) following cleavage by caspase-3. The generation of M10 depends on the presence of an aspartic acid residue at position 1398 (D1398) of MET. Substitution with glycine (D1398G) impairs M10 formation and its downstream antifibrotic activity.
In preclinical models, M10 has demonstrated potent anti-fibrotic properties in both in vitro and in vivo systems. In lung fibroblasts, A549 lung epithelial cells, and alveolar epithelial cells expressing the D1398G MET variant, decreased MET autophosphorylation leads to reduced Ras/MAPK signaling and elevated expression of fibrotic markers such as type I collagen and connective tissue growth factor (CTGF).
Treatment with M10 significantly reduces type I collagen levels in both scleroderma-derived and TGF-β–stimulated normal lung and skin fibroblasts. Molecular docking and immunoprecipitation studies reveal that M10 binds to the MH2 domain of Smad2, inhibiting TGF-β–induced Smad2 phosphorylation and downstream collagen synthesis.
Systemic sclerosis (SSc) is a chronic multi-organ fibrotic disease marked by progressive skin thickening and internal organ involvement. Interstitial lung disease (ILD)—particularly pulmonary fibrosis—is a major cause of morbidity and mortality in SSc.
Hepatocyte growth factor (HGF), through its receptor c-MET, has been identified as a key endogenous anti-fibrotic factor. However, in a subset of patients with severe SSc-ILD, lung fibroblasts exhibit impaired MET signaling due to the D1398G MET variant, which abrogates the receptor's protective effects.
The M10 peptide bypasses this dysfunction, acting downstream of MET to restore anti-fibrotic regulation. In vivo, M10 administration to mice with bleomycin-induced lung fibrosis resulted in marked reductions in fibrotic burden, supporting its potential as a therapeutic candidate for SSc-ILD and other fibrotic lung diseases.
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