Beyond TGFβ inhibition: Chitosan oligosaccharide targets PGC-1α-mediated mitochondrial repair to combat pulmonary fibrosis

Background and purpose: Pulmonary fibrosis is a progressive fatal disease with no therapies addressing upstream epithelial injury. Mitochondrial dysfunction drives pulmonary fibrosis pathogenesis through bioenergetic collapse, oxidative stress and chronic inflammation, perpetuating irreversible fibrosis. Although chitosan oligosaccharides exhibit mitochondrial protective effects, their therapeutic potential and mechanism in pulmonary fibrosis remain unexplored.

Experimental approach: Using pirfenidone as a clinical benchmark, we assessed the efficacy and mechanisms of chitosan oligosaccharides in a bleomycin-induced pulmonary fibrosis mouse model and two human primary alveolar epithelial cell (AEC) subtypes: - functional type I (AEC-I) and reparative type II (AEC-II). Bleomycin and transforming growth factor beta 1 (TGFβ1) were employed to model AEC-I Apoptosis and AEC-II epithelial-mesenchymal transition (EMT), respectively.

Key results: Orally administered chitosan oligosaccharides alleviated pulmonary fibrosis pathophysiology, outperforming pirfenidone at equivalent doses. Chitosan oligosaccharides attenuated epithelial remodelling by inhibiting AEC-I Apoptosis and compensatory EMT of AEC-II, reducing Collagen deposition and alveolar damage. Mechanistically, chitosan oligosaccharides promoted mitochondrial renewal and functional recovery through activation of the Peroxisome Proliferator-activated Receptor gamma coactivator 1-alpha (PGC-1α)/PTEN-induced putative kinase 1 (PINK1)/nuclear factor erythroid 2-related factor 1 (NRF1) axis, restoring bioenergetics and redox homeostasis. Pharmacological PGC-1α inhibition abolished these benefits, confirming pathway dependency.

Conclusion and implications: This study defines a mitochondrial repair mechanism for chitosan oligosaccharides in pulmonary fibrosis via PGC-1α/PINK1/NRF1 activation, directly targeting epithelial injury. It establishes carbohydrate-based mitochondrial precision intervention as a transformative strategy for fibrosis, surpassing conventional TGFβ inhibition in addressing upstream pathology.

apoptosis; chitosan oligosaccharide; epithelial‐mesenchymal transition; mitochondria; pulmonary fibrosis.