Role of FGF19 in regulating mitochondrial dynamics and macrophage polarization through FGFR4/AMPKα-p38/MAPK Axis in bleomycin-induced pulmonary fibrosis.

BACKGROUND

In the bleomycin (BLM)-induced pulmonary fibrosis model, macrophage polarization and mitochondrial dynamic imbalance are critical drivers of fibrogenesis. Although fibroblast growth factor 19 (FGF19) has been reported to alleviate fibrosis, its mechanism of regulating mitochondrial dynamics and macrophage polarization through the FGFR4/AMPKα-p38/MAPK axis remains unclear.

OBJECTIVE

To investigate whether FGF19 mitigates alveolar epithelial injury and pulmonary fibrosis by restoring mitochondrial fusion/fission balance and modulating macrophage phenotype switching.

METHODS

A BLM-induced C57BL/6 mouse fibrosis model was employed, with lung-specific FGF19 overexpression via lentivirus. An in vitro RAW264.7 macrophage-alveolar epithelial cell coculture system was used to assess mitochondrial morphology (transmission electron microscopy), mtDNA content (qPCR), protein expression (MFN1/2, Drp1-pSer616; Western blot), and macrophage polarization (flow cytometry). Pharmacological inhibition (SB203580, a p38/MAPK inhibitor) and MFN1/MFN2 siRNA knockdown were applied to validate pathway specificity.

RESULTS

(1) FGF19 overexpression significantly attenuated BLM-induced alveolar destruction, collagen deposition, and inflammatory infiltration (H&E, P < 0.01); (2) FGF19 activated the FGFR4/AMPKα-p38/MAPK pathway, upregulated mitochondrial fusion proteins MFN1/2 (P < 0.01), suppressed Drp1 phosphorylation (Ser616)-mediated fission (P < 0.05), and shifted macrophages toward an M2 phenotype (CD206↑, P < 0.01); (3) p38/MAPK inhibition or MFN1/2 knockdown reversed FGF19-driven M2 polarization (P < 0.01); (4) FGF19 reduced alveolar epithelial apoptosis (Annexin V-FITC, P < 0.01) and inflammatory cytokine release (TNF-α, IL-6; ELISA, P < 0.01) by inhibiting M1 polarization.

CONCLUSION

FGF19 alleviates pulmonary fibrosis by restoring mitochondrial dynamics via the FGFR4/AMPKα-p38/MAPK axis, thereby inhibiting M1 macrophage polarization and epithelial injury. These findings highlight FGF19 as a potential therapeutic target for antifibrotic interventions.