Roll with the punches: Fibroblast growth factor 10 alleviates pyroptosis of alveolar epithelial cells in different immune niches.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by high mortality with no specific treatments. Fibroblast growth factor 10 (FGF10) is recognized for its tissue repair and anti-inflammatory roles in injured lungs; however, its clinical relevance and mechanistic role in ARDS remain unclear. METHODS: Serum FGF10 levels were measured in patients with ARDS and analyzed for associations with clinical outcomes. An LPS-induced mouse model of acute lung injury (ALI) was used to evaluate the effects of FGF10 treatment in vivo. Single-cell RNA sequencing of lineage-traced alveolar epithelial cells (AECs) was performed to identify transcriptional changes following FGF10 administration. In vitro co-culture systems involving macrophages or neutrophils with AECs were established to investigate immune cell-specific mechanisms. RESULTS: We found that serum FGF10 levels were significantly reduced in ARDS patients, and this reduction correlated with poor prognosis. Moreover, FGF10 treatment alleviated lung inflammation by decreasing inflammatory cell infiltration and pro-inflammatory cytokine release in mice. Leveraging single-cell RNA sequencing of lineage tracing alveolar epithelial cells (AECs), we identified that the mRNA expression of Ripk1, Casp8, and Casp3 were decreased after FGF10 treatment. In in vitro co-culture experiments, we noticed that FGF10 did not inhibit macrophage pyroptosis. Instead, FGF10 effectively blocked the downstream RIPK1/caspase-8/caspase-3/gasdermin E (GSDME) signaling pathway in AECs. Additionally, FGF10 suppressed AMP-activated protein kinase (AMPK) activation by modulating ATP production, thereby preventing RIPK1 cleavage. CONCLUSION: FGF10 alleviates acute lung injury by inhibiting AMPK-RIPK1/caspase-8/caspase-3/GSDME-mediated pyroptosis in AECs primed by distinct immune cell populations, supporting its potential as a therapeutic strategy for ARDS. KEY POINTS: Our study reveals a marked decrease of serum FGF10 levels in ARDS patients, correlating with P/F ratio, hospitalisation days and mortality rates. We clarify how FGF10 prevents AECs' pyroptosis triggered by different immune cell infiltrations in different ways. FGF10 restored ATP levels to attenuate RIPK1 phosphorylation via AMPK to disrupt pyroptosis in the AECs.