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Cyc.AM-derived FGF9 ignites FGFR1-p38-MAPK-SOX9 axis to reverse acute lung injury

Year: 2026
Type: article
Abstract: Background and objective : Acute lung injury (ALI) is a life-threatening syndrome driven by alveolar epithelial barrier impairment, with incomplete understanding of alveolar repair mechanisms. This study aimed to identify the cellular and molecular axis mediating alveolar repair and validate its therapeutic potential for ALI. Methods : Previous Single-cell RNA sequencing (scRNA-seq) was used to profile bronchoalveolar lavage fluid cells from ALI mice. In vitro assays (co-culture, CCK-8, wound healing, Western blot) investigated the role of FGF9 and the FGFR1-p38-MAPK-SOX9 pathway in AECII cell function. A hydrochloric acid-induced mouse ALI model was used to evaluate the therapeutic effect of exogenous intratracheal FGF9 administration. Results : A novel cycling alveolar macrophage subset (Cyc.AMs, CD68 + MCM4 + ) was identified as the key source of FGF9 in ALI. FGF9 bound to FGFR1 on SOX9 + AECII cells, activating the p38-MAPK pathway to upregulate SOX9, and drive SOX9 + AECII proliferation, migration and differentiation into AECI cells. Endogenous FGF9 secretion by Cyc.AMs was insufficient for full repair; exogenous FGF9 significantly attenuated ALI severity, reduced lung inflammation, and accelerated alveolar barrier restoration in mice. Conclusion : The Cyc.AM-FGF9-FGFR1-p38-MAPK-SOX9 + AECII axis is a critical mediator of alveolar repair in ALI. Exogenous FGF9 administration effectively alleviates ALI, establishing this axis as a promising targeted therapeutic target for ALI and its severe form, ARDS.
DOI: 10.1186/s13287-026-05347-0
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $3,190
OpenAlex ID: W7162077268
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