Impaired Alveolar Barrier Integrity Exposes FGFR1 Orchestrating Tight Junction Homeostasis via Occludin Transcription Maintenance

The integrity of the alveolar epithelial barrier is fundamental to pulmonary homeostasis, yet the molecular regulators governing its tight junction (TJ) dynamics remain incompletely understood.Here, we uncover a critical, non-canonical function for FGFR1 as a master regulator of TJ homeostasis.We demonstrate that the RET inhibitor pralsetinib (Pral) induces fatal interstitial lung disease by inhibiting FGFR1, not RET, leading to the selective loss of occludin (OCLN).This disruption stems from transcriptional repression, mediated by the transcription factor CREB1.By integrating in vitro and in vivo studies, including lung epithelial-specific Fgfr1-knockout mice, we confirm that Fgfr1 deficiency alone is sufficient to disrupt tight junctions, reduce OCLN expression, and trigger spontaneous lung injury.Our findings establish the FGFR1-CREB1-OCLN axis as a central regulator of TJ integrity, offering new therapeutic perspectives for lung diseases associated with TJ dysfunction.