SYISL promotes pulmonary epithelial-mesenchymal transition and fibrosis through DSP–Hippo/YAP pathway

Long non-coding RNAs (lncRNAs) are pivotal regulators of cellular processes, but their specific functions in pulmonary epithelial homeostasis and idiopathic pulmonary fibrosis (IPF) pathogenesis are not fully defined. Building on our previous finding that SYISL modulates fibroblast behavior, we investigated its role in the epithelial compartment. We discovered that SYISL is significantly upregulated in alveolar epithelial cells from both IPF patients and bleomycin-induced fibrotic mice. Mechanistically, we identified desmoplakin (DSP) as a direct binding partner of SYISL. SYISL promotes DSP degradation, thereby relieving a key constraint on epithelial integrity. This event initiates a downstream signaling cascade, activating the PI3K-AKT pathway and promoting YAP1 dephosphorylation and nuclear translocation. Furthermore, we delineate how this axis reshapes the epigenetic landscape at the vimentin locus, enhancing H3K4me3 and H3K27ac marks to facilitate YAP1-driven transcription, which collectively promotes an EMT-associated state and increased epithelial plasticity. The resultant aberrant epithelial-mesenchymal crosstalk contributes to pathological extracellular matrix (ECM) deposition. Translating these insights into therapy, we show that intratracheal delivery of AAV-shSYISL prevents fibrosis, while SYISL-targeting antisense oligonucleotides (ASOs) can reverse established fibrotic lesions. In summary, our study defines a novel SYISL-DSP-Hippo/YAP regulatory axis that licenses pro-fibrotic epithelial plasticity and nominates SYISL as a promising therapeutic target for IPF.