CRIPTO1, a novel SASP factor induces fibroblast reprogramming in senescence-associated pulmonary fibrosis

Aging is the major risk factor for idiopathic pulmonary fibrosis (IPF). Senescent cells accumulate in aged and diseased lungs, and their senescence-associated secretory phenotype (SASP) promotes chronic inflammation and impairs regeneration. However, molecular targets to prevent or reverse senescence-driven fibrosis remain unidentified, limiting effective IPF treatments. Here, we aimed to identify SASP factors involved in fibrosis using a novel clinically relevant lung model. Human precision-cut lung slices were irradiated (IR-hPCLS) and multiplex immunofluorescence, cytokine array, and transcriptomics were used to characterize senescence-associated fibrosis. IR-hPCLS exhibited alveolar epithelial cellular senescence, stem cell dysfunction, and inflammation, along with fibrotic signaling and extracellular matrix remodeling. A longitudinal secretome analysis revealed a novel SASP factor, CRIPTO1, whose expression was upregulated in the senescent alveolar epithelium of IR-hPCLS. Mechanistically, senescent alveolar type (AT)2 cells (IR, H 2 O 2 , or Doxorubicin) showed increased CRIPTO1 expression mediated by the NF-κB signaling pathway. Moreover, CRIPTO1 activated primary human lung fibroblasts, as shown by upregulation of smooth Muscle Actin Alpha 2, Fibronectin 1, and alpha-1 Type I Collagen in an ALK5 receptor-dependent manner. Fibroblast activation was reversed by senolytics or anti-CRIPTO1 compounds in fibrotic and IR-hPCLS. Notably, IPF patients exhibited higher circulating levels of CRIPTO1 and accumulation of senescent CRIPTO1+AT2 cells in the lung, which were reduced by antifibrotics ex vivo. In conclusion, CRIPTO1 is a novel SASP factor mediating epithelial-to-mesenchymal crosstalk in senescence-associated fibrosis as a potential biomarker and therapeutic target for IPF. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany