Existing animal models of cystic fibrosis (CF) have provided key insights into CF pathogenesis but have been limited by short lifespans, absence of key phenotypes, and/or high maintenance costs. Here, we report the CRISPR/Cas9-mediated generation of CF rabbits, a model with a relatively long lifespan and affordable maintenance and care costs. CF rabbits supplemented solely with oral osmotic laxative had a median survival of approximately 40 days and died of gastrointestinal disease, but therapeutic regimens directed toward restoring gastrointestinal transit extended median survival to approximately 80 days. Surrogate markers of exocrine pancreas disorders were found in CF rabbits with declining health. CFTR expression patterns in WT rabbit airways mimicked humans, with widespread distribution in nasal respiratory and olfactory epithelia, as well as proximal and distal lower airways. CF rabbits exhibited human CF–like abnormalities in the bioelectric properties of the nasal and tracheal epithelia. No spontaneous respiratory disease was detected in young CF rabbits. However, abnormal phenotypes were observed in surviving 1-year-old CF rabbits as compared with WT littermates, and these were especially evident in the nasal respiratory and olfactory epithelium. The CF rabbit model may serve as a useful tool for understanding gut and lung CF pathogenesis and for the practical development of CF therapeutics.

The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a crucial role in regulating immune homeostasis, inflammatory responses, and intestinal barrier function. Indole compounds and their derivatives are ligands of AHR, which can activate the AHR signal transduction pathway and show significant regulatory potential in various inflammatory and immune diseases. Cystic fibrosis (CF) is a life-threatening autosomal recessive genetic disorder. Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction affects multiple systems throughout the body. The core of its pathological process is chronic infection, abnormal inflammation, and tissue damage caused by mucus accumulation. Exploring alternative or adjunctive therapeutic strategies targeting pathological pathways downstream of CFTR is of significant importance. The aim of the present study is to explore the multiple beneficial effects that indole compounds may exert in regulating pulmonary infection and inflammation, repairing intestinal barrier function, and regulating immune homeostasis in CF patients by activating the AHR signaling pathway. Additionally, this study discusses the risks and challenges associated with developing indole compounds as CF drugs, offering a novel research approach distinct from traditional CFTR modulators for creating new CF therapeutics.

Keratin, a core structural protein in epithelial cells, is essential for maintaining epithelial tissue integrity. Numerous studies have confirmed its critical role in proliferative disorders, including lung/liver cancer, idiopathic pulmonary fibrosis (IPF), and hepatic fibrosis (HF). Post-translational modification (PTM) regulates protein activity, and keratin undergoes phosphorylation, acetylation, and methylation—modifications that modulate fibrosis and cancer progression by regulating relevant signaling pathways. However, how these modifications reshape keratin’s structure and function in these diseases remains understudied, underscoring the necessity for a systematic review. This review first summarizes keratin’s classification, physiological functions, and roles in epithelial cells, then focuses on the physiological significance of keratin modifications in fibrosis and cancer, while dissecting the molecular mechanisms by which keratin PTMs drive disease progression to address the knowledge gap regarding modification-related keratin changes. Elucidating the mechanisms of keratin and its PTMs is pivotal for understanding disease progression and developing targeted therapies; meanwhile, keratin-targeted strategies—such as keratin siRNAs and small-molecule compounds that regulate keratin expression or modification—have shown therapeutic potential. In summary, this review synthesizes current research findings and provides novel insights for the treatment of fibrosis and cancer.