Six1 promotes alveolar epithelium senescence in pulmonary fibrosis through regulating Tp53

Idiopathic pulmonary fibrosis (IPF) is a deadly respiratory condition distinguished by gradual fibrotic restructuring and diminishing pulmonary capacity, with cellular senescence serving as a critical factor in its pathogenesis. This study investigated the function of Sine oculis homeobox homologue 1 (Six1), a transcription factor, in pulmonary fibrosis (PF) and assessed its therapeutic potential as a target. The expression of Six1 was reduced in type II alveolar epithelial cells (AECII) in both patients with IPF and mouse models of PF induced by bleomycin (BLM). Conditional overexpression of Six1 in AECII exacerbated fibrosis severity, as confirmed by histological analysis and impaired lung function. RNA sequencing indicated the involvement of Six1 in pathways related to immune response, inflammation, and cellular senescence. Mechanistic studies revealed that Six1 promotes cellular senescence in AECII by directly upregulating Tp53 transcription, a process mitigated by treatment with PFN-α, a Tp53 inhibitor. Inhibition of Six1 using the specific repressor NCGC00378430 (NCG) attenuated fibrotic changes and improved pulmonary function in both Six1-overexpressing and wild-type mice. These findings suggest that Six1 is a contributor to the progression of IPF by regulating AECII senescence, emphasizing the therapeutic potential of targeting Six1 to alleviate PF. This study underscores the necessity of exploring Six1 inhibitors further as promising candidates for treating IPF. • Six1 was downregulated in pulmonary fibrosis, particularly in AECII. • AECII-specific Six1 overexpression exaggerated BLM-induced pulmonary fibrosis. • Six1 aggravated AECII senescence by directly transcriptional activation of Tp53. • Six1 Inhibitor, NCG, played preventive and therapeutic roles in pulmonary fibrosis.