Targeting Senescence-Associated Fibrotic Signatures Identifies Syringin as an Effective Modulator of the ATR/CHK1–p53 Axis in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease closely associated with aging, yet the contribution of cellular senescence to fibrotic remodeling and its therapeutic implications remain incompletely understood. Syringin, a phenylpropanoid glycoside derived from Acanthopanax senticosus, has been reported to possess anti-inflammatory and antioxidant activities, but its role in IPF has not been elucidated. In this study, bulk lung transcriptomic data from the GTEx project and nine IPF cohorts were integrated with IPF scRNA-seq data to characterize senescence-associated fibrotic programs. A systems-level compound prioritization strategy incorporating reversed gene expression scoring, network proximity analysis, drug-likeness and toxicity evaluation was applied to identify candidate molecules. The results revealed a pronounced aging-associated transcriptomic profile in IPF lungs, with strong concordance between age-related and IPF-related gene programs. Single-cell analyses further identified senescent fibroblast populations as key cellular hubs characterized by elevated expression of SASP factors. Syringin was subsequently validated in TGFβ1–stimulated fibroblasts, and a murine model of bleomycin-induced pulmonary fibrosis. Syringin consistently attenuated fibroblast activation, cellular senescence markers, and pulmonary fibrosis in vivo and in vitro. Mechanistically, syringin markedly reversed the activation of replication stress–associated signaling pathways. Molecular docking and CETSA suggested a potential interaction between syringin and CHK1. Furthermore, CHK1 knockdown partially abrogated the regulatory effects of syringin on the ATR/CHK1–p53 signaling cascade, supporting CHK1 as a functional mediator of syringin activity. Collectively, these findings identify syringin as a natural small molecule with anti-senescent and anti-fibrotic properties, and may represent a potential therapeutic strategy for IPF.