Transmembrane Protein PTCHD4 Is a Novel Regulator of Cellular Senescence and Age‐Related Pathologies

Abstract

Cellular senescence is a key driver of age‐related pathologies. Our study focuses on PTCHD4, a transmembrane protein with previously undefined physiological functions in aging processes. We found that PTCHD4 expression was increased across multiple cellular senescence models and showed an age‐associated increase in mouse tissues and human lung transcriptomic datasets. Functionally, PTCHD4 deficiency attenuated senescence progression, whereas its overexpression promoted this process. In vivo, PTCHD4 deficiency alleviated D‐galactose‐induced aging‐related phenotypes and functional deterioration, accompanied by an extension of median lifespan in mice. In a bleomycin‐induced pulmonary fibrosis model, PTCHD4 deficiency reduced collagen deposition, attenuated senescence‐ and inflammation‐associated signals, and preserved pulmonary function. Mechanistically, PTCHD4 promoted aging‐associated AKT activation, and restoration of AKT signaling reversed the anti‐senescent effects of PTCHD4 deficiency. Taken together, these findings support PTCHD4 as a contributor to cellular senescence and age‐associated tissue dysfunction, and suggest that the PTCHD4‐AKT axis warrants further investigation as a candidate target in senescence‐associated diseases.