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

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.