Polymerase Ⅰ and transcript release factor (PTRF)/cavin-1 is an essential component in the biogenesis and function of caveolae, invagination of the plasma membrane involved in signal transduction.We showed that levels of PTRF/cavin-1 and acetylation of p53 (ac-p53) were increased by sublethal concentration of hydrogen peroxide (H2O2) (30 μM) in Chang cells.In the induction of senescence, H2O2 induced activations of Akt and p38 mitogen-activated protein kinase (MAPK), which were found to be necessary for cellular senescence and expressions of PTRF/cavin-1 and ac-p53.We found that inhibition of PTRF/cavin-1 by small interfering RNAs (siRNAs) could not completely reduced the expressions of related molecular and prevented cellular senescence by H2O2.Level of ac-p53 under incubation of PTRF/cavin-1 siRNA, was significantly activated and subsequently up-regulated by SIRT1 siRNA.Moreover, senescent phenotypes were also partially observed when p53 pathway was blocked by its siRNA.The reduction of cellular senescence was enhanced by combined effect of both siRNAs.PTRF/cavin-1 siRNA and p53 siRNA also separately reduced partial expression of p21waf1/Cip1.PTRF/cavin-1 siRNA combining with p53 siRNA completely reduced the p21Wafl/Cip1 Moreover, knockout of p21Walf/Cip1 totally reduced the H2O2-induced senescence.Thus, we demonstrated that the H2O2-induced cellular senescence via activation of Akt and p38 pathways divided into PTRF/cavin-1 and p53 pathways.Cellular senescence by H2O2 could be regulated by PTRF/cavin-1, a p53-independent pathway.PTRF/cavin-1 not only regulated p53 but also directly activated the p21Waf1/Cip1 to induce the premature senescence in Chang cells.