Redox Activity of APE1 Mediates SASP Suppression in Senescent Fibroblasts

Cellular senescence, triggered by multiple stressors, was characterized by senescence-associated secretory phenotype (SASP) that drive age-related pathologies. Apurinic apyrimidinic endonuclease 1 (APE1), a bifunctional enzyme with redox and DNA repair activities, regulates inflammation and senescence, but its role in SASP expression remains unclear. This study aimed to elucidate how APE1 regulates SASP and to identify new target for senomorphic therapy. APE1-deficient senescence models were established in human fibroblasts, and senescence markers (SA-β-gal, SenTraGor, p16/p21) and SASP factors (IL-6, IL-8, TNF-α, CCL5) were assessed via RT-qPCR, RNA-seq, and Western blot. APE1 inhibitors and point mutation plasmids were used to further investigate the contributions of the dual functions of APE1 in SASP modulation. Contrary to classical senescence models, APE1 deficiency induced premature senescence but paradoxically suppressed SASP expression. Transcriptomic profiling revealed that APE1 knockdown attenuated cytokine signaling and NF-κB pathway activation, accompanied by downregulation of key SASP factors (IL-6, IL-8, CCL5, TNF-α, IFN-β). Mechanistically, inhibiting the redox activity of APE1 resulted in the inactivation of NF-κB/C/EBPβ signaling and suppression of SASP expression, while the impaired DNA repair activity of APE1 triggered cellular senescence. Furthermore, inhibiting the redox function of APE1 via E3330 attenuated radiation-induced SASP. In conclusion, APE1 governs SASP expression through NF-κB/C/EBPβ signaling, highlighting its dual role in senescence and SASP regulation. Targeting the redox function of APE1 represents a senomorphic strategy to alleviate SASP-related aging, and provides therapeutic potential for age-related and radiotherapy-associated conditions.