ALDH1A3 Regulates Cellular Senescence and Senescence-Associated Secretome in Prostate Cancer

Background: Radiotherapy is a key treatment for cancer, effectively controlling local tumor growth through DNA damage that induces senescence or apoptosis in cancer cells. However, radiotherapy can trigger complex cellular reactions, such as cell senescence, which is characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors known as the senescent-associated secretory phenotype (SASP). Methods: This study investigates the regulatory role of ALDH1A3, a key enzyme implicated in cancer cell metabolism and radiotherapy resistance, in the induction of senescence and SASP. Using in vitro models, we demonstrate that ALDH1A3 knockdown accelerates cellular senescent-like phenotype while regulating the SASP through the cGAS-STING immune response pathway. Results: Our results indicate that while ALDH1A3 knockdown promotes senescence, it reduces the secretion of pro-inflammatory factors via inhibition of the cGAS-STING pathway, potentially mitigating SASP-related tumor progression. Conclusions: These findings provide insights into the molecular mechanisms underlying prostate cancer cell senescence and suggest that ALDH1A3 could be a potential therapeutic target to enhance the efficacy of radiotherapy while controlling the adverse effects of SASP.