Abstract B003: cGAS inhibits TP53 and prevents DLBCL cell lines from ferroptosis death

Abstract Although the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been well recognized as the sensor of cytosolic DNA and plays a critical role in regulating anti-tumor immunity and cell death, whether and how cGAS plays a role in tumorigenesis and tumor progression is not well understood. Here we show that high level of cGAS was associated with poor prognosis in DLBCL patients. Using CRISPR-cas9 cGAS knockout DLBCL cell lines, we find that cGAS inhibition leads to a significant decrease of cell viability, cell growth and proliferation rate, and a significant increase of ferroptosis with mitochondrial and lipid ROS accumulation. These phenotypes can be largely rescued with ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1). Pharmaceutically inhibition of cGAS with a cGAS inhibitor G140 exhibited the same phenotype. Furthermore, we find that this cGAS induced ferroptosis resistance is not STING dependent. In vivo mouse xenograft models also showed a decrease of tumor growth with cGAS knockout. Mechanically, cGAS inhibits tumor suppressor TP53 protein expression and prevents DLBCL cell lines from undergoing ferroptosis. cGAS knockout leads to a rescue of TP53 and a decrease of MDM2, which sensitizes cells to ferroptosis. Our findings uncover a new mode of tumor promotion based on cGAS regulation of p53-MDM2, ROS responses and ferroptosis. Collectively, this previously unrecognized role for cGAS in cancer progression suggests that cGAS can serve as potential targets for new cancer interventions. Citation Format: Rui Wang, Bingzong Li. cGAS inhibits TP53 and prevents DLBCL cell lines from ferroptosis death [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B003.