Mechanism of interaction between ANXA6 and cGAS to regulate STING signaling pathway and promote ferroptosis in cervical cancer

Annexin A6 (ANXA6), a calcium-dependent phospholipid protein, is closely related to the prognosis of a variety of tumors. However, the function and its regulatory mechanism in tumors is largely unknown. Here, we found that tumor microenvironment ANXA6 expression was associated with unfavorable prognosis of patients with cervical cancer. Downregulation of ANXA6 in cervical cancer cells suppressed tumor cell migration, colony formation and promoted tumor cell death. Furthermore, we identified ANXA6 co-localized with cGAS and function as an inhibitor of the cGAS-STING signaling pathway by promoting the ubiquitination of cGAS. Inhibiting ANXA6 expression resulted in increase of cGAS and activation of the cGAS-STING signaling pathway, leading to elevated expression of phosphorylated TBK1, IRF3, and type I IFN stimulated gene MX1, ISG15, ISG56. In addition, downregulation of ANXA6 in cervical cancer cells impedes the K63-linked ubiquitination process of cGAS protein, resulting in an upregulation of cGAS expression. This subsequently facilitates the activation of the cGAS-STING signaling pathway, leading to increased production of reactive oxygen species and lipid peroxides in cervical cancer cells. Ultimately, these events induce ferroptosis in tumor cells. Therefore, our findings revealed that inhibiting ANXA6 can promote tumor cell ferroptosis by activating the cGAS-STING pathway, thereby provide potential strategies that enhancing the efficacy of anti-tumor immunotherapy in cervical cancer.