Three-prime repair exonuclease 1 (TREX1) (TREX1)

Three-prime repair exonuclease 1 (TREX1) is the major 3'-to-5' DNA exonuclease in mammalian cells, primarily localized to the cytosolic face of the endoplasmic reticulum. It serves as an essential gatekeeper of immune homeostasis by degrading cytosolic DNA fragments originating from endogenous retroelements, micronuclei, or external pathogens, thereby preventing the aberrant activation of the cGAS-STING innate immune sensing pathway. Loss-of-function mutations in the TREX1 gene cause severe 'interferonopathies,' such as Aicardi-Goutières syndrome and systemic lupus erythematosus, characterized by chronic production of type I interferons and systemic inflammation. Conversely, cancer cells often upregulate TREX1 to clear immunogenic DNA generated by genomic instability or therapy, allowing them to evade immune detection. In drug development, TREX1 has emerged as a high-value oncology target where inhibition is used to 're-arm' the innate immune system within the tumor microenvironment, potentially synergizing with existing checkpoint inhibitors and radiotherapy. Several biotech companies are advancing small-molecule inhibitors to induce local STING activation and improve antitumor responses. Beyond oncology, TREX1 activators are being explored to clear circulating cell-free DNA in rheumatoid arthritis, while its role in HIV-1 uncoating makes it a candidate for antiviral strategies. Notable developmental compounds include tool inhibitors like VB-85680 and natural activators like pterostilbene.

Other names

TREX-1DNase IIIDeoxyribonuclease III3'-5' exonuclease TREX1AGS1DRN3CRVHERNS

TREX1 inhibitors block the degradation of cytosolic DNA, leading to its accumulation and subsequent activation of the cGAS-STING pathway, which induces type I interferons to enhance antitumor immunity. In inflammatory contexts, TREX1 activators enhance the clearance of cell-free DNA to suppress chronic innate immune activation.