The circSNX6 restricts dengue virus replication in association with PARP1 and ferroptosis

Dengue virus (DENV) infection poses a persistent global health challenge with no specific antiviral therapy. Although circular RNAs (circRNAs) regulate antiviral immunity, their roles in DENV infection remain largely unexplored. Here, transcriptome sequencing of peripheral blood mononuclear cells (PBMCs) from dengue patients across disease phases and severities identified 15 circRNAs consistently dysregulated across all clinical stages, enriched in ferroptosis, glutathione metabolism, and endocytosis pathways. Among these, hsa_circ_0031607 (circSNX6) was the sole circRNA linked to all three pathways and was upregulated in both dengue patients and DENV2-infected human umbilical vein endothelial cells (HUVECs). circSNX6 overexpression suppressed DENV2 replication, whereas its knockdown enhanced viral propagation. Mechanistically, circSNX6 localized to the cytoplasm and interacted with PARP1. DENV2 infection induced partial PARP1 redistribution from nucleus to cytoplasm. circSNX6 suppressed PARP1 expression; its knockdown increased global PARylation, accompanied by enhanced NRF2 PARylation and altered TFR1 and GPX4 expression. In cultured cells, ferrostatin-1 reduced and erastin enhanced DENV2 replication; olaparib or ferrostatin-1 partially attenuated the proviral effects of circSNX6 knockdown, while erastin partially reversed the antiviral effect of circSNX6 overexpression. In mice, olaparib reduced serum and hepatic viral loads and attenuated hepatic pathology; ferrostatin-1 produced comparable effects, and erastin cotreatment partially diminished olaparib-mediated protection. Together, these results delineate the circRNA landscape across dengue disease progression and identify circSNX6 as a host factor that restricts DENV2 replication in part through suppression of the PARP1-ferroptosis axis.