CircSP3 modulates apoptosis and participates in inorganic arsenic carcinogenesis through phosphorylation and ubiquitination of p65

Inorganic arsenic (iAs) is a well-established carcinogen known to dysregulate gene expression, but its impact on circular RNAs (circRNAs) remains poorly characterized. Here, we demonstrated that NaAsO₂ (20, 40, 60 μmol/L) upregulated circSP3 (hsa_circ_0002642) expression in A549 cells (human lung adenocarcinoma cell line), independent of its methylated metabolites (MMA and DMA). Functionally, circSP3 silencing induced mitochondrial apoptosis, evidenced by reduced Bcl-2/Bax ratio, cytochrome c release, and caspase-7/PARP1 cleavage. Crucially, circSP3 knockdown attenuated NF-κB signaling through ubiquitin-mediated degradation of p65, concomitant with decreased phosphorylation of p65 (Ser536) and IκBα (Ser32/36). RNA immunoprecipitation revealed direct interactions between circSP3 and both p65 and IκBα, with iAs exposure reducing these binding affinities despite increasing circSP3 abundance. Collectively, our findings identify circSP3 as an iAs-responsive regulator of NF-κB-driven survival via post-translational control of p65 stability, providing mechanistic insights into iAs carcinogenesis.