Arsenic-responsive hsa_circ_0000118 couples early stress granule dynamics to later NF-κB-related signaling adaptation in NSCLC.

Arsenic exposure is closely associated with lung carcinogenesis, but how cells transition from early stress buffering to later adaptive remodeling remains unclear. Stress granules (SGs) are key cytoplasmic condensates formed during acute stress, yet whether arsenic-responsive circular RNAs (circRNAs) participate in this process in non-small cell lung cancer (NSCLC) is poorly understood. Here, we identified hsa_circ_0000118 as an arsenic-responsive circRNA that was upregulated in both arsenic-exposed human subjects and arsenite-treated NSCLC cells. Silencing hsa_circ_0000118 impaired cell viability, promoted apoptosis, suppressed proliferation, and increased vulnerability to sustained arsenic stress. Mechanistically, acute arsenite exposure induced mitochondrial dysfunction and SG assembly before overt cytotoxicity. Under these conditions, loss of hsa_circ_0000118 increased SG susceptibility and delayed SG clearance during recovery. The RNA-binding protein quaking (QKI) acted upstream in this process, as QKI knockdown reduced hsa_circ_0000118 expression, weakened its association with G3BP1-related complexes, and phenocopied the SG-sensitive state. In contrast, under sustained arsenic stress, loss of hsa_circ_0000118 disrupted nuclear factor kappa B (NF-κB)-related adaptive output, characterized by accumulation of p105 and p65 but reduced downstream survival-related signaling. P65 also showed partial colocalization with G3BP1-positive granules after acute arsenite exposure, suggesting a possible spatial link between early SG remodeling and later NF-κB-related signaling dysregulation. Overall, hsa_circ_0000118 is associated with both acute SG dynamics and sustained NF-κB-related survival output in arsenite-treated NSCLC cells. These findings identify hsa_circ_0000118 as a candidate component of arsenic-associated stress adaptation.