Circular RNAs (circRNAs) exert critical regulatory functions in tumor biology by modulating pathways associated with oncogenesis or tumor suppression. Despite substantial progress in elucidating their roles in several malignancies, the contribution of circRNAs to the pathogenesis of driver gene-negative lung adenocarcinoma (LUAD), a molecular subtype lacking actionable genetic alterations and exhibiting limited response to existing targeted or immunotherapeutic strategies, remains poorly defined.

The expression of circRNF10 in driver gene-negative LUAD was analyzed using circRNA microarray analysis followed by RT-qPCR validation. A series of functional assays were performed both in vitro and in vivo to evaluate the effects of circRNF10 on tumor cell behavior, including proliferation (EdU incorporation), migration (wound healing), and invasion (transwell assays), as well as tumor growth in a murine model. To elucidate the underlying molecular mechanism, we employed a combination of computational and experimental approaches, including AlphaFold3-based structural prediction, in vitro transcription, biotin-labeled RNA pulldown, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays.

In this study, we identified a previously uncharacterized circular RNA, circRNF10, which is markedly downregulated in driver gene-negative lung adenocarcinoma (LUAD) and positively associated with favorable clinical outcomes. Functional analyses revealed that circRNF10 overexpression suppresses LUAD cell proliferation, migration, and invasion in vitro and in vivo, primarily through inhibition of the Wnt/β-catenin signaling pathway. Mechanistically, circRNF10 directly interacts with β-catenin via its cyclization site, thereby promoting β-catenin degradation. Moreover, circRNF10 functions as a competing endogenous RNA by sequestering miR-1275, thereby alleviating the miR-1275-mediated suppression of DKK3, a potent inhibitor of the Wnt pathway. Our findings further confirm that circRNF10 promotes β-catenin degradation through direct interaction and modulation of the miR-1275/DKK3 signaling cascade.

Collectively, our findings highlight circRNF10 as a tumor suppressor in driver gene-negative LUAD and suggest that restoring circRNF10 expression represents a promising therapeutic approach for this refractory subtype.