m6A‐methylated circFANCB Promotes Gastric Cancer Progression by Regulating Cellular Ferroptosis Through miR‐454‐3p/CEACAM5

Abstract

Gastric cancer (GC) is a major global digestive malignancy with high incidence and mortality. Circular fanconi anemia complementation group B (circFANCB) expression is elevated in cancer, and its suppression suppresses tumor progression. However, research on the function of circFANCB in GC has not been reported yet. The role and mechanism of circFANCB in GC were investigated through circular RNA (circRNA) sequencing, database prediction, and experimental validation, including quantitative real‐time PCR (qRT‐PCR), ribonuclease R assay, nuclear‐cytoplasmic fractionation, 5‐ethynyl‐2′‐deoxyuridine assay, flow cytometry, wound healing assay, Transwell assay, tube formation assay, western blot, dual‐luciferase reporter assay, and enzyme‐linked immunosorbent assay. Furthermore, its mechanism was further explored in vivo using a xenograft nude mouse model and immunohistochemistry. Online prediction tools, methylation‐dependent RNA immunoprecipitation (MeRIP), and RNA immunoprecipitation (RIP) assays were employed to investigate whether methyltransferase‐like protein 3 (METTL3) targeted circular FANCB (circFANCB) via m6A methylation. In GC, circFANCB expression was upregulated. Knockdown of circFANCB inhibited cell proliferation, migration, invasion, and angiogenesis while promoting cell death. CircFANCB increased CEACAM5 expression by binding to miR‐454‐3p. CEACAM5 suppressed ferroptosis in GC cells. Rescue experiments confirmed that circFANCB inhibited ferroptosis by upregulating CEACAM5, thereby promoting GC cell proliferation. Animal models demonstrated that circFANCB knockdown inhibited GC tumor growth. Additionally, METTL3 enhanced circFANCB expression through m6A methylation. Rescue experiments further confirmed that METTL3 promotes the malignant phenotype of GC cells by upregulating circFANCB. The m6A‐modified circFANCB promotes the malignant progression of GC by regulating ferroptosis via the miR‐454‐3p/CEACAM5 axis, providing a theoretical basis for potential clinical therapeutic strategies.