M6A-ALKBH5-dependent RBMS3-AS3 down-regulation suppresses ferroptosis to promote lung adenocarcinoma progression through HNRNPDL/ZEB1/GPX4 axis.

N6-methyladenosine (m6A) methylation modification can influence lung adenocarcinoma (LUAD) progression by regulating gene expression. Ferroptosis, a novel regulated cell death, is involved in various malignant progression. This study aimed to elucidate the role of ferroptosis-related long non-coding RNA (lncRNA) with m6A modification in LUAD. By integrating MeRIP-seq and RNA-seq data from in-house samples and public databases, we identified that lncRNA RBMS3-AS3 was abnormally downregulated in LUAD. The low expression of RBMS3-AS3 predicted poor prognosis in LUAD patients. RBMS3-AS3 was downregulated by m6A "eraser" ALKBH5 in an m6A-dependent manner. Reduced RBMS3-AS3 expression promoted LUAD progression in vitro and in vivo through inhibiting ferroptosis. Mechanistically, RBMS3-AS3 directly bound to HNRNPDL, recruiting it from the nucleus to the cytoplasm to stabilize ZEB1 mRNA. ZEB1 interacted with the E-box motif in the GPX4 promoter, suppressing GPX4 transcription and thereby promoting ferroptosis. In conclusion, RBMS3-AS3, epigenetically downregulated by ALKBH5, facilitates LUAD progression by inhibiting ferroptosis via the HNRNPDL/ZEB1/GPX4 axis, and may serve as a novel therapeutic target for LUAD.