Identifying a Novel Six‐LncRNA Signature Evaluates Survival and Reveals AC129507.1 as the m 6 A‐Target to Regulate Ferroptosis in Gastric Cancer

ABSTRACT Gastric cancer (GC) has become a serious threat to global health with escalating incidence and mortality. There is a lack of effective approach to evaluate prognostic survival and stratify high‐risk patients due to the highly heterogeneous characteristics of GC. In this study, we integrated N6‐methyladenosine (m 6 A) RNA modification, ferroptosis gene sets, and lncRNA transcriptomic data together, established and validated a novel six‐lncRNA profile associating with the survival of GC. The m 6 A‐ferroptosis lncRNA signature could identify high‐risk GC patients and characterize the immunosuppressive tumor microenvironment (TME). In our GC cohort, the 3‐ and 5‐year survival rates of the high‐risk compared with low‐risk subgroup were 27.8% versus 54.8% and 22.2% versus 50.0%, respectively. Multiplex immunofluorescence assays indicated that high‐risk GC samples frequently had less infiltration of CD8 + T cells but exhibited abundant immunosuppressive M2‐polarized macrophages and Tregs. The differentially expressed genes were primarily enriched in oxidative stress response, reactive oxygen species, RNA metabolic processes, the PI3K‐Akt signaling axis, and leukocyte transendothelial migration pathways. Accordingly, high‐risk patients might be sensitive to inhibitors targeted at PDK1, tyrosine kinase, PI3K, and HIF‐proly1 hydroxylase, whereas the low‐risk subgroup might benefit from blockade of ErbB, TrkA, PARP, and Ribosomal S6 kinase. Moreover, we demonstrated that the high‐risk factor AC129507.1 in the lncRNA signature was a novel target of the m 6 A regulatory axis WTAP/YTHDF3/ALKBH5, and depletion of AC129507.1 could markedly induce ferroptosis in GC. Collectively, these findings provide a candidate strategy for risk classification and better clinical management of GC and shed new insight into the underlying mechanism of AC129507.1 in GC development.