AC129507.1 is a ferroptosis-related target identified by a novel mitochondria-related lncRNA signature that is involved in the tumor immune microenvironment in gastric cancer.

Background: Gastric cancer (GC) is one of the most common malignancies. Previous studies have shown that mitochondrial metabolism is associated with malignancies. However, relevant research on mitochondria-related lncRNAs in GC is lacking.

Methods: We integrated the corresponding information of patients with GC from The Cancer Genome Atlas (TCGA) database. Mitochondria-related lncRNAs were selected based on differential expression and a correlation analysis to construct a prognostic model. The mutation data were analyzed to distinguish differences in the tumor mutation burden (TMB). Single-sample gene set enrichment analysis (ssGSEA) was performed to evaluate immunological differences. A series of cell-based experiments were adopted to evaluate the biological behavior of GC.

Results: A total of 1571 mitochondria-related lncRNAs were identified. A prognostic signature incorporating nine lncRNAs was built based on 293 suitable GC cases and could predict patient prognosis. The TMB and ssGSEA indicated that the low-risk group displayed increased immune function. The enrichment analysis indicated that the differentially expressed genes were enriched in metabolic functions. AC129507.1 was significantly upregulated in GC cells and associated with a poor prognosis, and its knockdown inhibited the proliferation and migration of GC cells. Mechanistically, silencing AC129507.1 led to abnormal glycolipid metabolism and oxidative stress, thus inducing ferroptosis.

Conclusions: Our nine-lncRNA risk signature could powerfully predict patient prognosis. AC129507.1 promoted the malignant phenotypes of GC cells. AC129507.1 could play a nonnegligible role in GC by promoting the formation of a immunosuppressive tumor microenvironment by inhibiting the initiation of ferroptosis, which needs to be further explored.