Identification of a Novel Signature Based on Ferritinophagy-Related Genes to Predict Prognosis in Lung Adenocarcinoma: Focus on AHNAK2

Abstract

Background: Lung adenocarcinoma (LUAD) accounts for over 40% of all non-small cell lung cancer (NSCLC) cases and continues to be difficult to treat despite advancements in diagnostics and therapies. Ferritinophagy, a newly recognized autophagy process linked to ferroptosis, has been associated with LUAD development. Recent studies have shown a dysregulation of genes related to ferritinophagy in LUAD, indicating its potential as a therapeutic target. Methods: We constructed a predictive model using seven genes associated with ferritinophagy. The model’s accuracy was evaluated across three independent gene expression datasets. We analyzed the biological functions, immune environment, mutations, and drug sensitivities in groups with high and low risk. Utilizing a single-cell sequencing (scRNA-seq) dataset, we confirmed the expression of the model genes and identified a subtype of epithelial cells expressing AHNAK2. We further investigated the impact of the ferritinophagy-related gene AHNAK2 on LUAD cell proliferation, invasion, migration, and ferroptosis in vitro. Results: Our prediction model, comprising seven genes (AHNAK2, ARNTL2, CD27, LTB, SLC15A1, SLC2A1, and SYT1), has shown potential in predicting the prognosis of individuals diagnosed with LUAD. Notably, AHNAK2 impedes ferroptosis, promoting LUAD progression in vitro. Conclusions: Our research suggests that ferritinophagy-associated genes are promising prognostic markers for LUAD and lay the groundwork for further exploration of ferritinophagy’s role in LUAD. Furthermore, we present AHNAK2 as a novel regulator of ferroptosis, which requires further investigation to understand its mechanism.

Keywords

• lung adenocarcinoma
• ferritinophagy
• prognostic signature
• immune landscape
• therapeutic response
• AHNAK2