A novel disulfidptosis-related prognostic gene signature and experimental validation identify ACTN4 as a novel therapeutic target in lung adenocarcinoma

Background: Lung adenocarcinoma (LUAD) is a prevalent form of malignancy globally. Disulfidptosis is novel programmed cell death pathway based on disulfide proteins, may have a positive impact on the development of LUAD treatment strategies.

Objective: To investigate the impact of disulfidptosis-related genes (DRGs) on the prognosis of LUAD, developed a risk model to facilitate the diagnosis and prognostication of patients. We also explored ACTN4 (DRGs) as a new therapeutic biomarker for LUAD.

Methods: We investigated the expression patterns of DRGs in both LUAD and noncancerous tissues. To assess the prognostic value of the DRGs, we developed risk models through univariate Cox analysis and lasso regression. The expression and function of ACTN4 was evaluated by qRT-PCR, immunohistochemistry and in vitro experiments. The TIMER examined the association between ACTN4 expression and immune infiltration in LUAD.

Results: Ten differentially expressed DRGs were identified. And ACTN4 was identified as potential risk factors through univariate Cox regression analysis (P< 0.05). ACTN4 expression and riskscore were used to construct a risk model to predict overall survival in LUAD, and high-risk demonstrated a significantly higher mortality rate compared to the low-risk cohort. qRT-PCR and immunohistochemistry assays indicated ACTN4 was upregulated in LUAD, and the upregulation was associated with clinicopathologic features. In vitro experiments showed the knockdown of ACTN4 expression inhibited the proliferation in LUAD cells. The TIMER analysis demonstrated a correlation between the expression of ACTN4 and the infiltration of diverse immune cells. Elevated ACTN4 expression was associated with a reduction in memory B cell count. Additionally, the ACTN4 expression was associated with m6A modification genes.

Conclusions: Our study introduced a prognostic model based on DRGs, which could forecast the prognosis of patients with LUAD. The biomarker ACTN4 exhibits promise for the diagnosis and management of LUAD, given its correlation with tumor immune infiltration and m6A modification.