Identification of prognostic biomarker of non-small cell lung cancer based on mitochondrial permeability transition-driven necrosis-related genes and determination of anti-tumor effect of ARL14.

Abstract

Background: Mitochondrial permeability transition (MPT)-driven necrosis (MPTDN) is a non-apoptotic mode of cell death triggered by oxidative stress and cytosolic Ca²⁺ overload. Recent evidence suggests that activation of MPTND can effectively induce cancer cell death and may represent a novel therapeutic strategy for cancer. Yet, the role of MPTDN-related genes in non-small cell lung cancer (NSCLC) remains unrevealed. This study aimed to identify MPTDN-related biomarkers for predicting prognosis and guiding treatment in NSCLC.

Methods: Gene expression profiles and clinical information of NSCLC were collected from public databases, and MPTDN-related genes were obtained from published article. Differential expressed MPTDN-related genes in NSCLC and control were screened, and molecular clusters were obtained. Based on the differentially expressed genes (DGEs) between clusters, univariate Cox and LASSO regression analyses were performed to screen biomarkers, followed by nomogram construction. Correlations between these biomarkers and immune cell infiltration, immune checkpoints, and chemotherapeutic agents were observed. Expression levels of MPTDN-related biomarkers were detected using RT-qPCR in NSCLC tissues and cells. Moreover, the biological function of ARL14 in NSLCL was verified in vitro.

Results: Thirty-five differential MPTDN-related genes were identified, and two molecular clusters were obtained. Three biomarkers with prognostic values were finally screened, including ARL14, ZDHHC11B, and HLF. Among them, ARL14 was significantly upregulated in tumor samples, while ZDHHC11B and HLF were downregulated. Nomogram containing three genes exhibited predictive accuracy in 1, 3, and 5-year survival rates. Three gene were strongly associated with most immune cells, immune checkpoints, and drugs sensitivity. RT-qPCR confirmed that expression levels of three genes in tissues or cells were consistent with the results of bioinformatics analysis. Finally, ARL14 knockdown inhibited the malignant phenotype of NSCLC cells.

Conclusion: We first performed the comprehensive analysis of MPTDN in NSCLC and screened three NSCLC-related biomarkers as promising biomarkers. ARL14 might be a new potential target for therapy of NSCLC.