A Model of Cellular Proliferation and Mitochondrial Biogenesis Predicts Prognosis and Immunotherapy Response in Lung Adenocarcinoma

Background: Lung adenocarcinoma (LUAD), which is the leading subtype of non-small cell lung cancer (NSCLC), constitutes considerable difficulties in accurate prognostic assessment and targeted therapeutic options. Cellular proliferation-related genes (CPGs) and mitochondrial biogenesis-related genes (MBGs) play critical roles in tumor metabolic reprogramming; however, their prognostic value and molecular mechanisms in LUAD are poorly understood.

Methods: By utilizing The Cancer Genome Atlas (TCGA)-LUAD and GSE72094 datasets, this investigation formulated a risk scoring model through differential expression screening combined with Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis. The molecular characteristics and clinical implications of the risk model were investigated via immune microenvironment evaluation, genomic alteration analysis, and drug sensitivity prediction. The functional contributions of key genes were further substantiated using quantitative reverse transcription polymerase chain reaction (qRT-PCR), commercial assay kits, the JC-1 fluorescent probe, the Cell Counting Kit-8 (CCK-8), Transwell invasion assays, and wound healing assays.

Results: A risk model based on seven CPGs and MBGs (PLK1, HMMR, CYP27A1, LDHA, NPAS2, KRT17, CIDEC) demonstrated dependable predicted outcomes in both GSE72094 and the TCGA-LUAD cohorts. Enhanced tumor heterogeneity and an immunosuppressive microenvironment were observed in high-risk group. Drug sensitivity analysis pointed that the risk model could guide personalized treatment strategies; for instance, high-risk patients showed increased susceptibility to agents such as Docetaxel and 5-Fluorouracil. In vitro experiments demonstrated that the key gene CIDEC exhibited upregulated expression in LUAD tissues and cells. Knockdown of CIDEC led to enhanced cellular energy metabolism and increased mitochondrial membrane potential, while also effectively suppressing cell invasion, proliferation, and migration.

Conclusions: The established MBGs/CPGs prognostic model provides a novel tool for stratification treatment planning in LUAD, underscoring the crucial roles of cellular proliferation and mitochondrial biogenesis in tumor progression. Functional validation of CIDEC offers experimental support for the development of potential therapeutic strategies.