Abstract
Background: Lung adenocarcinoma (LUAD) stands as a prominent subtype within the realm of non-small cell lung cancer and constitutes a primary contributor to cancer-related mortality on a global scale. Notably, hypoxia, a prevalent attribute within solid tumor environments, and mitophagy, a selective manifestation of autophagy dedicated to the removal of damaged mitochondria, have risen to prominence as pivotal factors influencing the initiation and advancement of tumorigenesis. Methods: This investigation harnessed publicly accessible genomic datasets encompassing LUAD patients to delineate genes linked to hypoxia and mitophagy, termed hereafter as hypoxia and mitophagy-related genes (HMRGs). Large-scale repositories furnished both gene expression profiles and clinical particulars. The expression profiles of HMRGs were meticulously scrutinized across 1,093 LUAD specimens, leveraging resources such as The Cancer Genome Atlas and Gene Expression Omnibus datasets. A methodical exploration of HMRG patterns within LUAD led to the discernment of two distinct molecular subtypes. Moreover, a discernible correlation emerged between the subtypes and their respective clinical attributes. A risk scoring system was formulated to prognosticate overall survival (OS) and therapeutic responsiveness in LUAD patients. Subsequently, the reliability of this scoring system was authenticated, and a nomogram was adopted to refine the clinical utility range of the risk score. The proliferation and migration impacts of KRT8 on LUAD cells were evaluated through cck8 assays, edu assays, and transwell assays, the results were further validated in vivo. Results: Elevated risk scores were indicative of unfavorable OS probabilities. Furthermore, these risk scores exhibited associations with immune checkpoints and chemotherapeutic drug sensitivity. Collectively, our exhaustive analysis of HMRGs in LUAD patients unveiled their conceivable participation in configuring the multifaceted tumor microenvironment, encompassing clinicopathological attributes and prognosis. A sequence of experiments illuminated the pro-proliferative and pro-migratory attributes of KRT8 in vitro and vivo, thus underscoring its carcinogenic potential. Conclusions: In this study, we have unearthed innovative gene signatures tethered to HMRGs, which harbor prognostic implications concerning patient outcomes. These insights hold potential for steering the development of targeted therapeutic modalities tailored for LUAD.