Transcriptomic Analysis Reveals Mitochondrial and Cytoskeletal Rewiring in Anlotinib-Treated Non-Small Cell Lung Cancer CellshoA/ROCK Signaling in Non–Small Cell Lung Cancer
DOI:
https://doi.org/10.64229/6nkpjy56Keywords:
Anlotinib, Non-small cell lung cancer, Mitochondrial metabolism, Oxidative phosphorylation, Extracellular matrix remodeling, RhoA/ROCK signaling, Bioinformatics, RNA-sequencing, Bioinformatics analysis, Tumor drug targetingAbstract
The dense extracellular matrix (ECM) and elevated mechanical stress within solid tumors significantly hinder antitumor drug penetration and therapeutic efficacy. Anlotinib, a multi-target tyrosine kinase inhibitor, has emerged as a promising agent capable of improving intratumoral drug distribution; however, the mitochondrial mechanisms underlying its stromal-modulating effects remain insufficiently characterized. RNA-sequencing data from Anlotinib-treated and control A549 non-small cell lung cancer (NSCLC) cells were retrieved from the GEO database (GSE237818). Differentially expressed genes (DEGs) were identified using DESeq2. A comprehensive mitochondrial and oxidative phosphorylation gene panel was curated from MitoCarta3.0, MitoPathways, Molecular Signatures Database (MSigDB), and Reactome. Mitochondrial-related differentially expressed genes (MG-DEGs) were identified by intersecting DEGs with mitochondrial gene sets. Protein-protein interaction (PPI) networks were constructed using STRING, hub genes were identified using CytoHubba, and functional enrichment analyses were performed using Gene Ontology (GO) and pathway databases. Anlotinib treatment induced widespread transcriptional remodeling in NSCLC cells, with robust differential expression across multiple metabolic and structural pathways. Intersection analysis identified 191 mitochondrial-related DEGs, indicating selective modulation of mitochondrial function. PPI analysis revealed tightly interconnected mitochondrial networks, with hub genes enriched in oxidative phosphorylation, electron transport chain activity, and mitochondrial ATP synthesis. Functional enrichment further demonstrated significant associations with cytoskeletal organization and RhoA/Rho-associated protein kinase (ROCK) signaling pathways, suggesting a mechanistic link between mitochondrial metabolism, ECM remodeling, and tumor mechanical properties. Collectively, this integrative transcriptomic analysis identifies mitochondrial bioenergetic reprogramming as a prominent feature of Anlotinib-treated NSCLC cells and suggests a potential association between mitochondrial metabolism and tumor mechanical regulatory pathways. These findings are hypothesis-generating and provide a computational framework for future experimental studies investigating the mitochondrial-ECM interplay in tumor drug response.
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