AQP1/4, CLIC5 dysregulation and lipid metabolism alterations in lung cancer.

To advance the development of novel therapies for lung cancer, we investigated tumor-associated molecules implicated in tumorigenesis. RNA-seq data were generated from paired tumors and adjacent normal tissues of four patients with lung squamous cell carcinoma (LUSC) and five patients with lung adenocarcinoma (LUAD). Additional analyses utilized RNA-seq data from The Cancer Genome Atlas (TCGA), including paired tumor and adjacent normal samples (51 LUSC, 57 LUAD) and tumor-only samples (450 LUSC, 461 LUAD). Adjacent normal tissues served as controls. Our RNA-seq results showed strong concordance with TCGA data. Ion channels Aqp1, Aqp4, and Clic5 were significantly downregulated in lung tumors, whereas enzymes involved in membrane lipid metabolism, including phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol (Cho), were upregulated in lung tumors. Cardiolipin (CL), a mitochondrial inner membrane lipid, was downregulated in lung tumors. These changes might have impaired oxygen permeability and mitochondrial function, promoting hypoxia and reactive oxygen species (ROS) production. Hif1α expression was elevated in both LUSC and LUAD, along with a hypoxia-responsive protein kinase Csnk2a1 and its downstream targets Hdac1 and Hdac2. ROS-responsive transcription factors Yy1, Foxm1, E2f1, and E2f8 were also significantly upregulated in both LUSC and LUAD. Notably, the master epigenetic regulator Uhrf1 activated by these transcription factors showed marked overexpression in tumors compared to that in normal tissues. TCGA data corroborated these findings. Our study identified tumor cell membrane-associated molecules, including ion channels (Aqp1, Aqp4, Clic5) and membrane lipid metabolism enzymes (PC, SM, Cho, and CL), as critical contributors to lung tumorigenesis. These molecules represent promising targets for developing innovative anti-cancer therapies. [BMB Reports 2026; 59(6): 329-340].