Elucidating the interplay between phospholipid biosynthesis and oxidative stress responses in the tumorigenesis of Clear Cell Renal Cell Carcinoma

Background: Phospholipids are essential components of biological membranes that regulate diverse cellular processes. Cardiolipin (CL) is a mitochondria-specific phospholipid crucial for maintaining mitochondrial structure and function. However, its role in clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: Comprehensive phospholipidomic profiling of paired tumor and normal kidney tissues from ccRCC patients was performed using LC-TQMS. Quantitative data were integrated with immunoblotting, immunohistochemistry, and transcriptomic analyses from both TCGA and an institutional RNA-seq cohort. Results: CL levels were significantly reduced in tumor tissues compared with normal renal cortex, whereas other phospholipids (PA, PI, PS and PG) showed no significant differences. Reduced CL content paralleled decreased VDAC1 expression, indicating lower mitochondrial abundance. Lipidomic analysis revealed selective suppression of unsaturated CL species in tumors, suggesting mitochondrial membrane remodeling induced by oxidative stress. Analyses of gene expression showed a consistent increase in the expersiion of enzymes involved in CL synthesis and remodeling, namely TAMM41 and TAZ, in both TCGA and in-house datasets, with ACSL5 being the only gene that was significantly increased in fatty acid activation. Conclusions: ccRCC is characterized by quantitative and qualitative cardiolipin remodeling, reflecting mitochondrial reduction and adaptation to oxidative stress. Altered CL metabolism may represent a key mechanism of mitochondrial reprogramming in tumor cells and a potential therapeutic target in renal cancer. Statement of significance: This study identifies cardiolipin remodeling as a hallmark of mitochondrial reprogramming in clear cell renal cell carcinoma, revealing a potential therapeutic vulnerability in mitochondrial lipid metabolism.