A DNA Methylation–LDHA–Deoxycarnitine Regulatory Axis Promotes Tumorigenesis in Clear Cell Renal Cell Carcinoma

Background: Clear cell renal cell carcinoma (ccRCC) is the predominant histological subtype of renal cancer, characterized by high recurrence and metastasis rates. Despite advances in targeted therapies, treatment resistance and poor prognosis persist, necessitating the identification of novel molecular mechanisms. Methods: We systematically investigated the role of the DNA methylation–LDHA–deoxycarnitine axis in ccRCC progression by integrating two-sample Mendelian randomization (MR), summary-data-based Mendelian randomization (SMR), and mediation analyses. Cis-eQTL, mQTL, and metabolomic GWAS datasets were utilized to establish causal relationships between DNA methylation, LDHA expression, deoxycarnitine levels, and ccRCC risk. Results: Our findings demonstrate that elevated LDHA expression, driven by hypomethylation at specific CpG sites (cg02232751, cg15700009, cg19631472), causally promotes ccRCC development. LDHA overexpression was associated with reduced deoxycarnitine levels, reflecting disrupted mitochondrial metabolism. Mediation analyses revealed that DNA methylation regulates ccRCC risk predominantly through modulation of LDHA expression and subsequent metabolic reprogramming. Furthermore, deoxycarnitine emerged as a significant metabolic mediator linking LDHA activity to tumor progression. Conclusions: This study identifies a novel epigenetic–metabolic pathway wherein DNA methylation regulates LDHA expression, reshapes deoxycarnitine metabolism, and drives ccRCC progression. These insights illuminate potential biomarkers for early detection and highlight LDHA and its metabolic network as promising therapeutic targets. Future validation in functional models and diverse populations will be critical to translate these findings into clinical applications.