Systemic Dyslipidemia Drives Pan-Cancer Prognosis via Epigenetic Remodeling: A Hybrid Pi-Score Analysis

Background/Objectives: Dyslipidemia is a prevalent metabolic disorder and a recognized risk factor for cancer mortality. However, it remains unclear whether systemic lipid profiles in the general population share epigenetic landscapes that drive cancer aggressiveness. Methods: We analyzed blood DNA methylation profiles alongside three key lipid variables (triglycerides [TGY], total cholesterol [TCH], and HDL cholesterol [HDL]) from 2749 individuals in the KoGES cohort. These were integrated with TCGA data across 32 cancer types using a novel ‘Hybrid Pi-score’ algorithm to capture robust epigenetic associations. Results: The global epigenetic landscape revealed that triglycerides (TGY) share a significantly broader and stronger epigenetic network with cancer prognosis compared to cholesterol markers, particularly in metabolic cancers like LIHC and KIRC. Directional consistency analysis confirmed that methylation alterations associated with hypertriglyceridemia in healthy individuals mirror those observed in high-mortality cancer groups. Network analysis identified CPT1A (carnitine palmitoyltransferase 1A) as a master epigenetic locus, acting as a central hub linking dyslipidemia to tumor progression. Conclusions: This study provides molecular evidence that systemic dyslipidemia, particularly elevated triglycerides, drives oncogenic epigenetic remodeling. The identification of CPT1A suggests that managing lipid profiles may be critical for mitigating the “metabolic fuel” that accelerates cancer progression. These findings advocate for integrating lipid biomarkers into cancer risk stratification.