Hepatic lipid metabolism has been implicated in cancer development, with cholesterol dysregulation linked to tumor initiation and progression. We examined the association between low-density lipoprotein cholesterol (LDL) levels and prostate cancer (PCa) risk in the UK Biobank cohort. This multicenter, community-based cohort study, conducted from March 2006 to December 2010, included 502,511 participants from the UK Biobank. Morbidity and mortality were analyzed in August 2023. Hazard ratios (HRs) for PCa related to hepatic blood value changes were calculated, adjusting for key variables. We extracted 204,403 healthy men and 13,205 PCa patients, subdivided into 3751 with PCa at inclusion and 9454 who developed PCa during 14.1 years of follow-up. Elevated LDL ≥ 3.65 mmol/L was associated with a reduced risk of PCa (HR = 0.83, 95% CI = 0.77–0.90, p < 0.01). To exclude confounding from cardiovascular morbidity, we compared the prevalence of myocardial infarction, stroke, and peripheral arterial disease between LDL groups. The combined prevalence of myocardial infarction, stroke, or peripheral arterial disease was similar between low and high LDL (2.67% vs. 2.49%; OR = 0.93, p < 0.01). Fine–Gray competing risk models further confirmed that high LDL remained inversely associated with PCa risk (sHR = 0.92, 95% CI = 0.88–0.96, p < 0.01), indicating that the observed association is not explained by excess cardiovascular mortality or differential cardiovascular morbidity. A significant association was also found between paternal PCa and the risk of PCa (HR = 1.34, 95% CI = 1.16–1.54, p < 0.01). Elevated alanine aminotransferase (ALT ≥ 50 U/L) was protective (HR = 0.69, 95% CI = 0.56–0.84, p < 0.01), and matched cohort analyses confirmed a protective association with diabetes mellitus (HR = 0.78, 95% CI = 0.68–0.90, p < 0.01). Elevated LDL was consistently associated with a reduced risk of PCa, independent of cardiovascular morbidity and competing mortality. ALT elevation and diabetes mellitus also showed protective associations, though less pronounced.
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