Lipid-lowering drugs affect lung cancer risk via sphingolipid metabolism: a drug-target Mendelian randomization study.

The causal relationship between lipid-lowering drug (LLD) use and lung cancer risk is controversial, and the role of sphingolipid metabolism in this effect remains unclear. Genome-wide association study data on low-density lipoprotein (LDL), apolipoprotein B (ApoB), and triglycerides (TG) were used to develop genetic instrumental variables (IVs) for LLDs. Two-step Mendelian randomization analyses were performed to examine the causal relationship between LLDs and lung cancer risk. The effects of ceramide, sphingosine-1-phosphate (S1P), and ceramidases on lung cancer risk were explored, and the proportions of the effects of LLDs on lung cancer risk mediated by sphingolipid metabolism were calculated. inhibition decreased the lung cancer risk in ever-smokers via ApoB (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.70-0.92, = 0.010), LDL (OR 0.82, 95% CI 0.71-0.96, = 0.040), and TG (OR 0.63, 95% CI 0.46-0.83, = 0.015) reduction by 1 standard deviation (SD), decreased small-cell lung cancer (SCLC) risk via LDL reduction by 1 SD (OR 0.71, 95% CI 0.56-0.90, = 0.016), and decreased the plasma ceramide level and increased the neutral ceramidase level. inhibition decreased the lung adenocarcinoma (LUAD) risk (OR 0.60, 95% CI 0.43-0.84, = 0.039) but increased SCLC risk (OR 2.18, 95% CI 1.17-4.09, = 0.029) via ApoB reduction by 1 SD. inhibition increased SCLC risk via ApoB reduction by 1 SD (OR 3.04, 95% CI 1.38-6.70, = 0.014). The agonist decreased SCLC risk via ApoB (OR 0.20, 95% CI 0.07-0.58, = 0.012) and TG reduction (OR 0.58, 95% CI 0.43-0.77, = 0.003) while increased the plasma S1P level. inhibition decreased the ceramide level. Neutral ceramidase mediated 8.1% and 9.5% of the reduced lung cancer risk in ever-smokers via ApoB and TG reduction by inhibition, respectively, and mediated 8.7% of the reduced LUAD risk via ApoB reduction by inhibition. We elucidated the intricate interplay between LLDs, sphingolipid metabolites, and lung cancer risk. Associations of , , and inhibition and agonist with distinct lung cancer risks underscore the multifaceted nature of these relationships. The observed mediation effects highlight the considerable influence of neutral ceramidase on the lung cancer risk reduction achieved by and inhibition.