Mendelian Randomization Identifies Lipidomic Signatures of Depression Risk That Are Partly Reflected in Cortisol-Induced Membrane Remodeling and Modulated by St. John’s Wort Extract (Ze 117)

Major depressive disorder (MDD) is associated with altered membrane lipids, but the causal species remain uncertain. Using two-sample Mendelian randomization (MR) on lipidomic GWAS data and the latest MDD meta-analysis (~400,000 cases; 1.5 million controls), we identified 49 lipid species linked to MDD risk, notably enriched for phosphatidylcholines. Protective lipids were enriched for long-chain polyunsaturated fatty acids (20:3–20:5), whereas shorter-chain or less unsaturated species, particularly 18:2-containing lipids, increased risk. These associations were also observed in a subset of clinically assessed MDD cases. Colocalization supported shared causal variants between many lipid traits and MDD, prominently at the FADS1/2 locus and additional loci, suggesting multiple entry points into lipid metabolism that differ partly from bipolar disorder. MR-implicated lipid shifts overlapped with cortisol-induced changes in a human cell stress model and were often reversed by co-treatment with St. John’s wort extract (Ze 117). Cholesteryl ester 20:3 emerged as a robust candidate marker, showing protective MR effects in two cohorts, colocalizing genetic support, normalization by Ze 117, and an inverse correlation with depressive symptom severity in a non-clinical sample. Together, these results define a depression-associated lipidomic signature centered on polyunsaturated fatty acid metabolism with biomarker and therapeutic potential.