Dissecting Immune Cell Ferroptosis via Single-Cell Multi-Omics Identifies RPL8 as a Potential Therapeutic Target for...

Depression is a major global health burden with limited treatment efficacy. Ferroptosis, an iron-dependent form of regulated cell death, is implicated in its pathogenesis, but causal genetic links and cell-type-specific mechanisms remain unclear. We employed a multi-omics framework integrating two-sample Mendelian randomization (MR) using blood cis-eQTLs (eQTLGen/GTEx) and depression (FinnGen), single-cell eQTL (sceQTL) mapping in peripheral immune cells (OneK1K cohort), bioinformatic analyses, and in silico molecular docking. MR identified 42 ferroptosis genes associated with depression. Replication across cohorts pinpointed ribosomal protein RPL8 as a key protective factor (β = -0.02 to -0.06, P_FDR < 0.05). RPL8 expression was enriched in blood/immune cells. sceQTL analysis revealed its protective effect was mediated through 11 immune cell subtypes (e.g., CD4+/CD8+ T, B, NK cells; β range: -0.016 to -0.040, P_FDR < 0.05). Molecular docking predicted high-affinity binding between RPL8 and the ferroptosis execution ligand Ncoa4-9A (ΔG = -9.3 kcal/mol). PheWAS indicated a favorable safety profile for RPL8 modulation. This study presents genetic evidence suggesting a potential causal link between ferroptosis and depression, and identifies RPL8 as a potential immune cell-mediated protective factor. Based on these findings, we propose the "immune-ribosome-ferroptosis" axis as a promising direction for future therapeutic exploration.