Identification of ATG4B and NLRP1 as M1 Macrophage-Activating-Related Plasma Proteins in Systemic Lupus Erythematosus via Multi-Omics Approaches.

Introduction: This study aimed to identify systemic lupus erythematosus (SLE)-associated plasma proteins, particularly those linked to M1 macrophage activation, using an integrative multi-omics approach.

Methods: We performed two-sample Mendelian randomization (MR) analysis using protein quantitative trait loci data and SLE genome-wide association study (GWAS) data to assess associations between genetically predicted plasma protein levels and SLE risk. Validation was conducted using FinnGen SLE data, supplemented by single-cell RNA sequencing (scRNA-seq), Bayesian colocalization, in vitro M1 macrophage experiments of primary human peripheral blood monocytes and THP-1 cells, SLE patients' plasma sample validation, and molecular dynamics simulations.

Results: By integrating MR analysis, scRNA-seq analysis, Bayesian colocalization analysis, and in vitro M1 macrophage activation experiments, this study identified ATG4B, NLRP1, and PDCD4 as important causal plasma proteins associated with M1 macrophage activation. The plasma samples of patients with SLE validated the protein expression of ATG4B and NLRP1. Phenome-wide association studies (PheWASs) found no significant links between these proteins and other complex traits. Drug target analysis, molecular docking, and molecular dynamics simulations supported the strong binding affinities and stability for the target proteins ATG4B and NLRP1 with their candidate drugs.

Conclusion: Our multi-omics and molecular dynamics simulation identified ATG4B and NLRP1 as potential SLE biomarkers and therapeutic targets, with implications for M1 macrophage-driven pathogenesis.