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Single-cell eQTL Mendelian randomization reveals the monocyte-associated PRKCB-CTSL axis as a candidate regulatory
Pengli Wang1, Guohang Shen1,2, Wenhua Liao1
1Department of Pediatric Surgery, Beijing Anzhen Nanchong Hospital of Capital Medical University & Nanchong Central Hospital, Second Clinical Medical College of North Sichuan Medical College, No. 97 Renmin South Road, Shunqing, Nanchong, 637000, Sichuan, China.
Objectives:
Rheumatoid arthritis (RA) involves persistent immune dysregulation, but cell-specific genetically regulated pathways remain unclear. We integrated cell-specific genetic and multi-omics evidence to prioritize candidate regulatory pathways.
Methods:
cis-eQTLs from 17 immune-cell populations were integrated with RA GWAS data by two-sample Mendelian randomization. Transcriptomics, WGCNA, and machine-learning feature selection identified convergent candidates. Single-cell and virtual perturbation analyses assessed cellular localization and downstream changes. Molecular docking and dynamics computationally prioritized compounds, and knockdown/rescue experiments evaluated the PRKCB-CTSL relationship.
Results:
Eleven candidates had convergent genetic and transcriptomic support. PRKCB was retained by LASSO, SVM, and random forest and preferentially expressed in monocytes. Virtual perturbation implicated CTSL and antigen-processing/presentation pathways. PRKCB knockdown reduced CTSL expression and NF-κB phosphorylation, whereas CTSL restoration partially rescued NF-κB phosphorylation. Separately, structure-based analyses computationally prioritized ursodiol for the most favorable predicted PRKCB interaction among evaluated compounds.
Conclusions:
Genetic, transcriptomic, single-cell, computational, and in vitro evidence supports monocyte-associated PRKCB-CTSL as a candidate regulatory pathway in RA. Further mechanistic and in vivo studies are required to establish its causal and pharmacological relevance. Key Points • Multi-omics analysis identified 11 key RA-associated targets. • RA was classified into two molecular subtypes with distinct immune features. • PRKCB was identified as the core target enriched in monocytes. • The PRKCB-CTSL axis may drive RA inflammation, and ursodiol showed therapeutic potential.
