Multi-omics study of ABCA1 in sepsis: Integrating mendelian randomisation, single-cell transcriptomics, in silico knockout and virtual screening.

Authors

Yang Yu, Sheng Zhang

Published in

Computational biology and chemistry. Volume 125. Pages 109311. Aug 07, 2026. Epub Aug 07, 2026.

Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysreg- ulated host response to infection, with the immune status dynamically evolving from an early hyperinflammatory phase to a late immunosuppressive phase. ABCA1 (ATP-binding cassette transporter A1) is involved in cholesterol efflux and inflammatory regulation, but its causal relationship with sepsis, cellular ori- gin, and potential for drug targeting remain unclear. This study is the first to integrate Mendelian randomisation, single-cell transcriptomics, in silico knock- out, and virtual screening to systematically investigate ABCA1 in sepsis from genetics, cell biology, mechanisms, and translational potential.
A two-sample Mendelian randomisation (MR) analysis was per- formed using blood eQTLs of ABCA1 as the exposure and a sepsis GWAS as the outcome. Public single-cell dataset GSE151263 was analysed using Seurat to localise ABCA1 expression. In silico knockout of ABCA1 was performed in CD16 + monocytes, followed by Gene Ontology (GO) enrichment analysis. A two-stage virtual screening strategy was employed using DrugRep for initial screening of the FDA-approved drug library, followed by refined docking of the top 10 candidates using CB-Dock2.
MR suggested a protective trend of ABCA1 against sepsis (OR = 0.809, 95% CI 0.635-1.032, P = 0.088), with no heterogeneity or horizontal pleiotropy detected. Single-cell analysis of 25,234 cells revealed that ABCA1 was predominantly expressed in CD16 + monocytes (P < 0.001 vs. other im- mune subsets). Following in silico knockout, only three genes showed significant changes (ABCA1 log2 FC ≈ __15.8, SEC14L1 log2 FC ≈ 10.2, PTGES log2 FC ≈ 9.4; all Padj < 0.001), enriched in lipid transport and fever-related path- ways. Virtual screening of approximately 2500 FDA-approved drugs identified six drugs with strong binding to ABCA1, including Dihydroergotamine (-12.2 kcal/mol) and Nilotinib (-11.0 kcal/mol).
ABCA1 is specifically expressed in CD16 + monocytes, and its perturbation affects lipid-related pathways. Virtual screening has identified potential drug candidates led by Dihydroergotamine (-12.2 kcal/mol). This study offers multi-level evidence supporting ABCA1 as a protective molecule and therapeutic target in sepsis.

PMID:
42570643
Bibliographic data and abstract were imported from PubMed on 09 Aug 2026.

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