# Single-Cell Transcriptomics Uncover EEF1A1-Driven Ubiquitination Dysregulation in T Cell Exhaustion and SLE Pathogenesis via STAT1-Mediated Th1/Th2 Imbalance

## TL;DR

This study finds that the EEF1A1 gene contributes to lupus by disrupting T cell function and immune balance, offering a new therapeutic target.

## Contribution

The study identifies EEF1A1 as a novel driver of ubiquitination dysregulation in T cell exhaustion and SLE through STAT1-mediated Th1/Th2 imbalance.

## Key findings

- EEF1A1 overexpression increases p-STAT1 levels and impairs T cell function in SLE.
- EEF1A1 skews Th1/Th2 balance toward Th1 dominance, worsening lupus symptoms in mice.
- EEF1A1 is a potential biomarker and therapeutic target for SLE.

## Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder marked by immune dysregulation and multiorgan involvement. This study investigates the role of the ubiquitination-related gene EEF1A1 in SLE pathogenesis, focusing on T cell dysfunction.

Single-cell RNA sequencing (scRNA-seq) data from the GSE135779 dataset was analyzed to characterize the cellular composition of SLE samples. Clustering analysis identified 15 T cell subpopulations, with seven clusters notably depleted in SLE. Trajectory analysis indicated progressive transcriptional dysregulation during T cell differentiation. High-dimensional weighted gene coexpression network analysis (hdWGCNA) and LASSO regression highlighted EEF1A1 as a key ubiquitination-related hub gene. EEF1A1 expression was significantly elevated in SLE T cells, while its ubiquitinated form was reduced, suggesting impaired proteasomal degradation.

Functional assays demonstrated that EEF1A1 overexpression enhances STAT1 phosphorylation (p-STAT1) without altering total STAT1 protein levels, leading to T cell dysfunction. In vitro and in vivo experiments revealed that EEF1A1 overexpression skews the T helper 1 (Th1)/T helper 2 (Th2) balance towards a Th1-dominant phenotype. In MRL/lpr mouse models, EEF1A1 overexpression exacerbated renal pathology, including increased proteinuria and immune complex deposition.

These findings suggest that EEF1A1 contributes to SLE pathogenesis by promoting STAT1-mediated T cell dysfunction and Th1/Th2 imbalance. EEF1A1 emerges as a potential biomarker and therapeutic target, offering new insights into the post-translational regulatory mechanisms underlying SLE.