Bioinformatics Analysis Reveals ALDH5A1 : A Novel Molecular Brake on Th17 Cell Pathogenicity in Systemic Lupus Erythematosus

ABSTRACT Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder with diverse clinical manifestations, in which aberrant Th17 cell differentiation plays a critical pathogenic role and contributes to the persistent challenges in its treatment. We performed a bioinformatics analysis using RNA sequencing (RNA‐seq) data obtained from the GEO database, with the aim to identify genes with altered expression during SLE progression that may be associated with Th17 cell differentiation. Our analysis identified 12 glutamine metabolism‐related genes (GlnMRGs) and constructed a nomogram to indicate the risk of SLE. Among the GlnMRGs, ALDH5A1 is the highest‐scoring gene in the random forest (RF) model. In patients with SLE, the expression of ALDH5A1 in the peripheral blood was reduced, and it was inversely correlated with the Th17 immune score ( r = −0.51) and negatively correlated with SLEDAI score ( r = −0.2066, p < 0.001). Additionally, single‐cell RNA sequencing (scRNA‐seq) confirmed that the expression of ALDH5A1 was downregulated specifically in Th17 cells. To validate these conclusions, we performed verification in SLE patients and pristane‐induced mouse models. Additionally, we performed in vitro assays using small interfering RNA (siRNA) and overexpression plasmids. The functional findings confirmed that Aldh5a1 knockdown aggravated the activation, proliferation, and Th17 differentiation of CD4 + T cells, while overexpression of Aldh5a1 suppressed this phenomenon. Collectively, our findings suggest that ALDH5A1 may influence Th17 differentiation and play a role in the pathogenesis of SLE.