Downregulation of ferroptosis-related ATF3 alleviates lupus nephritis progression.

BACKGROUND

The role of ferroptosis in lupus nephritis (LN) is unclear. This study aimed to explore the effects of ferroptosis-related genes in LN through bioinformatics prediction and experimental validation.

METHODS

Sample data were collected from the GEO dataset and divided into glomeruli and tubulointerstitium. We collected 382 ferroptosis-related genes. The intersection of ferroptosis-related genes with glomeruli and tubulointerstitium data, respectively, was performed. Machine learning methods (including unsupervised cluster typing and random forests) were operated to identify ferroptosis subtyping and ferroptosis important genes in LN. Immune infiltration and functional analysis were performed. The expression of ferroptosis important gene ATF3 was validated in vivo and in vitro.

RESULTS

6 ferroptosis important genes common to glomeruli and tubulointerstitium were screened, including ATF3, CD44, CYBB, JUN, NCF2, and NNMT. ATF3 decreased in the LN group compared to the Control. Silencing ATF3 mitigated LPS/erastin-induced ferroptosis. Functional analysis showed that ATF3 was markedly enriched in the interferon-gamma-mediated signaling pathway, ECM-receptor interaction, and cell adhesion. In glomeruli, T cells regulatory (Tregs) infiltration decreased and Macrophages M1 levels increased with elevated ATF3 expression. Levels of immune cell infiltration were altered in different ferroptosis subtypes of LN glomeruli and tubulointerstitium.

CONCLUSIONS

Ferroptosis-related ATF3 levels decreased in LN. Inhibition of ATF3 might alleviate LN development by affecting the macrophage M1 and Treg cell infiltration. These implied that ATF3 might be a potential target for developing LN therapeutic strategies.