Environmental exposure may function as a contributing risk factor in the development of systemic lupus erythematosus (SLE). Recently, the global issue of microplastics (MPs) pollution has garnered increasing concern, yet its potential impact on SLE remains unexplored. This study seeks to elucidate the ramifications of MPs exposure on lupus manifestations in spontaneous lupus MRL/lpr mice and normal C57L/6 mice. MPs exposure demonstrated the capacity to induce lupus-like symptoms in C57BL/6 mice and exacerbate lupus symptoms in MRL/lpr mice. This was manifested by MPs triggering abnormal elevation of spleen DN T, plasma cells, serum anti-dsDNA, ANA, IL-6, and TNF-α, coupled with a reduction in spleen CD4/CD8 cell ratio, and impairment in renal pathology. Moreover, a 4D-DIA quantitative proteomic analysis was employed to unveil substantial alterations in renal proteins attributed to MPs exposure. The findings indicated that the KEGG pathways significantly enriched by MPs-associated different proteins in C57BL/6 mice were closely aligned with the enriched KEGG pathways associated with lupus. Unlike C57BL/6 mice, there were no significantly enriched KEGG pathways identified among the MPs-associated different proteins in MRL/lpr mice. In addition, proteins related to the SLE pathway illuminated that MPs exposure induced renal damage through activation of MHCII and histone H3, culminating in the production of MAC in both C57BL/6 and MRL/lpr mice. However, a specific elevation in cathepsin and elastase caused by MPs was observed in C57BL/6 mice but not in MRL/lpr mice. This study represents a significant stride in bridging the existing knowledge gap pertaining to the intricate relationship between MPs exposure and the development of SLE.Copyright © 2023. Published by Elsevier B.V.