Abstract

Background Systemic lupus erythematosus (SLE) is characterized by complex immune dysregulation, including abnormalities in macrophage polarization. Pyrroloquinoline quinone (PQQ) has been reported to exert anti-inflammatory and immunoregulatory effects in various disease models, but its role in SLE remains unclear. Objective To evaluate the therapeutic effects of PQQ in SLE and SLE-associated diffuse alveolar hemorrhage (DAH) and to assess its impact on macrophage activation. Methods Pristane-induced DAH mice and lupus-prone MRL/ lpr mice were used to assess in vivo efficacy. Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (bulk RNA-seq) analyses were performed to characterize immune remodeling and explore underlying mechanisms. RAW264.7 macrophages were used to examine the inhibitory effects of PQQ on M1 macrophage polarization. Results PQQ alleviated lung injury in SLE-DAH mice and reduced splenomegaly, autoantibodies, renal inflammation, and systemic cytokines in MRL/ lpr mice. Flow cytometry and scRNA-seq consistently demonstrated reductions in inflammatory macrophage populations. Bulk RNA-seq further indicated that PQQ modulated inflammatory pathways associated with macrophage activation. Moreover, PQQ significantly reduced the expression of inflammatory mediators (IL-6, TNF-α, and IL-1β), inhibited M1 macrophage polarization, and decreased the production of oxidative stress-associated indicators (ROS and NO) in LPS/IFN-γ-stimulated RAW264.7 cells. Finally, PQQ regulated ERK/MAPK signaling, which contributed to the attenuation of inflammatory responses. Conclusion PQQ attenuates SLE and its pulmonary complication DAH by regulating macrophage polarization and may serve as a potential immunomodulatory therapeutic candidate.