Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by complex pathogenesis, diverse clinical manifestations, and fluctuating disease course [1]. SLE affects multiple organs, among which diffuse alveolar hemorrhage (DAH) represents one of the most severe and life-threatening pulmonary complications, characterized by immune-mediated alveolar injury and extensive intra-alveolar hemorrhage [[2], [3], [4]]. Globally, approximately 3.4 million individuals are affected by SLE, with women comprising the majority of cases. China has the largest population of women with SLE worldwide [5]. Given its chronic nature and systemic involvement, the prevention and treatment of SLE and its complications remain a major focus in clinical and basic research.

A variety of immune cells contribute to SLE progression. Aberrant CD4+ T cell responses and B cell hyperactivation contribute to immune tolerance breakdown and sustained autoantibody production [6,7]. Within this broader immunological framework, macrophages have emerged as key amplifiers of lupus-related inflammation. Multiple studies have consistently reported disrupted macrophage polarization in SLE, characterized by enhanced M1 responses and impaired M2-mediated tissue repair programs [[8], [9], [10], [11]]. Consistent with these findings, our previous study in a pristane-induced lupus model in C57BL/6 J mice demonstrated a marked increase in splenic pro-inflammatory macrophage populations [12]. These findings suggest that restoring macrophage homeostasis may represent a valuable therapeutic strategy in SLE.

Current SLE treatment strategies rely primarily on glucocorticoids and immunosuppressive agents, which effectively control disease activity [13]. However, long-term exposure to these therapies is associated with substantial adverse effects, including osteoporosis, cardiovascular disease, and metabolic disturbances [14,15]. These limitations have prompted increasing interest in safer adjunctive approaches, particularly natural small-molecule immunomodulators with antioxidant and redox-regulating properties, for the management of chronic autoimmune inflammatory diseases [[16], [17], [18]].

Pyrroloquinoline quinone (PQQ) is a naturally occurring redox cofactor with potent antioxidant activities [19,20]. Emerging evidence indicates that PQQ exerts immunomodulatory effects by regulating immune cell activation and polarization, as demonstrated by its ability to suppress fibroblast-like synoviocyte–driven inflammation in rheumatoid arthritis models and to attenuate allergic airway inflammation via the JAK–STAT signaling pathway [21,22]. Despite these promising findings, the role of PQQ in autoimmune diseases such as SLE remains largely unexplored.

Therefore, the present study aimed to investigate the therapeutic potential of PQQ in lupus, with a particular focus on macrophage polarization and immune regulation. Using both a pristane-induced DAH model and the spontaneous MRL/lpr model, we evaluated the in vivo efficacy of PQQ. By integrating multi-omics analyses with in vitro validation in RAW264.7 macrophages, we sought to elucidate the mechanisms by which PQQ ameliorates lupus pathology and to provide new insights into its potential translational application in SLE.