Qihuang Jianpi Zishen decoction (JPZS) is used clinically as an adjunctive therapy for lupus nephritis (LN), but how it links gut microbial dysbiosis to renal immunometabolic alterations remains unclear.

Female MRL/lpr mice were treated with JPZS (6.305, 12.61, or 25.22 g/kg) or vehicle for 8 weeks, with C57BL/6 mice as healthy controls. Multi-omics profiling (faecal 16S rRNA sequencing, untargeted serum metabolomics, and renal transcriptomics) was performed in Control, Model, and high-dose JPZS groups. Renal function, autoantibodies, inflammatory indices, histopathology, and glomerular IgG deposition were assessed. Integrated analyses were followed by targeted quantification of renal lactate/pyruvate and validation of hexokinase 3 (HK3) and Ldhal6b expression.

JPZS attenuated proteinuria and serum creatinine elevation, reduced glomerular IgG deposition, and ameliorated renal histopathological injury in MRL/lpr mice. JPZS reshaped lupus-associated dysbiosis, prominently enriching Akkermansia, and was associated with shifts in predicted microbial carbohydrate-related functions. Serum metabolomic profiles were remodeled accordingly. Renal transcriptomics indicated suppression of a glycolysis-related program centered on HK3, and targeted assays confirmed reduced renal lactate accumulation, a lower lactate/pyruvate ratio, and downregulation of HK3 and Ldhal6b after JPZS treatment.

JPZS alleviates LN, at least in part, by enriching Akkermansia and dampening HK3-associated glycolysis, thereby reducing intrarenal lactate burden and supporting an Akkermansia–HK3–lactate immunometabolic axis along the gut–kidney pathway.