Xijiao Dihuang Decoction derived formula attenuates dyslipidemic SLE skin lesions by modulating PPARγ-mediated fatty acid oxidation

Background Cutaneous involvement is a common manifestation of systemic lupus erythematosus (SLE), and dyslipidemia has emerged as a metabolic factor that aggravates lupus-associated skin injury. Purpose This study investigated the effects of Xijiao Dihuang Decoction derived formula (XJDHD) on dyslipidemia-aggravated lupus skin injury and its underlying immunometabolic mechanisms. Methods A high-fat diet (HFD)-exacerbated lupus-like skin injury model was established in lupus-prone mice. Histopathological, lipid metabolic, inflammatory, and oxidative stress analyses were conducted. Mechanistic exploration integrated molecular docking, network pharmacology, RNA sequencing, and macrophage-based assays. Results XJDHD markedly alleviated HFD-aggravated lupus-like skin lesions, reduced lipid accumulation, and suppressed cutaneous inflammation. Integrated analyses identified PPARγ-associated fatty acid oxidation and mitochondrial regulation as central pathways. XJDHD enhanced fatty acid oxidation, restored mitochondrial homeostasis, reduced oxidative stress, and inhibited pro-inflammatory macrophage polarization. PPARγ, ACADM, and NDUFAB1 were identified as key targets. Conclusion XJDHD attenuates dyslipidemia-associated lupus skin injury by restoring immunometabolic balance through regulation of fatty acid oxidation and mitochondrial homeostasis via the PPARγ-ACADM-NDUFAB1 axis, supporting metabolic-targeted herbal therapy for cutaneous manifestations in SLE.