Wuwei Ganlu and Myricetin alleviate rheumatoid arthritis by inhibiting M1 macrophage polarization through modulation of SHBG/SREBP1-mediated lipid metabolism.

BACKGROUND: Rheumatoid arthritis (RA) is primarily characterized by imbalanced macrophage polarization. Wuwei Ganlu (WGL), a classical Tibetan topical formula, has been widely used in RA management.

PURPOSE: Nonetheless, the underlying mechanisms of WGL in protecting against RA and the bioactive components in WGL remain unclear.

STUDY DESIGN: This study employs multi-omics strategies, to elucidate the role and mechanism of the main bioactive component within WGL in macrophage polarization and RA.

METHODS: The macrophage polarization was assessed by flow cytometer, and the molecular mechanism of WGL was investigated using RNA sequencing, gene interference technology, molecular docking, and pharmacology experiments.

RESULTS: WGL inhibited macrophage M1 polarization by inhibiting reactive oxygen species (ROS) generation and IL-6/iNOS expression. RNA sequencing and pathway enrichment analysis identified that WGL might affect lipid metabolism by acting on sex hormone-binding globulin (SHBG). SHBG knockdown significantly inhibited M1 macrophage polarization by upregulating SREBP1, a master transcription factor in lipid metabolism. UPLC-Q-TOF-MS analysis revealed that Myricetin (Myr) was one of the main active flavonoid components in WGL. Myr ameliorated the symptoms of arthritis in a spontaneous RA model of IL-1Ra-deficient (IL-1Ra-/-) mice. Myr prevented M1 macrophage polarization by inhibiting SHBG to improve SREBP1-mediated lipid metabolism, akin to WGL. These findings highlight that WGL alleviates RA progression by targeting the SHBG-SREBP1 axis to reprogram macrophage lipid metabolism and suppress macrophage M1 polarization, with Myr serving as a key active constituent in WGL.

CONCLUSION: This study provides mechanistic evidence to support the modern application of WGL in RA management.