Xijiao Dihuang decoction ameliorates sepsis by regulating macrophage polarization via activation of the itaconate-mediated Nrf2/HO-1 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis is a leading cause of mortality in critically ill patients and is predominantly triggered by infection. Xijiao Dihuang Decoction (XJDH), a classic traditional Chinese medicine formula, has demonstrated clinical efficacy in the early intervention of sepsis. However, its underlying mechanism remains to be elucidated.

AIM OF THE STUDY: This study aimed to investigate the therapeutic effects of XJDH on sepsis and its potential molecular mechanism.

MATERIALS AND

METHODS

A sepsis mouse model was established by intraperitoneal injection of lipopolysaccharide (LPS). Systemic inflammation was assessed using ELISA and hematological analysis. Histopathological damage in multiple organs was evaluated by hematoxylin and eosin (H&E) staining, and the expression of macrophage polarization markers (CD86 and CD206) was detected by immunofluorescence staining. In vitro, an LPS-stimulated THP-1 cell model was employed to further validate the regulatory effects of XJDH on macrophage polarization and inflammatory responses. The expression of Irg1, Nrf2, and HO-1 was examined using Western blot and qRT-PCR to explore the potential molecular mechanism.

RESULTS

In vivo experiments demonstrated that XJDH significantly ameliorated systemic symptoms, alleviated inflammatory responses and multi-organ damage, and promoted macrophage polarization towards the M2 phenotype in septic mice. Following administration of the itaconate inhibitor (Irg1-IN-1), the inflammatory response showed no improvement. In vitro experiments further confirmed that XJDH dose-dependently promoted the phenotypic switch of LPS-induced THP-1 cells from M1 to M2, downregulated pro-inflammatory cytokines, and upregulated anti-inflammatory cytokines. This mechanism involved XJDH-mediated upregulation of Irg1 expression and activation of the Nrf2/HO-1 signaling pathway.

CONCLUSION

This study is the first to demonstrate that XJDH alleviates inflammatory responses and multi-organ damage in sepsis by activating the itaconate-mediated Nrf2/HO-1 signaling pathway to regulate macrophage polarization, thereby providing a new scientific basis for its clinical application.