2. Academic Validation
  3. Xuebijing injection alleviates sepsis-induced acute lung injury by triggering ferroptosis of CCR2hi monocytes

Xuebijing injection alleviates sepsis-induced acute lung injury by triggering ferroptosis of CCR2hi monocytes

  • Phytomedicine. 2025 Nov 29:150:157641. doi: 10.1016/j.phymed.2025.157641.
Jing Yang 1,  Jia Shi 2,  Xin Guan 1,  Huirong An 1,  Li Zhang 1,  Junlong Zhang 1,  Shasha Liu 1,  Yuan Zhang 2,  Jing Zhang 3,  Donghai Li 4,  Lei Yang 1,  Yuzhen Zhuo 1,  Jianbo Yu 5
Affiliations

Affiliations

  • 1 Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin NanKai Hospital, Tianjin Medical University, Tianjin 300100, China.
  • 2 Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin NanKai Hospital, Tianjin Medical University, Tianjin 300100, China; Department of Anesthesiology and Critical Care Medicine, Tianjin NanKai Hospital, Tianjin Medical University, Tianjin 300100, China.
  • 3 Department of Pain Management, Beijing Fengtai You'anmen Hospital, Beijing 100069, China.
  • 4 Department of Burn and Plastic Surgery, Beijing Fengtai You'anmen Hospital, Beijing 100069, China.
  • 5 Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin NanKai Hospital, Tianjin Medical University, Tianjin 300100, China; Department of Anesthesiology and Critical Care Medicine, Tianjin NanKai Hospital, Tianjin Medical University, Tianjin 300100, China. Electronic address: [email protected].
PMID: 41365193 DOI: 10.1016/j.phymed.2025.157641
Abstract

Background: Acute Lung Injury (ALI) significantly contributes to mortality in septic patients and lacks specific therapies. Although multicenter trials have confirmed that Xuebijing injection (XBJ) reduces sepsis mortality, the mechanisms underlying its anti-inflammatory effects remain unclear.

Purpose: This study aims to investigate the pharmacological efficacy of XBJ against ALI.

Methods: Histopathology and RT-PCR were used to evaluate the therapeutic effects of XBJ. Monocyte phenotype, viability, and function were assessed by flow cytometry and immunofluorescence. Western blotting was performed to analyze inflammatory, Ferroptosis, and cell survival-related signaling molecules.

Results: By employing cecal ligation and puncture (CLP) and LPS-induced murine sepsis models in WT, chemokine C-C-motif receptor 2 (CCR2)-/-, and nuclear factor erythroid 2-related factor 2 (Nrf2)-/- mice, we demonstrated that XBJ ameliorated sepsis-induced ALI by specifically reducing CCR2hi monocytes in the lungs without affecting neutrophils or the CCR2lo monocytes, thereby blocking the shift of pulmonary macrophages toward the M1 (classically activated macrophages) phenotype. This reduction was independent of the bone marrow mobilization of monocytes or improved tight junction protein expression. Mechanistically, XBJ triggers Ferroptosis in LPS-stimulated monocytes, suppressing their pro-inflammatory responses, including chemotaxis, cytokine secretion, and differentiation into pro-inflammatory macrophages. We demonstrated that Ferroptosis is a critical mechanism underlying the anti-inflammatory function of XBJ as evidenced by its effective reversal with the Ferroptosis inhibitor ferrostatin-1. The Nrf2/heme oxygenase-1 (HO-1) axis, a central regulator of Ferroptosis, was closely associated with the anti-inflammatory action of XBJ. In Nrf2-knockout models, the ferroptosis-inducing effect of XBJ on LPS-stimulated monocytes was abolished; co-administration of hemin (a pharmacological HO-1 Inducer) and XBJ inhibited LPS-induced monocyte Ferroptosis in vitro, counteracted the reduction of CCR2hi pro-inflammatory monocyte infiltration mediated by XBJ injection, and exacerbated pulmonary pro-inflammatory cytokine production in vivo.

Conclusion: This study confirms that XBJ treats sepsis by inducing Ferroptosis in pro-inflammatory monocytes, identifies monocytes as key cellular targets in ALI, and underscores the translational potential of targeting Ferroptosis to regulate dysregulated inflammation in sepsis.

Keywords

Acute Lung Injury; CCR2; Ferroptosis; Monocyte; Nrf2; XBJ.

Figures
Products