Single-cell transcriptomics reveals macrophage-neutrophil crosstalk in Haematitum-induced lung injury associated with gut dysbiosis.
5 affiliations
- 1School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China.
- 2Hubei Shizhen Laboratory, Wuhan, 430061, China.
- 3School of Pharmacy, Hubei University of Chinese Medicine, Wuhan, 430065, China. [email protected].
- 4Hubei Shizhen Laboratory, Wuhan, 430061, China. [email protected].
- 5Hubei University of Chinese Medicine, No. 16 Huangjiahuxi Road, Hongshan District, Wuhan City, Hubei Province, China. [email protected].
Abstract
Background
Haematitum is a mineral-based traditional Chinese medicine widely used in clinical applications. Both the Chinese Materia Medica and modern research indicate that it exhibits lung toxicity and should not be administered over prolonged periods. The precise mechanism underlying this toxicity, however, remains incompletely understood.Purpose
This study aims to systematically elucidate the toxic mechanism of lung injury induced by Haematitum administration, emphasizing the central role of the gut-lung axis in this process.Methods
The mouse model of lung injury induced by Haematitum was established. A combination of 16S rRNA sequencing, untargeted metabolomics, and single-cell RNA sequencing was utilized to comprehensively analyze alterations in the intestinal microbiota, lung tissue metabolism, and lung cell atlas. The pharmacological validation was conducted by administering PPARγ agonists and TNF-α inhibitors. Furthermore, the detoxification effect of its classical combination with Inula japonica Thunb. was also evaluated.Results
High-dose Haematitum disrupted the intestinal barrier and induced dysbiosis. Metabolites from the gut microbiota entered the bloodstream and exerted a pathogenic effect. Correlation analysis showed that gut microbiota dysbiosis is strongly associated with the pulmonary glycerophospholipid metabolic pathway. Results from single-cell sequencing and macrophage/TNF-α colocalization experiments indicated that the macrophages' PPAR signaling pathway was inhibited, inactivating their anti-inflammatory function and triggering the release of inflammatory factors such as TNF-α. Acting as a key messenger, TNF-α activated the TNF signaling pathway in neutrophils, driving them to acquire a highly destructive phenotype. The synergy between macrophages and neutrophils ultimately provoked inflammation and cell apoptosis in lung tissue. Pharmacological intervention of the PPARγ/TNF-α axis can effectively reverse cellular abnormalities and significantly alleviate lung injury. The combination with Inula japonica Thunb. also reduced lung toxicity, and components within this herb are predicted to act as natural PPARγ agonists.Conclusions
This study has revealed a potential toxic mechanism. The intestinal barrier in mice was compromised, with an increase in the relative abundance of Klebsiella, entry of microbial metabolites into the bloodstream, and disruption of glycerophospholipid metabolism in the lungs, which in turn resulted in dysfunction of pulmonary immune cells. It clarifies that the core mechanism of Haematitum-induced lung injury lies in inhibiting the PPAR signaling pathway in macrophages and activating the TNF signaling pathway in neutrophils. Administering Haematitum at a common dose or in combination with Inula japonica Thunb. mitigates these safety risks. These findings advance understanding of the toxicology of mineral-based medicines and provide a reference for the safe clinical application of these traditional Chinese medicines.
Related
- Mechanistic insights into TLR2-mediated acute pancreatitis exacerbation via macrophage-ferroptotic acinar cell crosstalk
- Neutrophil heterogeneity and crosstalk with cerebral-resident cells: therapeutic targets for ischemic stroke
- Airway epithelial cell–lung macrophage crosstalk in type 2-high and low asthma endotypes: mechanisms and therapeutic strategies
- SPP1-CD44-Mediated Crosstalk Between Endothelial and Macrophage Subpopulations Promotes Pancreatic Ductal Adenocarcinoma Progression Through S100A6 Upregulation
- Ductular reaction as a spatial fibrogenic niche: cholangiocyte-macrophage-fibroblast crosstalk in chronic liver disease.
BibTeX
@article{lu2026singlecell,
title = {{Single-cell transcriptomics reveals macrophage-neutrophil crosstalk in Haematitum-induced lung injury associated with gut dysbiosis.}},
author = {Min Lu and Hangjie Zhu and Yifan Peng and Shamei Zhu and Bisheng Huang and Yan Cao},
journal = {Journal of translational medicine},
year = {2026},
month = sep,
doi = {10.1186/s12967-026-08954-w},
url = {https://europepmc.org/article/MED/42919386},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Single-cell transcriptomics reveals macrophage-neutrophil crosstalk in Haematitum-induced lung injury associated with gut dysbiosis.
AU - Min Lu
AU - Hangjie Zhu
AU - Yifan Peng
AU - Shamei Zhu
AU - Bisheng Huang
AU - Yan Cao
PY - 2026
DA - 2026/09/01
JO - Journal of translational medicine
DO - 10.1186/s12967-026-08954-w
UR - https://europepmc.org/article/MED/42919386
AB - Background Haematitum is a mineral-based traditional Chinese medicine widely used in clinical applications. Both the Chinese Materia Medica and modern research indicate that it exhibits lung toxicity and should not be administered over prolonged periods. The precise mechanism underlying this toxicity, however, remains incompletely understood.Purpose This study aims to systematically elucidate the toxic mechanism of lung injury induced by Haematitum administration, emphasizing the central role of the gut-lung axis in this process.Methods The mouse model of lung injury induced by Haematitum was established. A combination of 16S rRNA sequencing, untargeted metabolomics, and single-cell RNA sequencing was utilized to comprehensively analyze alterations in the intestinal microbiota, lung tissue metabolism, and lung cell atlas. The pharmacological validation was conducted by administering PPARγ agonists and TNF-α inhibitors. Furthermore, the detoxification effect of its classical combination with Inula japonica Thunb. was also evaluated.Results High-dose Haematitum disrupted the intestinal barrier and induced dysbiosis. Metabolites from the gut microbiota entered the bloodstream and exerted a pathogenic effect. Correlation analysis showed that gut microbiota dysbiosis is strongly associated with the pulmonary glycerophospholipid metabolic pathway. Results from single-cell sequencing and macrophage/TNF-α colocalization experiments indicated that the macrophages' PPAR signaling pathway was inhibited, inactivating their anti-inflammatory function and triggering the release of inflammatory factors such as TNF-α. Acting as a key messenger, TNF-α activated the TNF signaling pathway in neutrophils, driving them to acquire a highly destructive phenotype. The synergy between macrophages and neutrophils ultimately provoked inflammation and cell apoptosis in lung tissue. Pharmacological intervention of the PPARγ/TNF-α axis can effectively reverse cellular abnormalities and significantly alleviate lung injury. The combination with Inula japonica Thunb. also reduced lung toxicity, and components within this herb are predicted to act as natural PPARγ agonists.Conclusions This study has revealed a potential toxic mechanism. The intestinal barrier in mice was compromised, with an increase in the relative abundance of Klebsiella, entry of microbial metabolites into the bloodstream, and disruption of glycerophospholipid metabolism in the lungs, which in turn resulted in dysfunction of pulmonary immune cells. It clarifies that the core mechanism of Haematitum-induced lung injury lies in inhibiting the PPAR signaling pathway in macrophages and activating the TNF signaling pathway in neutrophils. Administering Haematitum at a common dose or in combination with Inula japonica Thunb. mitigates these safety risks. These findings advance understanding of the toxicology of mineral-based medicines and provide a reference for the safe clinical application of these traditional Chinese medicines.
SN - 1479-5876
ER -