Dexmedetomidine Curbs Chemotherapy-Related Heart Fibrosis in Mouse Study

The work, led by Bing Zhang and colleagues, identifies a molecular route involving the gene Serpine1 and the STAT3/Notch-1 signaling pathway in cardiac fibroblasts, the cells that drive scarring in heart tissue.

The study aimed to examine whether dexmedetomidine could ease this fibrosis and to clarify the regulatory mechanism behind any protective effect.

To test the drug, the researchers established a mouse model of myocardial fibrosis induced by doxorubicin and trastuzumab. They assessed cardiac function and scarring using echocardiography, hemodynamic testing and histopathological examination. In these animal experiments, dexmedetomidine effectively alleviated the fibrosis induced by the two drugs, according to the results section of the paper.

The team then turned to single-cell transcriptome sequencing of myocardial tissue. Differential expression analysis identified 888 differentially expressed genes after dexmedetomidine treatment. To narrow this list, the researchers combined several bioinformatic approaches: scoring against a mouse core gene set, weighted gene co-expression network analysis applied to the single-cell transcriptome data, and cell–cell communication analysis. This pipeline singled out Serpin Family E Member 1, or Serpine1, as a hub gene.

Experiments in cardiac fibroblasts probed what Serpine1 does. The researchers used immunofluorescence staining, quantitative real-time polymerase chain reaction, Western blotting, Cell Counting Kit-8 assays and wound healing assays. They found that dexmedetomidine inhibited the differentiation, migration and mitochondrial fusion of cardiac fibroblasts while promoting Serpine1 expression.

To confirm that Serpine1 was functionally important rather than merely correlated, the team suppressed its expression. Inhibition of Serpine1 led to enhanced differentiation and migration of the fibroblasts, exacerbated mitochondrial fusion, and altered signaling through signal transducer and activator of transcription 3 (STAT3) and Notch-1. In other words, removing Serpine1 reversed the beneficial cellular changes produced by dexmedetomidine.

A follow-up experiment tested whether the STAT3/Notch-1 pathway lay downstream of Serpine1. After Serpine1 expression was inhibited, the researchers treated the cells with DAPT, an inhibitor of the Notch pathway, and with colivelin, an agonist of STAT3. Both interventions suppressed fibroblast differentiation and migration and attenuated mitochondrial fusion, supporting the proposed pathway linking Serpine1 to STAT3 and Notch-1 signaling.

The authors conclude that dexmedetomidine inhibits mitochondrial fusion by promoting Serpine1 expression, which regulates the STAT3/Notch-1 pathway, thereby inhibiting cardiac fibroblast differentiation and ultimately alleviating doxorubicin- and trastuzumab-induced myocardial fibrosis. Because the findings come from an animal model and isolated cardiac fibroblast experiments, they represent preclinical evidence; the paper does not report tests in patients, and the published version is an early-release, peer-reviewed accepted article subject to further editorial revision. Whether dexmedetomidine could be repurposed to protect the hearts of patients receiving these cancer therapies would require clinical studies beyond the scope of this work.

Subject of Research: Dexmedetomidine's effects on chemotherapy-induced myocardial fibrosis via Serpine1 and the STAT3/Notch-1 pathway

Article Title: Single-cell RNA sequencing reveals that dexmedetomidine mediates the regulation of mitochondrial fusion in cardiac fibroblasts through the Serpine1-mediated STAT3/Notch-1 pathway to alleviate doxorubicin- and trastuzumab-induced myocardial fibrosis

Article References: Zhang, B., Sun, J., Zhang, J., Ainiwaer, Y., He, B., Geng, Q., & Zhang, Y. (2026). Single-cell RNA sequencing reveals that dexmedetomidine mediates the regulation of mitochondrial fusion in cardiac fibroblasts through the Serpine1-mediated STAT3/Notch-1 pathway to alleviate doxorubicin- and trastuzumab-induced myocardial fibrosis. European Journal of Medical Research. https://doi.org/10.1186/s40001-026-05356-y

Image Credits: AI Generated

DOI: 10.1186/s40001-026-05356-y

Keywords: dexmedetomidine, myocardial fibrosis, doxorubicin, trastuzumab, cardiotoxicity, cardiac fibroblasts, Serpine1, STAT3, Notch-1, mitochondrial fusion, single-cell RNA sequencing, preclinical study