Phytomedicine : international journal of phytotherapy and phytopharmacology · 2025
Fufang Danshen Pill improves mitochondrial homeostasis by regulating the S100a9/TLR4 axis to alleviate myocardial ischemia-reperfusion injury.
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Lu Ruixia, Sun Wenhao, Lin Wenyong, Zhu Siyue, Wang Dongyuan, Jin Qipeng, Wang Dan, Sang Zhenchi, Wang Xiaolong
Аннотация
BACKGROUND: S100a9 protein participates in regulating mitochondrial damage during Myocardial ischemia-reperfusion injury(I/R), but its cell type-specific mechanisms remain unclear. Fufang Danshen Pill (FDP), a traditional Chinese medicine for I/R treatment, requires further investigation to elucidate its therapeutic targets.
PURPOSE: Investigate the macrophage-specific role of S100a9 in I/R pathogenesis, and clarifies the molecular pathways through which FDP improves mitochondrial function by modulating S100a9.
METHODS: The murine I/R model was established and subjected to determine the optimal therapeutic dosage of FDP. By integrating Single-cell transcriptomics(scRNA-seq)with spatial transcriptomics, we conducted comprehensive analyses of myocardial tissues from sham, I/R, and FDP groups, including cellular subtyping, intercellular communication analysis, and spatial transcriptomic mapping. Mechanistic validation was performed using Adeno-associated virus serotype 2/9(AAV2/9)-mediated macrophage-specific S100a9 overexpression models to confirm key regulatory targets.
RESULTS: The medium-dose FDP (122.85 mg/kg) exhibited the best efficacy in improving cardiac function. FDP intervention markedly attenuated macrophage-cardiomyocyte cellular crosstalk. In I/R models, cardiomyocytes displayed significant alterations in mitochondrial-associated gene expression, whereas S100a9 emerged as the predominant differentially expressed gene in macrophages. Spatial transcriptomic mapping localized S100a9 predominantly within myocardial injury regions. Functional investigations revealed that AAV2/9-mediated macrophage-specific S100a9 overexpression exacerbated I/R pathological manifestations, including increased infarct size, reduced ejection fraction, elevated serum cardiac troponin levels, TLR4 signaling activation, and mitochondrial dysfunction. Notably, FDP treatment substantially reversed these pathological alterations.
CONCLUSION: This study demonstrates that macrophage-derived S100a9 mediates mitochondrial damage in cardiomyocytes during I/R injury. FDP effectively maintains mitochondrial functional homeostasis in cardiomyocytes by targeting and inhibiting macrophage S100a9 expression. These findings provide a important scientific basis for developing intervention strategies targeting the S100a9/TLR4 axis.
PURPOSE: Investigate the macrophage-specific role of S100a9 in I/R pathogenesis, and clarifies the molecular pathways through which FDP improves mitochondrial function by modulating S100a9.
METHODS: The murine I/R model was established and subjected to determine the optimal therapeutic dosage of FDP. By integrating Single-cell transcriptomics(scRNA-seq)with spatial transcriptomics, we conducted comprehensive analyses of myocardial tissues from sham, I/R, and FDP groups, including cellular subtyping, intercellular communication analysis, and spatial transcriptomic mapping. Mechanistic validation was performed using Adeno-associated virus serotype 2/9(AAV2/9)-mediated macrophage-specific S100a9 overexpression models to confirm key regulatory targets.
RESULTS: The medium-dose FDP (122.85 mg/kg) exhibited the best efficacy in improving cardiac function. FDP intervention markedly attenuated macrophage-cardiomyocyte cellular crosstalk. In I/R models, cardiomyocytes displayed significant alterations in mitochondrial-associated gene expression, whereas S100a9 emerged as the predominant differentially expressed gene in macrophages. Spatial transcriptomic mapping localized S100a9 predominantly within myocardial injury regions. Functional investigations revealed that AAV2/9-mediated macrophage-specific S100a9 overexpression exacerbated I/R pathological manifestations, including increased infarct size, reduced ejection fraction, elevated serum cardiac troponin levels, TLR4 signaling activation, and mitochondrial dysfunction. Notably, FDP treatment substantially reversed these pathological alterations.
CONCLUSION: This study demonstrates that macrophage-derived S100a9 mediates mitochondrial damage in cardiomyocytes during I/R injury. FDP effectively maintains mitochondrial functional homeostasis in cardiomyocytes by targeting and inhibiting macrophage S100a9 expression. These findings provide a important scientific basis for developing intervention strategies targeting the S100a9/TLR4 axis.