Zishen Huoxue Decoction shields the heart from reperfusion injury via ER-mitochondria crosstalk

Myocardial ischemia-reperfusion (I/R) injury remains a major obstacle in cardiovascular medicine. Although restoring blood flow to ischemic tissue is essential, reperfusion itself can paradoxically intensify oxidative stress, disrupt mitochondrial function, and drive cardiomyocyte death. Strategies that limit this secondary damage are urgently needed. In a study published in the Chinese Journal of Natural Medicines, researchers report that Zishen Huoxue Decoction (ZSHX), a traditional Chinese medicine formula, counteracts myocardial I/R injury by targeting endoplasmic reticulum (ER)-mitochondria homeostasis, which is a critical yet underexplored layer of cellular stress regulation.

The work extends an earlier high-impact study by the same group, published in 2025, which established that ZSHX alleviates ischemic myocardial injury by coordinating mitophagy and the mitochondrial unfolded protein response through a SIRT5-β-tubulin axis. While that paper defined how ZSHX supports mitochondrial quality control within a single organelle, the new study broadens the lens to organelle-organelle communication, asking how ZSHX restores the functional coupling between the ER and mitochondria that is progressively lost during reperfusion.

Using conditional-knockout animal and cellular models of NDUFS4 and DUSP1, together with single-cell RNA sequencing, metabolomics, network pharmacology, and in vivo and in vitro interventions, the team showed that I/R injury triggers ER stress and mitochondrial metabolic reprogramming, accompanied by downregulation of dual-specificity phosphatase 1 (DUSP1) and NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4). Single-cell sequencing further linked I/R damage to disrupted mitochondrial energy metabolism and cell-death programs, while metabolomics confirmed that ZSHX reshapes the metabolite landscape in affected myocardial tissue. Mechanistically, ZSHX preserves mitochondrial proteostasis, suppresses ER stress, restores intracellular calcium balance, and upregulates DUSP1 and NDUFS4, thereby sustaining respiratory-chain activity and enabling adaptive metabolic reprogramming under stress.

The researchers also identify kaempferol as the principal bioactive compound driving these effects. By enhancing DUSP1 and NDUFS4 expression, kaempferol prevents ER stress and inflammatory bursts, preserves mitochondrial function, and recodes mitochondrial metabolism after I/R injury. This finding helps connect the traditional compatibility principles of complex herbal formulas to defined molecular targets and measurable pharmacological effects.

Taken together, the two studies position ER-mitochondria crosstalk, rather than any single organelle or pathway, as a promising therapeutic axis for ischemic heart disease. By moving beyond single-target explanations and integrating multi-omics evidence with mechanistic pharmacology, the work offers a more coherent framework for translating traditional Chinese medicine into mechanism-based cardiovascular therapeutics.

The article was first published online ahead of print on July 16, 2025, and the final version appears in the April 2026 issue (Chinese Journal of Natural Medicines, Vol. 24, Issue 4), pp. 385–401. (https://doi.org/10.1016/S1875-5364(26)61171-5)

Related prior publication

Chang X, Zhou S, Huang Y, Liu J, Wang Y, Guan X, Wu Q, Liu Z, Liu R. Zishen Huoxue decoction (ZSHX) alleviates ischemic myocardial injury (MI) via Sirt5-β-tubulin mediated synergistic mechanism of “mitophagy-unfolded protein response” and mitophagy. Chinese Journal of Natural Medicines, 2025, 23(3): 311–321. DOI: 10.1016/S1875-5364(25)60838-7.