Background: Coronary Microvascular Dysfunction (CMD) represents a critical pathological substrate for ischemic heart disease and is strongly associated with major adverse cardiovascular events. Zacopride, known for its dual cardiovascular regulatory properties targeting the 5-HT₄ receptor and Kir2.1 channel, lacks evidence regarding its systemic impact on the gut microbiota-metabolism axis. Therefore, this study aims to elucidate the structural and metabolic characteristics of gut bacteria and fungi in CMD, and to explore the multidimensional therapeutic mechanisms of Zacopride through "microbial remodeling-metabolic regulation-microcirculation repair." Methods: Sixty Sprague–Dawley rats were randomized into three groups: coronary microvascular dysfunction (CMD), healthy control (NC), and Zacopride intervention (ZAC). CMD and ZAC groups received high-fat diet plus streptozotocin (STZ, 35 mg/kg) for modeling. ZAC rats were orally administered 5 mg/kg Zacopride daily for 7 days. Transthoracic Doppler echocardiography measured left anterior descending coronary artery resting/stress peak flow velocity and coronary flow reserve (CFR). Ileocecal contents underwent bacterial-fungal metagenomic sequencing to identify differential metabolic pathways. Spearman's correlation assessed cross-kingdom ecological interactions. Nine machine learning algorithms constructed classification models, with Random Forest (RF) and an optimal model identifying key genera. Linear Discriminant Analysis Effect Size validated microbial biomarkers. Results: Zacopride partially restored the CFR in CMD rats, demonstrating a therapeutic effect, and exerted a beneficial influence on the structure and diversity of the gut microbiota. The CMD state significantly reduced the expression levels of the Chlorophyll a and tryptophan metabolic pathways in the gut microbiota. Zacopride specifically restored the Chlorophyll a pathway but did not significantly recover the tryptophan metabolic pathway. RF and Elastic Net (ENET) identified JC017, Chromelosporium, and Barnesiella as biomarker microbiota for CMD. Notably, JC017 primarily mediate the therapeutic effects of Zacopride via direct or indirect modulation of the Chlorophyll a metabolic pathway. Chromelosporium, acting as an interactive hub between fungi and bacteria, formed a cross-kingdom symbiotic relationship with Bradyrhizobium. Additionally, the reduction in Barnesiella abundance constitutes a distinctive feature of gut microbial dysbiosis in CMD. Conclusion: This study provides the first evidence that the gut microbiota modulates the pathogenesis of CMD through the "chlorophyll/heme-tryptophan metabolic axis." Furthermore, we demonstrate that Zacopride exerts therapeutic effects by remodeling microbiota-host interactions and regulating this metabolic axis, revealing a novel mechanistic link between microbial metabolism and CMD progression. Graphical

Myocardial infarction (MI) poses a severe threat to human life and health. During acute MI, persistent myocardial ischemia and hypoxia induce pathological alterations in the microenvironment. Traditional therapeutic approaches exhibit limited capacity for targeted modulation of this infarcted microenvironment. Consequently, developing therapeutic strategies capable of precisely responding to the pathological microenvironment holds significant importance. Hydrogels, as a class of polymeric biomaterials with excellent biocompatibility, can be engineered into intelligent responsive hydrogels by incorporating environmentally responsive functional groups or constructing intelligent network architectures. These hydrogels are designed to sense and respond to key features of the MI pathological microenvironment, such as temperature, pH, reactive oxygen species, and enzyme concentrations. This review systematically summarizes the design strategies and research advances in intelligent responsive hydrogels for MI therapy over recent years, focusing on their distinct functional capabilities: alleviating oxidative damage, suppressing excessive inflammatory responses, enabling precise drug delivery, and modulating immune activity. Although current research predominantly remains at the preclinical stage and faces numerous challenges, the convergence of materials science and biomedical engineering positions smart responsive hydrogels as promising candidates to deliver innovative solutions for the precise treatment of MI.

Myocardial infarction (MI) remains a global health challenge despite advances in reperfusion therapies, as subsequent oxidative stress, inflammatory cascades, and electrical conduction abnormalities impede functional recovery. This study presents a tripartite therapeutic strategy addressing these pathological mechanisms through a clinically translatable multifunctional myocardial repair agent (MMRA). The system combines polypyrrole's and sinomenine's (Sino) anti-inflammatory/antioxidant effects, formulated within a conductive thermoresponsive Poloxamer 407 (P407) hydrogel platform. Injectable P407 hydrogel facilitates targeted delivery and sustained release of therapeutic components within the infarct zone. In vivo evaluations revealed MMRA's capacity to simultaneously: 1) Scavenge reactive oxygen species and downregulate pro-inflammatory cytokines, 2) Reprogram macrophage polarization toward tissue-reparative M2 phenotypes and 3) Restore electrical signal propagation through conductive hydrogel-mediated intercellular coupling. By synergistically modulating the post-infarction microenvironment while preserving myocardial electromechanical synchronization, this integrated therapeutic paradigm demonstrates significant potential for enhancing cardiac repair outcomes. The employment of clinically approved components (Sino and P407) further shows the excellent translational feasibility of the MMRA for MI treatment.