Search Results (989)

Mucuna pruriens (Linn.) DC. var. pruriens is used as a traditional medication to enhance male sexual function, yet integrated evidence linking vascular-cell mechanisms to in vivo efficacy and safety of a standardized extract remains limited. This study evaluated the ethanolic seed extract of M. pruriens var. pruriens (MPSE) on erectile function-related mechanisms, addressing the nitric oxide (NO)–cyclic guanosine monophosphate (cGMP)–phosphodiesterase type 5 (PDE5) pathway in vitro, together with mounting frequency, anxiety-like behavior, locomotor activity, and cardiovascular safety in vivo. Soxhlet extraction with 80% ethanol yielded a dark brown, syrupy extract (12.28% w/w), which was standardized by high-performance thin-layer chromatography to contain 278 mg/g extract (27.8% w/w) of L-DOPA (Rf 0.38). Mechanistic effects were assessed in human umbilical vein endothelial cells (HUVECs), pulmonary artery smooth muscle cells (PASMCs), and a PDE5A1 enzyme assay. Male Wistar rats received MPSE (50, 100, and 200 mg/kg) orally for 15 days, with hemodynamic assessment in normotensive and Nω-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. MPSE significantly increased eNOS expression and NO production in HUVECs, elevated intracellular cGMP in PASMCs, and directly inhibited PDE5A1 enzymatic activity. Repeated administration significantly increased mounting frequency relative to baseline without altering serum testosterone levels, anxiety-like behavior, locomotor activity, mean arterial pressure, or heart rate. These findings indicate that MPSE modulates erectile function-related mechanisms, primarily through peripheral vascular effects on the NO–cGMP–PDE5 pathway, and suggest a favorable safety profile. Erectile function itself was not directly assessed and warrants confirmation in models of erectile response. MPSE nevertheless represents a promising plant-derived candidate for erectile dysfunction. Full article

Impaired endothelial function, excessive oxidative stress, and persistent bacterial infection collectively contribute to delayed healing of diabetic chronic wounds. Methylglyoxal (MGO)-induced metabolic stress is a critical driver of endothelial injury; however, effective multifunctional strategies capable of restoring vascular function and maintaining cellular homeostasis remain limited. In this study, the endothelial protective potential of an amphibian-derived Bowman–Birk inhibitor (BBI)-type peptide, OSTI-1872, and its rationally designed structural analogues were investigated using an MGO-induced injury model in human umbilical vein endothelial cells (HUVECs). Among the tested peptides, the optimised analogue OSTI-2337 exhibited superior protective activity. OSTI-2337 markedly attenuated MGO-induced oxidative stress, restored nitric oxide bioavailability, enhanced VEGF expression, promoted endothelial migration and tube formation, and reduced oxidative DNA damage. Mechanistically, these effects were associated with coordinated regulation of MGO detoxification and redox homeostasis, as evidenced by enhanced GLO1 expression and modulation of the PI3K/AKT/GSK3β/Nrf2 axis, accompanied by increased expression of downstream antioxidant proteins HO-1 and NQO1. In addition, OSTI-1872 and OSTI-2337 displayed antibacterial activity against representative bacterial strains, suggesting their potential advantages for complex diabetic wound environments. Collectively, these findings demonstrate that structural optimisation significantly enhances the biological activity of amphibian BBI-type peptides and identify OSTI-2337 as a multifunctional peptide candidate capable of integrating endothelial protection, MGO detoxification, redox regulation, and antibacterial activity for the management of diabetes-associated vascular injury and chronic wound complications. Full article

Stem cell-derived extracellular vesicles (EVs) hold therapeutic potential for hypoxia-associated injury, yet the molecular mechanisms underlying their protective effects remain incompletely defined. Herein, we performed comparative proteomic profiling of extracellular vesicles (EVs) secreted by human placenta-derived perivascular stem cells (hPPSCs) and human umbilical cord mesenchymal stem cells (hUCMSCs). We found that hPPSCs-EVs are enriched in proteasome-related proteins. Enzymatic activity assays further confirmed that proteasome activity in hPPSCs-EVs was significantly higher than that in hUCMSCs-EVs. Additionally, we observed that hPPSCs-EVs were efficiently endocytosed by human umbilical vein endothelial cells (hUVECs), leading to marked downregulation of hypoxia-inducible factor 1-alpha (HIF-1α) and intracellular ubiquitinated proteins. Importantly, this HIF-1α degradation persisted even when the host ubiquitin–proteasome system was blocked, indicating that hPPSCs-EVs can function independently of the host proteasomal pathway. These results reveal that hPPSCs-EVs deliver functional proteasomes to endothelial cells, thereby compensating for impaired protein degradation and protecting cells under hypoxic stress. Collectively, our findings provide evidence for an intercellular transfer of proteolytic capacity via stem cell-derived EVs, a mechanism that preserves endothelial proteostasis and highlights the therapeutic potential of proteasome-rich EVs for hypoxia-associated diseases. Full article

Preeclampsia is a serious pregnancy complication characterised by maternal vascular dysfunction, placental dysfunction, and organ injury, with no effective treatment currently available. Kampo, a system of Japanese traditional medicine comprising standardised herbal formulations, could target pathophysiological pathways driving preeclampsia. We evaluated the effects of select Kampo formulations on markers of preeclampsia using primary human trophoblasts, placental explants, human umbilical vein endothelial cells (HUVECs), and uterine microvascular endothelial cells (UtMVECs). Twelve formulations were initially screened in HUVECs, and six formulations advanced for further study. TNFα was used to induce endothelial dysfunction, and angiogenic, antioxidant, inflammatory, and vascular dysfunction markers were assessed. Overall, Kampo formulations had minimal effect on sFlt-1 expression and only modest effects on sFlt-1 secretion by primary human trophoblast. In contrast, several formulations consistently increased placental growth factor (PlGF) expression and secretion, upregulated HMOX1 in trophoblasts, and enhanced PlGF secretion from placental explants. In endothelial cells, Kampo treatment partially reversed TNFα-induced dysfunction, demonstrated by reduced VCAM1 expression, and additional endothelial cell type-dependent effects on ET-1 and inflammatory pathways. These findings indicate that selected Kampo formulations modulate key pathways involved in the pathophysiology underpinning preeclampsia and warrant further investigation as potential therapeutic candidates. Full article

Background: Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide-1 receptor (GLP-1R) activation exert anti-diabetic and anti-obesity effects. Tirzepatide, a dual GIPR/GLP-1R agonist, has demonstrated cardiovascular benefits in clinical studies. However, the direct vascular actions of tirzepatide and their potential advantages over selective GLP-1 receptor agonists (GLP-1RAs) remain unclear. We investigated the vasoprotective effects of tirzepatide and compared them with those of GLP-1 receptor agonists in vivo and in vitro. Methods: Non-diabetic C57BL/6 and diabetic KK-Ay mice received tirzepatide, semaglutide, or vehicle. Arterial remodeling was induced by femoral artery wire injury. A subset of mice was co-treated with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME). After 4 weeks, biochemical, morphometric, and immunofluorescence analyses were performed. In vitro, human umbilical vein endothelial cells (HUVECs) were stimulated with tirzepatide or liraglutide to assess nitric oxide (NO) production. Results: In non-diabetic mice, tirzepatide suppressed intimal hyperplasia, including at a low dose that did not affect metabolic parameters, whereas semaglutide had no significant effect on intimal hyperplasia at the same molar dose. The protective effects of tirzepatide were abolished by L-NAME. In diabetic mice, tirzepatide and semaglutide similarly improved metabolic parameters and attenuated intimal hyperplasia. In HUVECs, tirzepatide increased NO production in a dose-dependent manner, and this effect was preserved under hyperglycemic conditions. Tirzepatide and liraglutide induced comparable NO production at equivalent molar concentrations. Conclusions: Tirzepatide, but not semaglutide, exerted vasoprotective effects under non-diabetic conditions in a NO-dependent manner, whereas both agents exhibited comparable vasoprotective effects under diabetic conditions. Full article

Polyhydroxyalkanoates (PHAs) are a family of microbial polyesters distinguished by their excellent biocompatibility and tunable degradation profiles. However, systematic evaluation of the interaction effect between their chemical structure, material properties, and biological performance remains limited, particularly in veterinary medicine applications. In this study, we conducted comprehensive in vitro and in vivo evaluations of five commercially available PHA (co)polymers: poly(3-hydroxybutyrate) (PHB); poly(3-hydroxybutyrate-co-4-hydroxybutyrate) containing 5 mol% or 15 mol% 4-hydroxybutyrate monomer (P34HB 5%, P34HB 15%); and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) containing 5 mol% or 15 mol% 3-hydroxyvalerate monomer (PHBV 5%, PHBV 15%). Material characterization confirmed that the introduction of proper comonomers effectively reduced crystallinity and accelerated the degradation process. Biological assays demonstrated quite excellent cytocompatibility and hemocompatibility among all tested PHA materials. Notably, P34HB 5% nanoparticles promoted human umbilical vein endothelial cell (HUVEC) migration. In a 12-week murine subcutaneous implantation model, the PHBV 15% group exhibited the thinnest fibrous capsule formation and the mildest inflammatory response. Furthermore, intramuscular injection of nanoparticles revealed favorable muscle tissue compatibility in all groups. These results provided a co-polymer ratio-based justification for PHA selection, thus providing support for the application of these biomaterials in veterinary drug delivery platforms, wound dressings, and biodegradable implants. Full article

Background: Hypertension-induced vascular injury involves endothelial dysfunction, inflammation, and oxidative stress, leading to vascular remodeling and cardiovascular complications. Flavin-containing monooxygenase 2 (FMO2) has been implicated in redox regulation, but its role in hypertensive vascular injury remains unclear. This study investigated whether KuJiang GanLuoYin (KJGLY) protects against hypertensive vascular injury and whether FMO2-associated Fat mass and obesity-associated protein (FTO)/N6-methyladenosine (m⁶A) signaling is involved. Methods: Spontaneously hypertensive rats (SHRs) were treated with KJGLY for eight weeks. Blood pressure, vascular remodeling, inflammation, oxidative stress, and global m⁶A RNA methylation were assessed. Integrated metabolomic and proteomic analyses were performed to identify treatment-associated molecular alterations and candidate proteins. AAV9-mediated FMO2 knockdown in SHRs and gain- and loss-of-function approaches in angiotensin II (Ang II)-stimulated human umbilical vein endothelial cells were used to examine the functional involvement of FMO2. Ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based chemical profiling and High-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS) quantification were performed to characterize the major constituents of KJGLY. Results: KJGLY significantly reduced blood pressure and alleviated vascular remodeling in SHRs. Metabolomic and proteomic analyses revealed treatment-associated alterations in inflammatory and lipid metabolic pathways and identified FMO2 as a treatment-responsive candidate. KJGLY restored FMO2 expression, reduced FTO abundance and NF-κB activation, increased global m⁶A levels, and attenuated inflammatory and oxidative stress responses in hypertensive aortas. Conversely, AAV9-mediated FMO2 knockdown aggravated vascular injury, enhanced inflammation and oxidative stress, reduced global m⁶A levels, and increased NF-κB activation. Co-immunoprecipitation showed an association between FMO2 and FTO, and MeRIP-qPCR indicated that FMO2 manipulation altered m⁶A enrichment of VCAM-1 mRNA. In Ang II-stimulated endothelial cells, linarin, the most abundant quantified constituent of KJGLY, partially recapitulated the cellular effects of KJGLY, including restoration of FMO2/FTO-associated signaling and attenuation of inflammatory activation. Conclusions: These findings support a functional role for FMO2 in hypertensive vascular injury and suggest that FMO2-associated modulation of FTO/m⁶A signaling may contribute to the vascular protective effects of KJGLY. Linarin recapitulated key protective effects in vitro, although its in vivo contribution to the formula remains to be determined. Full article

Endothelial dysfunction is an early event in the development of cardiovascular diseases and is characterized by impaired barrier function, inflammatory activation of endothelial cells (ECs), and alterations in lipid metabolism. In addition to typical (mononuclear) endothelial cells (TECs), multinucleated variant endothelial cells (MVECs) are present within the vascular wall; however, their functional role remains poorly understood. The aim of the present study was to investigate the molecular and functional characteristics of MVECs and their potential contribution to the development of endothelial dysfunction. Primary human umbilical vein endothelial cells (HUVECs) were used, and multinucleated cells were generated by polyethylene glycol-induced fusion. Cells were incubated under control conditions or exposed to low-density lipoproteins (LDL; 100 µg/mL, 24 h). A comprehensive analysis was performed, including transcriptomic and proteomic (secretome) profiling using gene set enrichment analysis (GSEA), as well as functional assays assessing transendothelial LDL transport, intracellular cholesterol accumulation, macrophage migration, and the expression and secretion of pro-inflammatory cytokines (IL-6, IL-8). MVECs exhibited pronounced differences compared to TECs. GSEA revealed reduced enrichment of pathways related to canonical nuclear factor kappa B (NF-κB) signaling and negative regulation of NF-κB transcription factor activity, actin cytoskeleton organization, focal adhesion assembly, basement membrane organization, and vesicle-mediated transport in MVECs relative to TECs, indicating impaired cytoskeletal integrity, altered cell–matrix interactions, dysregulated inflammatory signaling, and reduced vesicular trafficking activity. Functionally, MVECs demonstrated an increased capacity for cholesterol accumulation and enhanced transendothelial migration of macrophages. Notably, transendothelial LDL transport across the MVEC monolayer was not increased, suggesting a predominance of intracellular lipid accumulation. MVECs also exhibited a pronounced pro-inflammatory phenotype, characterized by elevated expression and secretion of IL-6 and IL-8. Taken together, these findings indicate that MVECs represent a functionally altered endothelial phenotype with impaired barrier function, dysregulated lipid metabolism, and enhanced inflammatory activity. Local accumulation of MVECs within the vascular wall may contribute to the formation of pro-atherogenic regions and play a role in the initiation and progression of endothelial dysfunction. Full article

Lactate is increasingly recognized as a signaling molecule capable of modulating gene expression and vascular function. This descriptive pilot study investigated the effects of different lactate concentrations (0 mM, 10 mM, 20 mM, and 30 mM) and exposure times (1 h, 3 h, and 6 h) on the transcriptomic responses of human umbilical vein endothelial cells (HUVECs). Using next-generation RNA sequencing, an unbiased genome-wide analysis was performed, followed by focused examination of genes relevant to endothelial biology, calcium signaling, and glycocalyx integrity. Results showed that there was no statistically significant effect of lactate concentration on the expression of the examined genes. In contrast, prolonged incubation time was associated with differential expression of KLF2, KLF4, FOXO1, CD34, and VCAM1. These findings suggest that exposure time, rather than lactate concentration, may be associated with endothelial gene expression patterns under static conditions. This exploratory pilot study provides preliminary transcriptomic observations and highlights the need for further mechanistic investigations including functional and protein-level analyses. Full article

An undescribed seco-kaurane diterpenoid, benincaside A (BA), was isolated from the seeds of Benincasa hispida. The seeds of B. hispida have been traditionally used in folk medicine and previous studies have reported anti-tumor potential in B. hispida seed extracts. Accordingly, we investigated the cytotoxicity and underlying mechanisms of BA in colorectal cancer cells. BA inhibited growth in HT29, Colo205, HCT116, and CT26 colorectal cancer cells, as determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while showing no toxicity toward normal human umbilical vein endothelial cells (HUVEC) and human fibroblast WS-1 cells. In HCT116 cells, BA-induced deoxyribonucleic acid (DNA) damage and apoptosis, as evidenced by morphological changes, 4,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining, and assays of caspase-8 and caspase-3 activities. BA triggered apoptotic cell death via the extrinsic pathway, as indicated by elevated caspase-8 and caspase-3 activities. Intracellular reactive oxygen species (ROS) generation was observed in BA-treated HCT116 cells. The growth-inhibitory effects were significantly attenuated by pretreatment with N-acetylcysteine (NAC, an antioxidant), caffeine (an ATM kinase inhibitor), z-VAD-fmk (pan-caspase inhibitor), or z-IETD-fmk (caspase-8-specific inhibitor). Colorimetric assays confirmed increased caspase-8 and caspase-3 activities in BA-treated cells. This study is the first to report ROS-dependent signaling as a key mechanism underlying BA-induced cell death in HCT116 human colorectal cancer cells. Full article

Hantaviruses are emerging zoonotic pathogens responsible for two severe clinical syndromes: (i) haemorrhagic fever with renal syndrome (HFRS) and (ii) hantavirus cardiopulmonary syndrome (HCPS), collectively causing more than 200,000 human cases annually worldwide. Despite their public-health importance, the molecular mechanisms governing the host response and the population-level dynamics of rodent-to-human spillover remain incompletely characterised. The timeliness of this framework is underscored by the April–May 2026 outbreak of Andes orthohantavirus aboard the MV Hondius cruise ship, the first such cluster in a maritime setting, with three deaths reported across multiple countries. This event revealed critical gaps in existing models that treat humans solely as dead-end spillover hosts. Our coupled Susceptible-Exposed-Infectious-Recovered-Dead (SEIRD) model assumes no human-to-human transmission and is therefore designed for hantavirus strains where spillover does not lead to secondary human cases, specifically Hantaan virus (HTNV), Puumala virus (PUUV), Sin Nombre virus (SNV), and Dobrava-Belgrade virus (DOBV). The Andes virus (ANDV) outbreak aboard the MV Hondius is used as a real-world case study to assess the boundaries of our model and to motivate future extensions, not as a direct validation target for its quantitative predictions. Here, we present an integrated computational study combining three complementary analyses. First, we performed a preliminary phylogenetic analysis of the viral sequence, identifying Orthohantavirus andesense as the likely etiological agent responsible for the vessel-associated outbreak. Second, we carried out a downstream transcriptomic analysis of Hantaan virus (HTNV)-infected human umbilical vein endothelial cells (HUVECs), using publicly available RNA-seq data (GEO accession GSE133751, $n=3$ per group). This analysis identified 184 upregulated and 19 downregulated genes, highlighting a transcriptional response dominated by interferon-stimulated genes (ISGs), including CXCL10, CXCL11, MX2, DDX58, IRF7, STAT1, OASL, and CMPK2. We then constructed a protein–protein interaction (PPI) network using STRING, comprising 176 nodes and 3210 edges, and applied a composite network centrality score to rank putative regulatory hubs. This analysis identified ISG15, IRF1, CXCL10, STAT1, and DDX58 as the most central nodes. Pathway enrichment analysis confirmed a strong activation of interferon signalling (Reactome, $p=1.3\times {10}^{-63}$), antiviral defence mechanisms (Gene Ontology, $p=3.8\times {10}^{-58}$), and NF-$\kappa$B-related pathways, together with a concurrent suppression of ribosomal translation. Finally, we developed a coupled SEIRD epidemiological model that explicitly represents rodent-to-rodent and rodent-to-human transmission with logistic rodent population growth. Preliminary simulation analysis demonstrates that reducing human exposure to rodent excreta is substantially more effective than rodent population control alone for reducing human disease burden, and that rodent control in isolation can paradoxically increase human cases through a dilution-like effect. The integrated framework provides molecular and epidemiological insights relevant to hantavirus surveillance, therapeutic target identification, and public-health intervention design. Full article

Hyperglycemia aggravates colorectal cancer (CRC) progression by driving inflammatory pathways and facilitating tumor–endothelial cell adhesion. Ginger extract exhibits well-known anti-inflammatory properties; however, its pharmacological efficacy under such metabolic stress conditions remains largely unclear. In this study, the effects of a fermented ginger extract prepared using natural deep eutectic solvents (FNGE) were examined on high-glucose-induced pathogenesis in human CRC cells. DLD-1 cells were exposed to high-glucose conditions with or without FNGE treatment. The expression of inflammatory mediators (cyclooxygenase-2 [COX-2], prostaglandin E2 [PGE2], interleukin [IL-6], and IL-8), the adhesion capacity of CRC cells to human umbilical vein endothelial cells (HUVECs), and activation of the NF-κB signaling pathway were examined. FNGE treatment significantly and dose-dependently attenuated the high-glucose-induced upregulation of COX-2 mRNA and PGE2 secretion, while concurrently suppressing the expression of IL-6 and IL-8. Furthermore, FNGE pretreatment markedly impaired CRC cell adhesion to HUVECs. Mechanistic analyses, including targeted COX-2 knockdown and pharmacological inhibition, revealed that FNGE exerts its anti-inflammatory and anti-adhesive effects primarily through the suppression of NF-κB activation, a master transcriptional regulator of these pathogenic pathways. These in vitro findings demonstrated that FNGE effectively mitigates high glucose-mediated inflammation and endothelial adhesion in CRC cells by downregulating the NF-κB/COX-2 signaling axis. Thus, this study provides a preliminary biochemical basis for the potential application of green-extracted phytochemicals under metabolic stress, highlighting the need for future in vivo validation to confirm their translational relevance. Full article

Background/Objectives: Tissue factor (TF)-expressing cancer cells and their extracellular vesicles (CaCe-dEVs) are key drivers of cancer-associated hypercoagulability and vascular dysfunction. While low-molecular-weight heparins (LMWHs) and direct FXa inhibitors are standard therapies for cancer-associated thrombosis, their direct effects on cancer cell procoagulant potential and endothelial responses remain incompletely defined. This study compared the impact of LMWHs (enoxaparin, tinzaparin), apixaban, and quercetin on cancer cell viability, thrombin generation, and CaCe-dEVs-induced endothelial injury. Methods: Pancreatic (BXPC3) and breast (MCF7) cancer cells and their vesicles were analyzed for TF expression and thrombin generation. Human umbilical vein endothelial cells (HUVECs) were pretreated with each agent prior to vesicle exposure. Cell viability, thrombin generation, and endothelial morphology were assessed using standard assays and microscopy. Results: Tinzaparin and quercetin significantly reduced cancer cell viability, whereas enoxaparin and apixaban showed no cytotoxicity. None of the agents affected HUVEC viability. All suppressed TF-mediated thrombin generation induced by cancer cells, with tinzaparin being most effective in BXPC3 cells. Quercetin exhibited a partial and limited protective effect on endothelial cells against CaCe-dEVs-induced dysfunction, while LMWHs and apixaban did not prevent endothelial damage. Conclusions: These findings suggest that LMWHs, apixaban, and quercetin modulate cancer-cell-driven hypercoagulability beyond anticoagulation, with quercetin and tinzaparin showing additional cytotoxic potential. Such dual effects may reduce thrombosis risk while impacting tumor progression, meriting further investigation. Full article

Thrombosis remains a critical challenge for blood-contacting implants, with early-stage protein adsorption and platelet activation playing decisive roles. In this study, we constructed a TiO₂/CuO semiconductor heterojunction on titanium surfaces to generate a stable built-in electric field, creating a self-activated bioelectric microenvironment without external stimulation. We evaluated its cytocompatibility and hemocompatibility through static in vitro assays. To distinguish the contributions of surface chemistry, topography, and bioelectric cues, we include control groups of Ti (untreated), TNW (TiO₂ network, topography control), and Ti/CuO (CuO nanoparticles without heterojunction, Cu²⁺ release control). The heterojunction significantly enhances human umbilical vein endothelial cell (HUVEC) adhesion and proliferation while simultaneously suppressing fibrinogen adsorption, platelet adhesion/activation (as assessed by morphological changes), and whole-blood cell adhesion. Compared with Ti/CuO, the heterojunction (TCH) induces substantially stronger endothelialization and anticoagulant effects despite similar Cu²⁺ release levels (~0.047 μM, far below the reported pro-angiogenic threshold of ~5.0 μM), indicating a predominant role of the built-in electric field. This study preliminarily demonstrates a previously unrecognized role of bioelectric cues in modulating early blood–material interactions. Following rigorous validation under physiologically relevant dynamic flow conditions and in vivo models, interfacial bioelectric engineering emerges as a promising new strategy for designing anticoagulant biomaterials. Full article

Myocardial infarction (MI) triggers excessive oxidative stress, a detrimental immune response, and insufficient angiogenesis, which collectively impede effective cardiac repair. This study developed a multifunctional composite polysaccharide hydrogel, termed KgXd^gel, based on konjac glucomannan (KGM) and xanthan gum (XG) functionalized with gallic acid (GA) and dopamine (DA), respectively, to integrate reactive oxygen species (ROS) scavenging, macrophage polarization, and pro-angiogenic activities. In vitro assays demonstrated that the KgXd^gel hydrogel exhibited excellent cytocompatibility, effectively scavenged ROS, promoted the polarization of macrophages towards the reparative M2 phenotype, and enhanced the migration and tube formation of human umbilical vein endothelial cells. In a rat MI model, treatment with KgXd^gel significantly improved cardiac function (e.g., left ventricular ejection fraction, LVEF; left ventricular fractional shortening, LVFS), attenuated left ventricular dilation (LVIDs), and favorably modulated the post-infarction microenvironment. This was evidenced by the upregulation of the M2 marker CD163 and the angiogenic factor VEGF, alongside the downregulation of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and the M1 marker iNOS. These findings conclusively demonstrate that the KgXd^gel hydrogel synergistically promotes cardiac repair post-MI through its integrated antioxidant, immunomodulatory, and pro-angiogenic functions, presenting a promising multi-targeted therapeutic strategy. Full article