The global burden of mortality is largely attributable to cardiovascular diseases (CVDs), where altered metabolic homeostasis plays a critical role. The identification of lactylation as an epigenetic modification mediated by lactate has transformed the conventional view of this glycolysis byproduct from a mere metabolic intermediate to a multifaceted signaling molecule. This review comprehensively reveals the mechanistic insights underlying lactylation in CVDs, particularly in myocardial ischemia, atherosclerosis, and heart failure, highlighting its pivotal role in disease pathogenesis through modulation of transcriptional regulation, metabolic adaptation, and cellular differentiation. Considering the enzyme-regulated reversibility of lactylation, this work systematically evaluates its druggable targets, thereby establishing a conceptual foundation for combined metabolism-epigenetic therapeutics.

Diabetic cardiomyopathy (DCM), a global cardiovascular complication of diabetes, is characterized by concurrent diastolic and systolic ventricular dysfunction that progressively leads to heart failure, arrhythmias, and cardiogenic shock. Despite advancements in modern therapeutics, DCM continues to exhibit high mortality rates, underscoring the critical need for novel preventive and therapeutic strategies. In recent years, traditional Chinese medicine (TCM) has gained prominence in DCM management due to its established safety profile and emerging evidence of clinical efficacy. Current research focuses on elucidating TCM's multitarget mechanisms, particularly its regulatory effects on metabolic homeostasis, oxidative stress, and inflammatory pathways-key pathological processes in DCM progression. This review systematically investigates the latest advancements in TCM for DCM management through 3 principal dimensions: First, it synthesizes the etiological understanding of DCM from both TCM theory and modern medical perspectives, highlighting their complementary mechanisms in disease pathogenesis. Second, it critically evaluates the therapeutic potential of clinically validated Chinese herbal agents, focusing on their bioactive compounds that target myocardial energy metabolism and oxidative stress pathways. Third, it systematically summarizes evidence-based TCM therapeutic strategies. By consolidating existing evidence, this review aims to provide a rigorous assessment of TCM's clinical value in DCM management, while proposing standardized frameworks to facilitate deeper integration of TCM principles with evidence-based cardiology practice.

Myocardial ischemia/reperfusion (I/R) injury remains a major clinical challenge, because blood flow restoration can exacerbate tissue damage. Apelin, an endogenous peptide acting through the APJ receptor, has demonstrated cardioprotective effects in experimental models. The APJ receptor, a G-protein-coupled receptor widely expressed in cardiovascular tissues, mediates vasodilation, cardiac contractility, and angiogenesis. This systematic review and meta-analysis evaluates its efficacy in myocardial I/R injury. A systematic search in Medline (PubMed), Embase, Scopus, and Web of Science was conducted up to 2024, identifying rodent studies of cardiac I/R injury (Langendorff/in vivo) treated with apelin. Studies on pretreatment or chronic ischemia were excluded. A random-effects meta-analysis reported standardized mean differences with 95% confidence intervals, assessing heterogeneity using the I 2 statistic. From 1765 records, 26 preclinical studies met inclusion criteria. Apelin significantly improved +LVdp/dtmax, -LVdp/dtmax, left ventricular end-diastolic pressure, left ventricular end-systolic pressure, left ventricular ejection fraction, left ventricular developed pressure × heart rate, cardiac output, stroke volume, coronary flow, and left ventricular developed pressure, but did not affect heart rate, mean arterial pressure, left ventricular end-diastolic volume, or left ventricular end-systolic volume. It reduced infarct size, fibrosis, lactate dehydrogenase, malondialdehyde, and apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay), while also reducing creatine kinase-MB and improving adenosine triphosphate, energy charge, and phosphocreatine. Meta-regression indicated most outcomes were dose independent, although a few (eg, mean arterial pressure, terminal deoxynucleotidyl transferase dUTP nick end labeling) showed dose-related responses. The risk of bias was high in most studies, and publication bias was observed for some outcomes. Apelin exerts cardioprotective effects in rodent I/R models, enhancing cardiac function and metabolism while reducing infarct size, oxidative stress, and apoptosis. Further standardized preclinical and clinical studies are warranted to optimize dosing protocols and define therapeutic applicability.

Hypertension is associated with significant changes in the vascular system and is an important risk factor for cerebrovascular disease. Moreover, hypertension is a dominant determinant of heart failure, and both contribute to the development of cognitive decline and dementia. Despite these links, there is limited understanding of how hypertension and risk of heart failure influence the structure, function, and mechanical properties of cerebral arterioles. We examined the effects of hypertension, alone or with predisposition for heart failure, on penetrating arterioles. Using arterioles isolated from rats with genetic hypertension, structural properties, mechanical behavior, and functional responses were characterized by pressure myography. Penetrating arterioles from spontaneously hypertensive heart failure (SHHF) rats exhibited eutrophic remodeling, reduced compliance, and increased stiffness. In contrast, penetrating arterioles from spontaneously hypertensive rats (SHR) were more compliant and less stiff despite similar structural remodeling. Increased collagen deposition in SHHF arterioles was consistent with reduced compliance, whereas SHR arterioles had unchanged collagen-elastin ratio. SHHF and SHR arterioles were functionally different when exposed to pharmacologic mediators of vasomotor response. After exposure to endothelial N-methyl- d -aspartate receptor coagonists, glutamate and d -serine, vasorelaxation was reduced in SHHF rats but not in SHR relative to normotensive controls. In contrast, acetylcholine-induced vasorelaxation was maintained in SHHF rats but enhanced in SHR. Furthermore, sodium nitroprusside caused vasorelaxation in normotensive arterioles, whereas vasoconstriction was observed in both hypertensive strains. Therefore, penetrating arterioles undergo compensatory adaptations in hypertension, but not when there is a genetic propensity for developing heart failure.

Systematic review screening underpins the evidence base for pharmacology and drug development but remains burdensome, error-prone, and resource-intensive. Synthesa AI, a large language model (LLM)-based abstract screening tool, was developed to streamline this process by providing a transparent and prompt-driven framework for abstract screening. In this validation study, Synthesa AI was tested across 17 benchmark meta-analyses on nine therapeutic domains relevant to pharmacology and clinical pharmacotherapy. The tool screened 270,626 abstracts retrieved from PubMed and Scopus. Synthesa AI successfully identified all 163 benchmark-included studies, achieving a sensitivity of 100% (95% CI: 97.7%–100.0%) and a specificity of 99.4% (95% CI: 99.37%–99.42%). Importantly, it reduced reviewer workload by 91.7%, with only 1,797 abstracts requiring manual review. Beyond replication, the tool identified 32 additional relevant studies that had been missed in the original reviews, representing a 19.6% increase in evidence yield. These findings highlight the potential of Synthesa AI to enhance pharmacological evidence synthesis by improving the reproducibility and comprehensiveness of systematic reviews used to evaluate drug efficacy, safety, and therapeutic positioning. Synthesa AI represents a transformative solution for living systematic reviews and large-scale evidence integration, offering a rigorous and efficient alternative to traditional human-led screening in pharmacology research.

:Triptolide (TP) is widely used clinically for multiple diseases, but its cardiotoxicity significantly limits its clinical applications. The underlying mechanisms of its cardiotoxicity are still unclear. Mitochondria are crucial for cellular survival and function. Here, we found that TP induced mitochondrial dysfunction and apoptosis of cardiomyocytes, which might be the key process underlying TP-induced cardiotoxicity. Moreover, the expression of prohibitin1 (PHB1) was significantly decreased after TP treatment in a time-dependent manner. Overexpression of PHB1 alleviated mitochondrial dysfunction and inhibited apoptosis of cardiomyocytes after TP treatment. Mechanistically, PHB1 might regulate mitochondrial dynamics, which maintain normal mitochondrial function. Based on the above results, PHB1 might be a potential therapeutic target for TP-induced cardiotoxicity.

:This study investigates the cardioprotective potential of soluble guanylate cyclase (sGC) and its α1 subunit in myocardial ischemia/reperfusion (I/R) injury, along with the underlying mechanisms. We used a model involving Sprague Dawley rats undergoing left coronary artery I/R, complemented by H9c2 cell cultures in an anaerobic environment to simulate I/R conditions in vitro. Both loss- and gain-of-function approaches were applied to assess the role of sGC and its α1 subunit in myocardial I/R injury. Immunofluorescence microscopy, western blotting, and RT-PCR were employed to examine how sGC and its α1 subunit influence oxidative stress and apoptosis. Our results showed that sGC and its α1 subunit were associated with reduced I/R injury severity in both in vitro and in vivo settings. Overexpression of sGC decreased cardiomyocyte apoptosis and maintained mitochondrial function during I/R, whereas sGC silencing heightened oxidative stress and apoptosis. In addition, pharmacological modulation of sGC affected signaling in the peroxisome proliferator–activated receptor-γ coactivator-1α/uncoupling protein 2 pathway. These findings demonstrate the crucial role of sGC and its α1 subunit in protecting against cardiac injury during I/R, suggesting that sGC-targeted therapies could offer promising strategies for managing myocardial damage associated with I/R injury.

Inflammation is increasingly recognized as a key mechanism driving impaired cardiac function and reduced cardiorespiratory fitness in heart failure. Interleukin-1 blockade with anakinra has shown consistent anti-inflammatory effects but inconclusive benefits on functional capacity in prior trials. In a pooled analysis of 73 patients, Hogwood et al reported that anakinra reduced hsCRP and modestly improved peak VO 2 across both younger (<60 years) and older (≥60 years) patients, with no difference in magnitude of benefit between age groups. These findings indicate that the functional response to IL-1 inhibition is preserved across age groups. Although the results are limited by small sample size, heterogeneous treatment duration, and lack of placebo control, they highlight the importance of age-stratified research and provide a rationale for larger randomized studies assessing long-term clinical outcomes.

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease marked by extracellular matrix deposition, oxidative stress, and profound microvascular remodeling. Endothelial dysfunction, particularly through endothelial-to-mesenchymal transition (EndMT), has been implicated in fibrotic progression but remains insufficiently characterized. In this study, human pulmonary microvascular endothelial cells were exposed to 5% serum from patients with IPF or healthy donors to model disease-associated vascular alterations. IPF serum stimulated a robust increase in reactive oxygen species (ROS) production and proliferation, concomitant with downregulation of endothelial markers (von Willebrand factor, CD31) and upregulation of mesenchymal markers (α-smooth muscle actin, collagen I), consistent with EndMT induction. Notably, pharmacological inhibition of NADPH oxidase (NOX) with diphenyleneiodonium markedly attenuated ROS generation, phenotypic switching, and junctional disruption observed under IPF serum exposure. Similarly, inhibition of protein kinase C (PKC) by chelerythrine suppressed ROS production and proliferative responses, implicating PKC-dependent pathways in ROS-mediated endothelial injury. Immunofluorescence analyses confirmed structural reorganization, revealing loss of endothelial junctional integrity and accumulation of mesenchymal proteins, both reversed by NOX inhibition. Together, these findings establish IPF serum-derived factors as potent drivers of endothelial oxidative stress and EndMT through NOX- and PKC-dependent mechanisms. Targeting these redox-sensitive pathways may represent a promising therapeutic strategy to mitigate vascular dysfunction, tissue remodeling, and disease progression in IPF.