The homeostasis balance of copper, as an essential trace element for life activities, is crucial for maintaining the normal function of cells. Cuproptosis, discovered in recent years, is a novel type of programmed cell death triggered by the accumulation of excessive copper ions in mitochondria. The core mechanism lies in that copper ions, after being reduced by ferridoxin (FDX1), directly target and induce the oligomerization of the acylated tricarboxylic acid (TCA) cycle enzyme, thereby triggering fatal protein toxic stress. This distinctive mechanism operates independently of other recognized pathways of cell death, offering a novel perspective for elucidating the pathological processes underlying various diseases. A review of pertinent research conducted over the past four years reveals that cuproptosis is not only significantly implicated in the onset, progression, and treatment resistance of tumors but is also intricately associated with diverse pathological processes, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, and immune abnormalities. This article conducts a multi-level summary from molecular mechanisms to physiological and pathological significance; deeply explores the interaction between cuproptosis and various subcellular structures, as well as their complex signal regulatory network; and systematically expounds the cutting-edge strategies for treating cuproptosis, including traditional copper chelating agents, ion carriers, and copper-based nanomedicines, with a particular focus on the latest progress in the field of natural product research. This review has systematically summarized the therapeutic potential demonstrated by numerous natural active ingredients when precisely regulating the cuproptosis pathway to provide a theoretical reference for future research in this field.

Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder. With the aging population and the continuous development of risk factors associated with AD, it will impose a significant burden on individuals, families, and society. Currently, commonly used therapeutic drugs such as Cholinesterase inhibitors, N-methyl-D-aspartate antagonists, and multiple AD pathology removal drugs have been shown to have beneficial effects on certain pathological conditions of AD. However, their clinical efficacy is minimal and they are associated with certain adverse reactions. Furthermore, the underlying pathological mechanism of AD remains unclear, posing a challenge for drug development. In contrast, natural plant molecules, widely available, offer multiple targeting pathways and demonstrate inherent advantages in modifying the typical pathologic features of AD by influencing the blood–brain barrier (BBB). We provide a comprehensive review of recent in vivo and in vitro studies on natural plant molecules that impact the BBB in the treatment of AD. Additionally, we analyze their specific mechanisms to offer novel insights for the development of safe and effective targeted drugs as well as guidance for experimental research and the clinical application of drugs for the prevention and treatment of AD.

Alzheimer's disease (AD) is an incurable neurodegenerative disease that has become one of the most important diseases threatening global public health security. Dihuang Yinzi (DHYZ) is a traditional Chinese medicine that has been widely used for the treatment of AD and has significant therapeutic effects, but its specific mechanism of action is still unclear.The aim of the study is to investigate the specific mechanism of DHYZ in treating AD based on brain metabolomics and network pharmacology. In this study, the classic APPswe/PS1E9 (APP/PS1) mice were selected as the AD animal model, and the mechanism of DHYZ was studied. The learning and memory ability of mice was detected by Y-maze test, and the ultrastructure of neural cells in the brain of the mice was observed by transmission electron microscope (TEM). Then, the mechanism of DHYZ intervention in AD was analyzed by constructing network pharmacology, and combined with brain metabolomics based on ultra performance liquid chromatography-mass spectrometry (UPLC-MS) to detect differential metabolic markers and their metabolic pathways. In addition, a joint analysis of differential metabolites and potential targets for DHYZ treatment of AD is conducted to deeply explore the relationship between key targets, differential metabolites, and metabolic pathways. After 30 days of DHYZ treatment, the spatial work and reference memory ability of APP/PS1 mice were significantly improved, the structure of mitochondria and synapses in the neurons of the brain were basically normal. 202 potential targets for DHYZ treatment of AD were screened through network pharmacology, and after enrichment analysis, these targets showed correlation with redox reactions, mitochondrial and synaptic functional pathways. And 7 differential metabolites were identified in brain metabolomics are Nicotinic acid, N-Formyl-L-glutamic acid, 5-(2-Hydroxyethyl)-4-methylthiazole, D-Gulono-1,4-lactone, Norepinephrine, 3-Methylotrophicacid, Palmitic acid. These differential metabolites mainly involve nicotinite and nicotinamide metabolism, pertussis, cAMP signaling pathway, cysteine and methionine metabolism. Notablely, through matching analysis of targets and metabolites, a total of 20 genes were found to match Nicotinic acid, 51 genes were found to match norepinephrine, and 14 genes intersected with the two metabolites, enrichment analysis of the intersected genes showed that neuroactive light receptor interaction, serotonergic synapse, and cAMP signaling were significantly affected, which is consistent with previous network pharmacology results. This study identified the main chemical ingredients of DHYZ intervention in AD may originated from Polygala tenuifolia Wild, Dendrobium nobile Line and Ophiogon japonicus (L.f) Ker-Gawl. Combined with Y Maze, TEM and brain metabolomics, revealed that DHYZ can improve the learning and memory abilities and brain pathological morphology of APP/PS1 mice by regulating nicotinic acid, 3-Methylthiopropionic acid, pertussis and their metabolic pathways, including nicotinate and nicotinamide metabolism, cAMP signaling pathway and cysteine and methionine metabolism. In short, this study provides a new research foundation and direction for the treatment of AD with traditional Chinese medicine.

Major depressive disorder (MDD) is a common mental illness. The traditional Chinese medicine compound Xiaojian Zhongtang (XJZT) has a good therapeutic effect on MDD, but the specific mechanism is not clear. The aim of this study is to explore the molecular mechanism of XJZT in the treatment of MDD through network pharmacology and bioinformatics. The traditional Chinese medicine system pharmacology database was used to screen the chemical components and targets of XJZT, while the online Mendelian inheritance in man, DisGeNET, Genecards, and therapeutic target database databases were used to collect MDD targets and identify the intersection targets of XJZT and MDD. A “drugs-components-targets” network was constructed using the Cytoscape platform, and the STRING was used for protein-protein interaction analysis of intersecting targets. Gene Ontology and Kyoto encyclopedia of genes and genomes analysis of intersecting targets was performed using the DAVID database. Obtain serum and brain transcriptome datasets of MDD from the gene expression omnibus database, and perform differentially expressed genes, weighted gene co-expression network analysis, gene set enrichment analysis, and receiver operating characteristic analysis. A total of 127 chemical components and 767 targets were obtained from XJZT, among which quercetin, kaempferol, and maltose are the core chemical components, and 1728 MDD targets were screened out, with 77 intersecting targets between XJZT and MDD. These targets mainly involve AGE-RAGE signaling pathway in diabetic complexes, epidermal growth factor receptor tyrosine kinase inhibitor resistance, and HIF-1 signaling pathway, and these core targets have strong binding activity with core components. In addition, 1166 differentially expressed genes were identified in the MDD serum transcriptome dataset, and weighted gene co-expression network analysis identified the most relevant gene modules (1269 genes), among which RAC-alpha serine/threonine-protein kinase (AKT1), D(4) dopamine receptor (DRD4), and kynurenine 3-monooxygenase (KMO) were target genes for the treatment of MDD with XJZT, these 3 genes are mainly related to the ubiquitin-mediated proteolysis, arachidonic acid (AA) metabolism, and Huntington disease pathways, and the expression of AKT1, DRD4, and KMO was also found in the MDD brain transcriptome dataset, which is significantly correlated with the occurrence of MDD. We have identified 3 key targets for XJZT treatment of MDD, including AKT1, KMO, and DRD4, and they can be regulated by the key components of XJZT, including quercetin, maltose, and kaempferol. This provides valuable insights for the early clinical diagnosis and development of therapeutic drugs for MDD.

Ulcerative colitis (UC) is a chronic, relapsing-remitting inflammatory disorder of the colorectal mucosa whose incidence is rising globally. Current therapies remain limited by incomplete efficacy and long-term safety concerns, underscoring the need for novel, multi-targeted therapeutic agents. Plant-derived saponins, a structurally diverse class of triterpenoid and steroidal glycosides widely distributed in botanical drugs, have emerged as promising candidates owing to their capacity to simultaneously modulate multiple pathogenic axes of UC. This structured narrative review provides an evidence-graded account of the physiological and pathological mechanisms of UC, the chemical characteristics and pharmacological basis of plant-derived saponins, and the molecular mechanisms through which saponins counteract experimental colitis. Five interconnected mechanistic axes are delineated: suppression of pro-inflammatory signaling cascades, particularly NF-kB/MAPK and NLRP3 inflammasome pathways; protection and renewal of the intestinal epithelial barrier through tight junction restoration and mucin regulation; remodeling of the gut microbiota and its metabolite output, including short-chain fatty acid production; regulation of intestinal immune homeostasis via macrophage polarization and Th17/Treg balance; and control of oxidative stress, ferroptosis, and immunometabolic reprogramming. Mechanistic claims are graded by evidence level-distinguishing direct target engagement, inhibitor/genetic validation, and correlative downstream readouts-and parent saponins are distinguished from their microbiota-derived deglycosylation metabolites. This review further discusses the structural determinants of saponin bioactivity, gut-microbiota-dependent biotransformation, and current limitations including poor oral bioavailability, hemolytic potential, scarcity of clinical trials, and inter-individual microbiome variability. Future directions encompass structure-activity-guided scaffold optimization, advanced colon-targeted delivery systems, microbiome-stratified biomarker development, and systems-level target integration. Collectively, convergent preclinical evidence identifies plant-derived saponins as selectively multi-targeted candidates for UC; however, no purified plant-derived saponin has yet been tested in a randomised controlled trial in UC, and therapeutic claims must await evaluation against STRIDE-II targets such as faecal calprotectin normalisation, endoscopic healing and histological remission.