This review systematically analyzes 186 valid data points derived from 157 distinct marine natural small-molecule drug leads discovered in China in the past decade (2015-2024). These compounds have all undergone phenotypic and target studies, and certain "structure-activity-target" relationships have been established, revealing the recent progress in the basic research of marine drug discovery in China. Therapeutically, antitumor agents dominated (50.0%), while emerging candidates for Alzheimer's disease (3.8%) and osteoporosis (5.4%) demonstrated the multi-target potential of marine chemistry. Ecologically, marine fungi (45.2%) and mangrove symbionts (11.8%) have emerged as prolific sources. Strikingly, 38.2% of the compounds exceeded Lipinski's 500 Da threshold, with higher-molecular-weight agents leveraging macrocyclic architectures (e.g., polyketide-alkaloid hybrids) to enhance bioactivity. These findings challenge traditional drug-likeness criteria and propose a "Marine Rule" framework that prioritizes conformational rigidity, ecosystem-driven scaffold optimization, and the repurposing of defense molecules. This review provides critical insights into China's evolving leadership in marine natural product research and offers strategic guidance for future innovations in the discovery of small molecule leads.
Chemical investigation of the soft coral Clavularia koellikeri led to the isolation of fourteen new diterpenoid derivatives clavukellines A-N (1-14) featuring the dolabellane-type skeleton. Structural characterization of these compounds was accomplished through an integrated analytical strategy combining NMR spectroscopy and HR-ESI-MS. Absolute configurations were unambiguously assigned using ECD spectral simulation and DP4 + probability analysis. Preliminary pharmacological evaluation indicated that compounds 8 and 13 exhibited anti-inflammatory activity, while compounds 1-14 showed antithrombotic activity. This study reveals promising anti-inflammatory and antithrombotic potentials that warrant further investigation.
Type 2 diabetes mellitus (T2DM) is fundamentally linked to gut microbiota dysbiosis, a condition that triggers a cascade of pathophysiological changes including aberrant host-microbe co-metabolism, compromised intestinal barrier integrity, and chronic low-grade inflammation, which collectively drive insulin resistance. While conventional therapies have limitations, traditional Chinese medicine (TCM) presents a promising therapeutic strategy. This review comprehensively elucidates the pathophysiological link between gut dysbiosis and T2DM. It then systematically summarizes the multi-target mechanisms by which TCM exerts its therapeutic effects, including: remodeling the gut microbial ecosystem; reprogramming host-microbe co-metabolism of short-chain fatty acids (SCFAs), bile acids (BAs), and branched-chain amino acids (BCAAs); reinforcing the intestinal barrier to mitigate metabolic endotoxemia; and modulating key signaling pathways involved in inflammation and immunity, etc. Key clinical evidence is also summarized. Furthermore, the review critically evaluates the preclinical and clinical evidence supporting these mechanisms, highlighting both therapeutic potential and current challenges, such as the need for standardization. Finally, current limitations and future prospects are considered, proposing a path forward for integrating microbiota-targeted TCM therapies into the modern, evidence-based management of T2DM.
Ulcerative colitis (UC) is defined as a chronic inflammatory disease with recurrent episodes, and current therapeutic strategies for this gastrointestinal disorder often fail to achieve satisfactory clinical outcomes. This clinical challenge underscores an urgent requirement to develop alternative treatment strategies. Patchouli alcohol (PA), a natural compound exhibiting anti-inflammatory and antioxidant properties, has shown potential; however, its precise mechanisms of action in UC remain to be fully elucidated. Our study shows that PA can effectively alleviate the symptoms of dextran sulfate sodium (DSS)-induced UC in mice. This therapeutic effect is achieved by reducing intestinal barrier impairment and inhibiting inflammatory reactions. In an LPS-induced inflammatory model using RAW264.7 cells, PA significantly downregulated the mRNA expression of il-1β and il-6. Mechanistically, protein disulfide isomerase (PDI) was identified as a direct target of PA. By inhibiting IRE1 activation via PDI, PA mitigates endoplasmic reticulum stress, thereby reducing intestinal epithelial injury and ultimately alleviating the severity of UC. In this research, it is determined that the ability of PA to protect the intestinal epithelial barrier is brought about by its specific targeting of PDI, which alleviates consequent endoplasmic reticulum stress and prevents cellular damage.
Costunolide, a natural germacranolide sesquiterpenoid, exhibits only moderate anti-HCC activity. To enhance its efficacy and tumor selectivity, a series of 37 dimeric costunolide-1,2,3-triazole conjugates was designed and synthesized by integrating dimerization and molecular hybridization strategies. Evaluation of their antiproliferative effects on HepG2, Huh-7, and SK-Hep-1 cells suggested that 25 compounds were more potent than either costunolide or sorafenib. The most active dimer 19 exhibited significant activity with IC50 values of 1.6, 1.3, and 0.7 μmol·L-1, which were 13.1, 14.2, and 34.9-fold greater than those of costunolide. Compound 19 showed favorable selectivity against human normal liver cells (THLE-2) and markedly inhibited colony formation. Through a combination of bioinformatics, docking, and molecular dynamics (MD) simulations, glucose-6-phosphate dehydrogenase (G6PD) was identified as a target of compound 19, which was subsequently validated by DARTS and SPR assays. Functional studies revealed that compound 19 arrested the HCC cell cycle at the G2/M phase, suppressed migration and invasion by inhibiting epithelial-mesenchymal transition, and triggered both apoptosis and ferroptosis. These findings establish triazole-linked costunolide dimer 19 as a promising lead candidate for the development of novel anti-HCC therapies.
Self-assembled nanoaggregates (SANs) derived from herbal decoctions have emerged as promising natural nanomedicines. However, their formation patterns in multi-herb formulations and therapeutic roles in central nervous system disorders remain unclear. Wuzhuyu decoction (WZYD) is a classical formula for migraine treatment. Here, we reveal that SANs in WZYD (N-WZYDs) are formed through synergistic interactions among multiple herbal ingredients with Euodiae Fructus as the focus. N-WZYDs consisted mainly of proteoglycan scaffolds and small-molecule active components. In chronic migraine (CM) rat models, N-WZYDs significantly alleviated symptoms with efficacy comparable to that of WZYD, potentially via inhibition of the IL-33/ST2/TRPA1 signaling pathway. In Caco-2 cells, transport studies indicated that ginsenoside Rg1, dehydroevodiamine, and rutaevin were poorly absorbed, whereas evodiamine and 6-gingerol were moderately absorbed but significantly active in efflux, indicating the intestine as a key site of action. As an oral medication, intact N-WZYDs accumulated primarily in the intestines and could be internalized by Caco-2 and enterochromaffin cells. Crucially, N-WZYDs promoted serotonin release from enterochromaffin cells more effectively than free active molecules alone and increased peripheral serotonin levels, thereby alleviating CM. By investigating the formation patterns, anti-CM mechanisms, and absorption behaviors of N-WZYDs, this study elucidated their material basis and brain-intestine interactions in treating CM, supporting their further development as therapeutic agents or drug delivery systems.
Hypertension raises cardiovascular risk via vascular remodeling, worsened by oxidative stress-linked VSMC dysfunction. Genistein (Gen), an antioxidant isoflavone, protects against cardiovascular diseases, but its role in hypertensive remodeling is unclear. This study explores if Gen eases remodeling by inhibiting oxidative stress via the GSK3β/FYN/Nrf2 pathway. In vivo, spontaneously hypertensive rats (SHR) and normotensive WKY rats got Gen (10-20 mg·kg-1·d-1) or valsartan (Val) for 10 weeks; aortic tissues were tested for morphology (HE/Masson), proliferation (PCNA), migration (MMP2/9), oxidative stress (NOX4), and VSMC phenotype (α-SMA/OPN). In vitro, SHR/WKY VSMCs were treated with Gen (10-40 μmol·L-1) to check proliferation (EdU), migration (scratch/Transwell), ROS, and Nrf2 markers. Network pharmacology predicts Gen inhibits vascular remodeling via reducing hypertension-related oxidative stress, verified by EdU, scratch, Transwell, and Western blot. Gen reduced SHR blood pressure, vascular wall thickness, and fibrosis, reversing PCNA, MMP2/9, NOX4, OPN overexpression and α-SMA underexpression. In VSMCs, it dose-dependently inhibited proliferation/migration, reduced ROS, and restored Nrf2 pathway activity. Network analysis found 52 shared targets, with GSK3β, FYN, Nrf2 as key nodes. Gen and pGSK3β inhibitor SNP reversed GSK3β/FYN overexpression and Nrf2 underexpression; Nrf2 inhibitor ML385 barely affected pGSK3β/FYN. Thus, Nrf2 may lie downstream of GSK3β and FYN. Gen inhibits oxidative stress injury in the aortic tissue of SHR rats through the GSK3β/FYN/Nrf2 pathway, thereby reducing vascular remodeling in hypertension, lowering blood pressure, and exerting a protective effect on vascular lesions in hypertension. These findings provide new experimental evidence for Gen as a potential therapeutic agent against hypertensive vascular remodeling.
Glycosyltransferases (GTs) are key enzymes in the glycosylation of plant secondary metabolites, primarily catalyzing the transfer of a sugar moiety from an activated donor to a specific acceptor molecule. Triterpenoid saponins, an abundant and diverse group of natural products, are composed of triterpenoid aglycones and one or more sugar chains, under the catalysis of GTs. Phytolacca Radix is a traditional Chinese medicine containing over 40 triterpenoid saponins with pharmacological values. However, the identification of glycosyltransferases related to triterpenoid saponin synthesis from Phytolacca species remains scarce. In this study, a novel glycosyltransferase, PamUGT, was identified from Phytolacca americana. PamUGT exhibits catalytic activity toward 28-/30-COOH of pentacyclic triterpenoids, and it exhibits a preference for the C-30 position when both carboxyl groups are available. To our knowledge, PamUGT is the first glycosyltransferase identified in Phytolacca species that can catalyze triterpenoids. Further analysis of substrate specificity revealed that PamUGT catalyzes the glycosylation of a wide range of compounds, including triterpenoids, flavonoids, diterpenoids, alkaloids, and phenolic acids. Our findings identify a highly promiscuous glycosyltransferase, offering a valuable enzymatic tool for modifying diverse natural products.
Postmenopausal women, elderly individuals, and transfusion-dependent patients are prone to bone marrow iron overload, which is closely associated with iron overload-associated osteoporosis (IOOP). Currently, the treatment of IOOP mainly focuses on promoting iron efflux and alleviating iron-induced damage, but the intervention value of natural active ingredients remains unclear. Naringenin (NAR), as a natural flavonoid, can regulate bone metabolism, yet its role and mechanism in IOOP have not been elucidated. In this study, an in vitro model was established by inducing MC3T3-E1 cells with ferric ammonium citrate (FAC), and an in vivo IOOP model was constructed by inducing mice with iron dextran to investigate the effects and mechanisms of NAR. The results showed that NAR improved the alkaline phosphatase (ALP) activity and mineralization capacity of FAC-induced iron-overloaded cells, upregulated the expression of collagen I (Col1a1) and runt-related transcription factor 2 (Runx2), reduced the accumulation of reactive oxygen species (ROS) and lipid peroxide (LPO), attenuated mitochondrial membrane potential (MMP) impairment, and inhibited apoptosis. In in vivo experiments, NAR restored the density and quantity of trabecular bone in iron-overloaded mice. Mechanistically, RNA sequencing indicated that the effect of NAR was associated with transcription factor EB (Tfeb)-dependent transcription: NAR promoted Tfeb nuclear translocation and upregulated p62 transcription under iron overload conditions. Co-immunoprecipitation (Co-IP) demonstrated that NAR enhanced the binding of p62 to kelch-like ECH associated protein 1 (Keap1), while increasing Nrf2 phosphorylation and upregulating its key effector proteins HO-1 and NQO1. Functional validation showed that the Nrf2 antagonist ML385 or siRNA could block the effects of NAR without affecting Tfeb expression, whereas the Tfeb inhibitor eltrombopag simultaneously inhibited Nrf2 expression and NAR-induced effects. In conclusion, NAR alleviates iron overload-induced oxidative damage and osteogenic disorders via the Tfeb/p62/Nrf2 pathway, suggesting that it may serve as a potential therapeutic agent for IOOP.
Cisplatin (DDP) remains a standard therapy for triple-negative breast cancer (TNBC), yet intrinsic or acquired resistance often limits its efficacy; here, we report that Ramulus Mori alkaloids (SZ-A), an approved botanical α-glucosidase inhibitors, synergize with DDP to suppress TNBC progression in vitro and in vivo by driving PLA2G2A-dependent ceramide accumulation. Combining SZ-A with DDP synergistically inhibits viability, clonogenicity, migration, and invasion, induces S-phase arrest and apoptosis, and attenuates tumor growth in xenograft models. Mechanistically, SZ-A directly binds to and stabilizes PLA2G2A, blocking its autophagic-lysosomal degradation, leading to accumulated PLA2G2A that suppresses fatty acid oxidation and triggers ceramide accrual via ADIPOR2 inhibition. Genetic ablation of PLA2G2A abrogates these effects. DDP further enhances SZ-A-induced PLA2G2A upregulation and ceramide accumulation, resulting amplified cytotoxicity. Our findings reveal SZ-A as a chemosensitizing agent that enhances the efficacy of DDP in TNBC.
Systematical screening of the metabolic profile of marine fungus Aspergillus sp. EGF 15-0-3 using OSMAC-GNPS molecular networking cascade followed by target isolation of the environmental-induced products resulted the identification of eight unprecedented indole diketopiperazine-based hybrids (1-8) featuring three distinct chemical backbones. The structures of the obtained compounds were established by combination of extensive spectroscopic analyses, X-ray crystallography, and ECD calculations. All these environmental-induced metabolites were demonstrated to be unusual tyrosyl-DNA phosphodiesterase 2 inhibitors. Compound 3, as the most outstanding example, showed selective synergistic antitumor effect when combined with the chemotherapeutic drugs.
Gelsemium elegans (G. elegans) is a toxic medicinal plant traditionally used to treat chronic pain, with its toxicity linked to indole alkaloids such as gelsemine and humantenmine (HMT). Chronic pain often co-occurs with depression, a condition known to disrupt host-microbiota interactions, potentially affecting drug metabolism and toxicity. However, the impact of comorbid depression on the toxicity of G. elegans remains unclear. This study investigates how depression exacerbates the neurotoxicity of G. elegans and explores the role of the gut microbiota-host metabolic axis in this process. Depression-model mice were treated with G. elegans aqueous extract, gelsemine and HMT. Multi-omics approaches, including 16S rRNA sequencing and shotgun metagenomics, were used to analyze microbiota changes under depressive conditions. Functional validation was performed using pseudo-germ-free mice, fecal microbiota transplantation, and supplementation with Clostridium species and lithocholic acid (LCA), as well as pregnane X receptor (Pxr) knockout models. The results showed that depression significantly heightened the neurotoxicity of G. elegans, gelsemine and HMT. Mechanistically, depression reduced Clostridium abundance and LCA levels, impairing PXR activation and downregulating hepatic CYP3A11 expression. This disruption of the Clostridium-LCA-PXR-CYP3A11 axis hindered the detoxification of indole alkaloids, leading to increased systemic exposure and exacerbated neurotoxicity. Restoration of this pathway through Clostridium or LCA supplementation alleviated the toxicity. These findings highlight the role of the Clostridium-LCA-PXR-CYP3A11 axis in the altered toxicity of G. elegans in a depressive state, and suggest that Clostridium species and their metabolites may serve as a potential strategy for mitigating toxicity.
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic metabolic disease that severely affects human health. Quzhou Fructus Aurantii ethyl acetate extract (QFAEE) is a mixture rich in diverse natural flavonoids that exhibits multiple pharmacological properties, including significant anti-inflammatory and antioxidant activities. However, the anti-MASH effects of QFAEE and the underlying mechanisms remain unknown. This study aimed to investigate the therapeutic effects of QFAEE on MASH and the related mechanisms. The therapeutic effects of QFAEE on hepatic steatosis, inflammatory responses, oxidative stress and apoptotic activity were systematically evaluated in both in vivo and in vitro models of metabolic stress. QFAEE administration significantly reduced hepatic lipid accumulation, inflammatory cell infiltration and liver injury in HFHC diet-fed mice. Combined RNA sequencing and network pharmacology analyses revealed that QFAEE exerted its anti-MASH effects through modulation of the PPAR signaling pathway. QFAEE ameliorated MASH by activating PPARα and subsequently upregulating CPT1A, which promoted mitochondrial and peroxisomal β-oxidation. Notably, PPARα inhibition promoted hepatic lipid accumulation, inflammation and oxidative stress in hepatocytes, all of which were significantly attenuated by QFAEE treatment. These findings suggest that QFAEE prevents metabolic stress-induced MASH progression by activating PPARα signaling.
Eleven new highly oxygenated cembrane-type diterpenoids (1-7 and 10-13) and two known analogues (8-9) were isolated from the South China Sea soft coral Sinularia pedunculata. Their structures were determined through extensive spectroscopic analysis, quantum mechanical-nuclear magnetic resonance (QM-NMR) approach and X-ray diffraction analysis. Notably, compounds 3 and 4 were rare cembrane diterpenoids featuring a tetrahydropyran moiety with 5,8-ether and 4,8-ether linkages, respectively, while compounds 4 and 9 inhibited HBV DNA replication with IC50 values of 0.87 and 1.15 μmol·L-1 in HepAD38 cells, respectively. Mechanism investigation suggested that compound 9 accelerated capsid formation without affecting the levels of HBV cccDNA, total RNA, or pgRNA.
Atherosclerosis (AS) is widely recognized as the principal pathological substrate underlying chronic cardiovascular diseases (CVDs). It is a chronic, progressive, and inflammatory disease characterized by excessive lipid deposition, oxidative stress, inflammatory response, plaque formation and rupture, thrombosis and vascular calcification (VC). Vascular smooth muscle cells (VSMCs) are essential for maintaining the normal structure of blood vessels and play a pivotal role in the pathological process of AS. Their proliferation, migration, differentiation, senescence and death processes critically influence the progression of AS. The specific mechanism of VSMCs participating in AS remains a central focus of research in the cardiovascular field. In recent years, natural products have garnered considerable attention in the field of AS prevention and treatment, primarily due to their multi-target effects, low toxicity and side effects. However, there is still a lack of systematic review of natural compounds that alleviate AS by regulating the function of VSMCs. This article focuses on the core role of VSMCs in the progression of AS, and systematically reviews the natural compounds targeting VSMCs metabolism and their molecular regulatory mechanisms. By combing the relevant pharmacological activities and potential targets, the pathological function of VSMCs in AS is further elucidated, thereby providing an important theoretical basis for the development of novel and efficient AS treatment strategies.
Pinoresinol diglucoside (PDG), an active component derived from Eucommia ulmoides, exhibits therapeutic effects against apoptosis, inflammation, and hypertrophy, etc. However, whether PDG plays a protective role in diabetic cardiomyopathy (DCM) is not fully elucidated. This study aimed to investigate the role and potential mechanism of PDG in DCM. The possible mechanism of PDG targeting DCM was identified by network pharmacology, bioinformatics, machine learning and molecular docking methods. The heart function of mice was evaluated using echocardiography. The pathological changes in the heart of mice were detected using H&E staining. Changes of Ca2+ fluorescence intensity values in H9c2 cells were assessed by confocal microscopy. Apoptosis was evaluated by TUNEL staining and flow cytometry. The expression of DCM-related genes and proteins, both in vivo and in vitro, was examined by qRT-PCR and Western blot. The results showed that PDG effectively improved the cardiac function and suppressed cardiac hypertrophy, inflammation, and cardiomyocyte apoptosis caused by DCM. Intriguingly, molecular docking results revealed that the therapeutic effect of PDG on DCM was associated with stromal interaction molecule 1 (STIM1), calcium release-activated calcium channel protein 1 (Orai1), and nuclear factor of activated T-cells 3 (NFAT3) signaling. Consistently, animal experiments results indicated that PDG significantly downregulated the expression of STIM1, Orai1, NFAT3 at the protein level, as well as the associated store-operated calcium entry (SOCE). Therefore, our findings revealed that PDG can alleviate cardiac hypertrophy, inflammation and apoptosis in DCM by downregulating the STIM1, Orai1, and NFAT3 signaling molecules. Thus, PDG may be a promising therapeutic candidate for treating DCM.
Insulin resistance is a hallmark of type 2 diabetes (T2DM) and can increase the risk of cognitive impairment, including Alzheimer's disease. Nuciferine, an alkaloid derived from lotus leaves, shows neuroprotective effects. This study investigated nuciferine's protective role in T2DM-induced cognitive impairment (T2DM-CI) and its mechanisms. Mouse models were created using high-fat diets and streptozotocin, along with high glucose-induced HT-22 cells. Nuciferine reduced blood glucose, improved cognitive function, and mitigated glial cell activation, neuron and synapse loss in T2DM mice. It enhanced insulin signaling by increasing protein levels of IR, IRS1, and IGF-1R, reversing PI3K and AKT phosphorylation, inhibiting GSK3β activity, and reducing hyperphosphorylated Tau in HT-22 cells and T2DM mice. mRNA levels of these molecules matched their protein levels. Further studies revealed that nuciferine directly interacts with IR, knocking out IR abolished its effects on the PI3K/AKT pathway. Thus, nuciferine activates the PI3K/AKT pathway via IR, improving insulin resistance and slowing T2DM-CI progression.
Psoriasis is a chronic skin disease driven by skin inflammation and abnormal subcutaneous blood vessels. Yinxie Granules (YXKL) is a clinically effective traditional Chinese medicine (TCM) formula that has shown promise in psoriasis treatment, but its pharmacological mechanisms and material basis remain unclear, limiting its clinical application and co-administration with other drugs. In this study, we explored the mechanism and active components of YXKL in the treatment of psoriasis using patient samples, IMQ-induced psoriatic mice, zebrafish, and in vitro assays. We discovered that YXKL alleviated skin inflammation and restored the skin barrier by reducing M1 macrophage/Th17 infiltration, lowering pro-inflammatory cytokines (IL-6, IFN-β, IL-23, IL-17), and increasing loricrin expression. Mechanistically, we identified a dynamic transition in STING signaling during psoriasis progression. Both the STING/IRF3 and STING/NF-κB pathways were activated in moderate psoriasis, while only the STING/NF-κB pathway was hyperactivated in severe disease. YXKL specifically targeted the STING/NF-κB pathway to mitigate inflammation and vasculopathy but had no significant impact on the upstream regulators, including TRAF6, LKB1, AMPK, and ULK1. Quercetin and kaempferol were identified as the primary STING-modulating components in YXKL, binding to STING proteins and inhibiting downstream pathway activation. These flavonoid components mediate the anti-psoriatic effects of YXKL by simultaneously suppressing skin inflammation and angiogenesis while enhancing vascular integrity through STING inhibition in both keratinocytes and endothelial cells. Our results elucidated the molecular basis of YXKL for psoriasis treatment, highlighting STING/NF-κB as a pivotal therapeutic target in mitigating psoriasis development and providing natural candidate compounds as potential STING inhibitors.
