Inflammatory bowel disease (IBD), particularly ulcerative colitis, involves disruption of the intestinal mucosal barrier due to ecological and metabolic imbalances in the gut as its underlying pathology. Current therapies for Ulcerative colitis (UC) exhibit limited efficacy and adverse effects, necessitating the development of novel treatment strategies. Naringin and osthole are natural herbal compounds that show therapeutic potential in various inflammatory models due to their excellent anti-inflammatory activity. However, their combined therapeutic effects and precise mechanisms in UC remain unreported. This study aimed to explore the therapeutic effectiveness and mechanism of naringin combined with osthole in addressing dextran sodium sulfate (DSS)-induced colitis. The investigation centered on their impact on the disruption of the intestinal epithelial cell barrier, modulation of intestinal flora composition, alteration of metabolites, and inflammation model in vitro. Modal assessment encompassed body weight, disease activity index (DAI) score, colon length, and histopathological examination. Intestinal barrier integrity was evaluated through Quantitative Real-Time PCR, western blotting, and immunofluorescence staining. Microbiota abundance and metabolic levels were assessed using 16S ribosomal RNA gene sequencing and metabolomics analysis. Protein expression levels of pertinent pathways and associated receptors were tested through network pharmacology prediction and western blot analysis. Naringin and osthole synergistically relieved colitis symptoms in mice compared with either drug alone or 5-aminosalicylic acid, as evidenced by weight loss recovery, DAI scores, and colon length preservation. Mechanistically, naringin combined with osthole down-regulated the expression level of JNK/NF-κB signaling pathway related proteins and repaired intestinal barrier. Furthermore, the combination regulates the composition of the microflora and promotes the restoration of a steady state of the microflora. Metabolomic revealed amino acid-tryptophan metabolism as a key metabolic pathway. It also reveals the microbiota-tryptophan pathway as a potential therapeutic strategy. Naringin combined with osthole can alleviate DSS-induced colitis more effectively by JNK/NF-κB signaling pathway, repairing barrier function and regulating intestinal microbiota and metabolites. These findings provide a theoretical basis for the combination therapy strategy to enhance the efficacy of potential functional food in treating ulcerative colitis.

Nitrogen-containing core structure pyrimidine has long been regarded as one of the privileged scaffolds for novel drug development. Natural products embedded with pyrimidine motifs are distinguished by their exceptional scaffold diversity and vast structural complexity, which endow them with versatile biological activities, including anticancer, antiviral, antifungal and anti-inflammatory activities. This review is dedicated to surveying a series of structurally distinctive naturally occurring compounds characterized by the presence of an aromatic heterocyclic pyrimidine moiety covering from 2004 to early 2025. Multiple key aspects of these 156 pyrimidine-containing compounds, including natural sources, features of chemical structure, biological activities, as well as biosynthetic studies are summarized. The review emphasizes the enduring potential of natural products, highlighting their inherent capacity for medication and optimization to fuel the pipeline of lead compound targeting major disease and providing new window for overview of these pyrimidine-containing natural products. Overall, this review aims to unlocking the potential of these isolates. It thus offers a fresh reference for the exploitation of pyrimidine-containing natural products, with the ultimate goal of realizing their therapeutic potential.

Atopic dermatitis (AD) is a persistent, relapsing skin inflammatory disorder characterised by epidermal barrier dysfunction, immune system anomalies, and microbial dysbiosis. Current therapies encompass calcineurin inhibitors, topical corticosteroids, and synthetic drugs such as JAK inhibitors and biologics, which, despite their efficacy, have safety issues and constraints on prolonged use. Recently, natural bioactive compounds namely flavonoids, polyphenols, and terpenoids have garnered interest for their anti-inflammatory, antioxidant, and skin-barrier-repairing characteristics. Recent studies emphasise the incorporation of these bioactive compounds into hydrophilic/hydrophobic polymeric conjugates and nanocarrier systems to promote skin distribution, increase efficacy, and minimise systemic adverse effects. This study encapsulates traditional and innovative medicines, highlights the promise of polymer-conjugated herbal formulations, and examines recent developments in nanotechnology and delivery technologies for AD management. The increasing interest in bioactive ingredient formulations and polymeric nanocarriers indicates a favourable shift towards safer, more effective, and patient-compliant treatment methodologies.

Prostate cancer (PCa) remains one of the most common malignant tumors among men worldwide, typically relying on the androgen receptor (AR) signaling pathway. Inducing ferroptosis, a novel form of iron-dependent cell death, represents a promising strategy; however, its regulation by AR signaling is complex. The molecular chaperone heat shock protein 70 (HSP70) is critical for AR stability and function, yet its role as a therapeutic target in this context is underexplored. The anti-proliferative effect of the compound nidurufin (Nid) was assessed across PCa cell lines using MTT, clonogenic, and 3D spheroid assays. Ferroptosis was evaluated by transmission electron microscopy, reactive oxygen species (ROS) detection, and lipid peroxidation analysis. Mechanistic insights were gained through Western blot, qPCR, immunofluorescence, ChIP-qPCR, molecular docking, and cellular thermal shift assay (CETSA). In vivo efficacy was validated in a zebrafish xenograft model. Nid exhibited potent, selective anti-proliferative activity against AR-positive PCa cells, particularly 22Rv1 (IC₅₀= 10.30 μM), and induced ferroptosis characterized by mitochondrial shrinkage and ROS accumulation. Mechanistically, Nid did not bind to AR, but it directly bound to HSP70, disrupting its chaperone function and leading to AR protein destabilization and transcriptional downregulation. This consequently suppressed the expression of the AR-target gene membrane-associated O-acyltransferase domain protein 2 (MBOAT2), a key ferroptosis suppressor enzyme. ChIP-qPCR confirmed AR directly binds the MBOAT2 promoter, and Nid treatment reduced this enrichment. In vivo, Nid significantly inhibited tumor growth and metastasis in a zebrafish xenograft model. Our study identifies Nid as a novel HSP70-targeted compound that triggers ferroptosis by disrupting the HSP70-AR-MBOAT2 axis. This work not only reveals a previously unrecognized connection between protein chaperone function and ferroptotic susceptibility but also positions HSP70 as a compelling therapeutic target for overcoming AR-pathway dependency in PCa.

The crisis of antimicrobial resistance (AMR) is escalating while the antibiotic pipeline remains stagnant. Our bibliometric analysis of eight decades of literature reveals a critical imbalance: research on AMR has grown, yet fundamental research on antibiotic discovery has declined. Most strikingly, research attention to Actinomycetota, the source of most clinical antibiotics, has sharply decreased since its mid-twentieth-century peak. This therapeutic disinvestment coincides with the intensifying AMR crisis. We argue for a strategic reinvestment in natural product discovery, now enabled by advances in genomics, artificial intelligence, and synthetic biology. These tools can unlock the vast, silent biosynthetic potential of actinobacteria, transforming discovery into a targeted and efficient endeavor. Rebalancing research priorities by coupling this historically proven source with modern technology is essential to revive the antibiotic pipeline. We urge funding agencies and industry to bridge the growing gap between a well characterized problem and a neglected solution.Graphic abstract

Plumbagin is a natural naphthoquinone with different pharmacological properties and abundantly present in the roots of Plumbago zeylanica L. In spite of its therapeutic anti-cancerous potential, its limited availability from plant sources has slowed down its large scale production. In the present study, we report the heterologous reconstruction of the complete plumbagin biosynthetic pathway in Saccharomyces cerevisiae using six functionally characterized genes from P. zeylanica viz. Polyketide synthase (PKS), Polyketide cyclase, Aldo-keto reductase (AKR1), two cytochrome P450 monooxygenases (CYP81B140 and CYP81B141), and a cytochrome P450 reductase (CPR). Stepwise pathway engineering was performed to evaluate the necessity and sufficiency of individual and combined gene sets. The expression of PKS alone was not able to synthesize measurable products, while the co-expression of PKS, cyclase, and AKR1 (PCA) enabled the biosynthesis of 3-methyl-1,8-naphthalenediol which is a key intermediate and also confirmed by LC-MS/MS. The addition of CYP81B140 and CPR (PCACC) led to the production of 3-methyl-1,8-naphthalenediol and isoshinanolone, and further addition of CYP81B141 (PCACCC) in yeast effectively biosynthesized plumbagin. These results confirm the functional roles of all six genes and demonstrate full pathway reconstruction in yeast from the primary precursors acetyl-CoA and malonyl-CoA. The present study establishes a microbial production platform for plumbagin and provides valuable insights into the biosynthesis of plant-derived naphthoquinones as well as paving the way for the sustainable and scalable production of medicinally important compounds.

Natural products (NPs) have long served as a cornerstone of drug discovery, yielding landmark therapeutics such as paclitaxel and artemisinin and providing sustained access to biologically relevant chemical space. Despite this legacy, NP-based discovery has gradually declined with the rise of synthetic chemistry and high-throughput screening, even as many contemporary “synthetic” drugs remain structurally inspired by natural scaffolds. Classical NP workflows—centered on phenotypic screening and bioassay-guided fractionation—continue to face persistent bottlenecks, including structural complexity, low bioactive yield, frequent rediscovery, and limited scalability. Rather than competing with NP research, artificial intelligence (AI) offers a complementary methodological framework to address these longstanding challenges. This review critically examines the bottlenecks inherent to traditional NP discovery and outlines how AI can be systematically integrated across the pipeline. We discuss AI-enabled advances ranging from natural language processing for mining ethnopharmacological knowledge to machine learning-driven dereplication, cheminformatics, and genome mining, with platforms such as GNPS2 exemplifying scalable progress. Case studies in antibiotic and anticancer discovery, as well as the modernization of traditional medicine, illustrate how AI-NP integration can accelerate early-stage discovery while enhancing translational relevance. Looking ahead, we examine emerging paradigms—including quantum machine learning, federated data ecosystems, and AI-assisted molecular design—that may further expand the scope of NP-based research. Collectively, this review presents a forward-looking framework in which AI functions not as a replacement for NP science, but as a synergistic discipline that enables more efficient, scalable, and informed exploration of nature-derived chemical diversity.

Iron homeostasis is critical for the survival of almost all organisms, yet its dysregulation is often caused by a synergistic effect of genetic and environmental factors. Previous studies have shown that trapping devices of the predominant nematode-trapping fungus (NTF) Arthrobotrys oligospora serve as an unprecedented iron sequestration system compensatory for lack of the crucial fungal vacuolar iron detoxification mechanism. Here, we found that among the Ascomycota phylum, only NTFs lacked gene coq7, which encodes COQ7 responsible for ubiquinol (UQ) biosynthesis and efficient iron chelation. Addition of exogenous UQ₁₀ or heterologous expression of yeast gene coq7 in A. oligospora inhibited the formation of fungal trapping devices. Interestingly, mutant nematodes with disruption of gene coq7 can greatly reduce nematode-capturing ability of fungal trapping devices. Exogenous COQ7s exhibit significant adsorption effects on fungal trapping devices both in vitro and in vivo. Transcriptional, metabolic, mutational, and phenotypic analyses indicated that A. oligospora utilized a chemotaxonomic class of highly oxygenated arthrobotrisins with similar characteristics to UQ₃, instead of UQs, in response to elevated oxygen levels. Loss of arthrobotrisin biosynthesis led to a delayed growth of the mutant △art but enhanced UQ₈ biosynthesis, trapping device formation, and nematicidal activity. Time-calibrated evolutionary analyses, combined with geological data, indicated that the NTF ancestor lost the coq7 gene after acquiring the art gene cluster during the cold “superoligotrophy” period, characterized by dramatic shifts in global oxygen levels and temperature changes. Our findings indicated that the trapping devices of NTF capture nematodes primarily for iron chelation therapy, rather than solely for food, which addresses the long-standing issue regarding the limited carnivorous ability of trapping devices.

Three new naphthomycin derivatives were isolated and identified from Streptomyces sp. HKIB0008, and were designated as naphthomycin R (1), naphthomycin S (2), and naphthomycin T (3). Their structures were elucidated using a combination of spectroscopic techniques, including high-resolution mass spectrometry, and NMR. The naphthoquinone core of 1 underwent carbon-carbon bond cleavage, resulting in a novel structural feature, and a corresponding Baeyer-Villiger oxidation mechanism was proposed. Compounds 2 and 3 possess a complex side chain when compared to known cystine modification on the naphthalenoid core as in the case of naphthomycins I and J. In addition, the minimum inhibitory concentration (MIC) assays for these compounds were conducted.

Six new polyketides, peniexpansones A-F (1-4, 6, 7), along with an additional novel compound, (2E,4E,6E)-8-methyldeca-2,4,6-trienoic acid (5), and a known naphthopyrone, were isolated from the ethyl acetate extract of rice fermented with the soil fungus Penicillium expansum DWS880. Structurally, peniexpansones A-D feature a highly oxygenated tetrahydronaphthalene moiety linked to an acyl chain. The structures of the new compounds were elucidated by extensive spectroscopic analysis (1D/2D NMR and HRESIMS) and further supported by quantum chemical calculations. Peniexpansone C showed weak cytotoxicity against HCT116 cells (IC₅₀ 22.81 ± 0.42 μM) and moderate antimicrobial activity against pathogens including Staphylococcus aureus and Candida albicans. Moreover, peniexpansones A and B, can significantly improve the anti-fungal activity of fluconazole against resistant Candida albicans. Our results provided new structures for the future development of efficiency enhancement agents for anti-fungal drugs.

Lignin, the most abundant aromatic biopolymer on Earth, is abundantly found as a by-product of biomass processing industries. Lignin presents remarkable properties, including antioxidant, UV-blocking, thermal stability, and antimicrobial; thus being considered a valuable feedstock to replace synthetic and fossil-based resources. Colloidal lignin particles (CLPs) are a promising strategy to overcome technical barriers in lignin valorization and have attracted increasing interest to be applied as multifunctional ingredients into several fields, including agriculture, biomedical, construction, and more recently, cosmetics. For this latter, CLPs stand out as promising Pickering stabilizers, creating opportunities for the development of surfactant-free cosmetic formulations. This review provides a current state of lignin research, focusing on the production of CLPs and Pickering emulsions and the key factors influencing their formation and stability. Recent progress in CLPs-stabilized Pickering emulsions is thoroughly addressed. Furthermore, it highlights advances on the multifunctional attributes of CLPs, including antioxidant activity, UV shielding, and demonstrated safety for cosmetic applications. The review concludes by discussing current challenges and future research directions for advancing the use of CLPs as sustainable materials in cosmetic science.

Phenazinoates A-E (1-5), comprising five pairs of methyl saphenate conjugates with genistein, o-aminophenol, p-acetaminophenol and glycerol, were isolated from the fermentation broth of mangrove soil-derived Streptomyces sp. OUCMDZ-4923. Their structures were determined through comprehensive one-dimensional and two-dimensional nuclear magnetic resonance spectroscopy, coupled with high-resolution electrospray ionization mass spectrometry. The absolute configurations of each isomer were established by comparing experimental electronic circular dichroism spectra with calculated counterparts. Based on the biosynthetic pathway analysis, compounds 1-3 were semi-synthesized from the reactions of methyl (R)-saphenate with genistein, o-aminophenol, and o-formamidophenol, utilizing microwave-assisted solid acid catalysis. The compounds were resolved as enantiomerically pure forms and subsequently tested for antibacterial efficacy against six pathogenic bacteria. Phenazinoates A (1) and B (2) demonstrated bioactivity against four Gram-positive bacterial strains, with minimum inhibitory concentration values ranging from 0.78 to 3.13 μg/mL.

The genus Calophyllum (Calophyllaceae), distributed mainly in tropical regions, is rich in chromanone derivatives with diverse molecular structures that exhibit potential antimicrobial and anticancer effects. Phytochemical investigation of the stem bark of C. calaba collected in Thailand led to the discovery of eight previously undescribed chromanones, calabanones A-H (1-8), and two known analogs, (-)-isocalomembranone P (9) and (-)-calomembranone P (10). The chemical structures of undescribed compounds were elucidated using spectroscopic analyses, particularly NMR and HRESIMS, while their absolute configurations were determined through ECD and NMR calculations combined with DP4+ probability analysis. Compounds 7 and 8 were identified as chromanone-steroid hybrids linked via an ester bond, representing the first report of such structures in plants. Cytotoxic evaluation of the isolated specialized metabolites revealed that compounds 6 and 9 displayed moderate activity against KB and HeLa S3 cancer cell lines, with IC₅₀ values ranging from 12.71 to 25.50 μM, while compounds 3-5 selectively inhibited the growth of KB cells, with IC₅₀ values in the range of 18.77-27.06 μM.

The oral microbiome plays a central role in maintaining both oral and systemic health, and disruptions in its balance can contribute to a wide range of diseases. This review brings together current evidence on how natural products modulate oral microbial communities, promote microbial equilibrium, and help prevent conditions such as dental caries, periodontitis, and chronic systemic disorders linked to oral dysbiosis. Recent studies highlight that phytochemicals particularly polyphenols, terpenoids, saponins, and alkaloids exert antimicrobial, anti-inflammatory, and antioxidant effects that influence bacterial adhesion, biofilm development, gene expression, and acid production. These compounds not only inhibit key oral pathogens but also support beneficial species, helping to sustain a stable and resilient microbiome. Evidence was gathered from PubMed, Scopus, ScienceDirect, and Google Scholar using relevant keywords and focusing on literature from 2015 to 2025. Insights into microbial diversity, environmental influences, host genetics, and advanced sequencing tools further strengthen understanding of oral microbial dynamics. While natural products show strong potential, challenges related to safety, bioavailability, regulatory clarity, and clinical translation remain to explore. This review outlines current progress and future directions needed to transform natural compounds into effective, evidence-based strategies for improving oral and systemic health through microbiome modulation.

Colitis-associated cancer (CAC) arises from persistent intestinal inflammation, immune dysregulation, and microbiota-driven epithelial injury, representing a major link between inflammatory bowel disease and colorectal malignancy. Despite advances in therapy, colon cancer remains one of the leading causes of cancer-related mortality worldwide, underscoring the urgent need for effective preventive and immunomodulatory interventions. Ardisiacrispin B (AB), a bioactive triterpenoid isolated from the Ardisia genus, has been reported to suppress tumor growth by regulating apoptosis and ferroptosis; however, its role in inflammation-driven colorectal tumorigenesis remains unexplored. In this study, we investigated the protective and antitumor effects of AB in an azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CAC mouse model, with a focus on inflammatory signaling pathways, epithelial remodeling, and gut microbiota modulation. AB administration markedly alleviated disease severity, as evidenced by a significant reduction in disease activity index, including body weight loss, diarrhea, and rectal bleeding. Histopathological evaluation revealed preserved colonic mucosal architecture, diminished inflammatory cell infiltration, and a pronounced reduction in tumor number and size. AB treatment partially modulated the gut microbiota, with a trend toward enrichment of beneficial taxa and a reduction in inflammation-associated bacterial populations. Concurrently, AB robustly downregulated the colonic expression of pro-inflammatory cytokines and chemokines. AB treatment was associated with increased expression of pro-apoptotic markers, indicative of enhanced apoptotic signaling in colonic epithelial cells, as indicated by increased expression of cleaved PARP, cleaved caspase-3, p53, and BAX, while markedly inhibiting cellular proliferation through suppression of Ki-67. Mechanistically, AB was associated with attenuation of key inflammatory and oncogenic signaling pathways, including IL-6/JAK2/STAT3, LPS/TLR4/MyD88/NF-κB, and MAPK cascades. Collectively, Ardisiacrispin B attenuates colitis-associated cancer by rebalancing gut microbiota, suppressing inflammation, and inducing tumor cell apoptosis through inhibition of key oncogenic signaling pathways.