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.

Neurological diseases (NDs) constitute a significant threat to global health and impose considerable economic burdens on society due to their complex etiology, poor prognosis, and chronic course. In recent years, significant research has highlighted the intricate connection between gut-brain axis (GBA) dysfunction and various NDs. The GBA facilitates bidirectional interactions linking the gastrointestinal (GI) tract and nervous system, preserving brain health through modulation of intestinal equilibrium, neural networks, and neuroendocrine, immune, and inflammatory pathways. Saponins, essential bioactive constituents in Traditional Chinese Medicine (TCM), have demonstrated substantial neuroprotective capabilities. Extensive studies indicate that saponins effectively prevent and manage NDs by influencing pivotal mediators within the GBA. Consequently, the GBA has emerged as a promising therapeutic target for saponins in neuroprotection. This review summarizes the interplay between the GBA and NDs and emphasizes recent findings on saponins as potential therapeutic agents targeting this axis, aiming to provide novel perspectives and therapeutic approaches for NDs.

Mitochondria are indispensable organelles that serve as the powerhouses of cells, playing a crucial role in maintaining cellular energy homeostasis. Consequently, mitochondrial dysfunction is recognized as a key pathogenic factor in a wide range of common diseases, including cardiovascular diseases, neurodegenerative disorders, metabolic syndromes and cancers. Due to their multitarget properties and favorable safety profiles, natural products have shown significant potential for regulating key mitochondrial biological processes, including mitobiogenesis, mitophagy, mitochondrial dynamics (fusion and fission), oxidative phosphorylation, and mitochondria-mediated apoptosis. Therefore, they have become an important resource for mitochondria-targeted therapy. Despite significant progress in mechanistic studies in vitro, translating these findings into clinical applications remains a major challenge. This translational gap is primarily due to unfavorable pharmaceutical properties, such as low bioavailability, poor targeted delivery, and rapid metabolic clearance. Additionally, the precise mechanisms governing mitochondria remain to be fully elucidated. In this review, we systematically summarize the specific mitochondrial pathological phenotypes in various diseases and provide a comprehensive overview of natural products that correspond to these phenotypes, along with their mechanisms of action. We also analyze common challenges associated with the absorption, distribution, metabolism, and excretion of these products. By bridging the gap between basic research and clinical application, this review aims to accelerate the development of novel therapeutic strategies for mitochondria-related diseases.

Ischemic stroke (IS) remains a major contributor to global disability and mortality. Astragalus polysaccharide (ASP), a naturally active component derived from Astragalus membranaceus, exhibits therapeutic potential against IS. However, their mechanism against IS via the microbiota-gut-brain axis remains unclear. Our study aimed to evaluate the mechanism of ASP against IS by middle cerebral artery occlusion (MCAO)-induced animal models combined with antibiotics (ABX) and fecal microbiota transplantation (FMT) experiments. In MCAO mice, our results showed that ASP significantly attenuated brain injury and intestinal barrier dysfunction. Transcriptomics, network pharmacology, and western blot identified LPS-TLR4-MAPK pathway as a key regulatory pathway in the regulation of IS-induced intestinal barrier dysfunction by ASP. Metagenomics and metabolomics indicated that ASP modulates SCFA-producing and anti-inflammatory bacterial genera (g_Anaerobutyricum and g_Caproiciproducens). Critically, ABX and FMT experiments confirmed that ASP’s neuroprotective effects in MCAO mice receiving gut microbiota from IS patients, with this therapeutic benefit being microbiota-dependent. Additionally, LPS levels were upregulated in clinical patients with IS. In conclusion, our findings indicated that ASP alleviates IS-induced brain injury via the microbiota-gut-brain axis.

Background Hederagenin is a naturally occurring pentacyclic triterpenoid found in several medicinal plants traditionally used for treating renal and metabolic disorders. Its ability to mitigate renal senescence in diabetic kidney disease (DKD) and the associated epigenetic mechanisms have not yet been fully elucidated. Methods db/db mice were used in vivo to model DKD-associated renal senescence, while palmitic acid-treated human renal proximal tubular epithelial cells (HK-2 cells) were used in vitro as a senescence model. Renal injury, senescence, DNA damage, and Klotho expression were evaluated using histological, biochemical, and molecular analyses. GEO datasets derived from human DKD samples and corresponding controls were analyzed to assess Klotho expression. Integrated target-binding and methylation analyses were performed to examine the interaction between hederagenin and DNA methyltransferase 1 (DNMT1), as well as the effects of hederagenin on Klotho promoter methylation and DNMT1 occupancy. Results Hederagenin reduced renal senescence, fibrosis, and DNA damage in vivo and in vitro, while restoring Klotho expression, which was decreased in patient datasets and experimental models. Mechanistically, hederagenin directly bound DNMT1, diminished DNMT1 recruitment to the Klotho promoter, and attenuated aberrant promoter hypermethylation, thereby reactivating Klotho. Conclusion Hederagenin mitigates renal senescence in DKD through a DNMT1-Klotho DNA methylation axis, supporting its ethnopharmacological potential for DKD management.

Guided by molecular networking, HSQC-based DeepSAT, and SMART analyses, a chemical investigation of the coral-derived fungus Talaromyces sp. TJ403-AL05 led to the isolation and identification of taladipyrones A−I (1−9), a series of new α-pyrone dimers with four distinct skeletons. Among these, compounds 1 and 9 represented two unprecedented classes of rearranged α-pyrone dimers, and compounds 5−7 were the first talarolactone-type dimers obtained as racemates. Extensive spectroscopic analysis, quantum chemical calculations, and X-ray diffraction analysis were used to determine their structures, including each enantiomer of racemic compounds 5−8 after chiral HPLC resolution. In human cardiomyocytes (AC16), compounds 1−6 and 8−9 attenuated injury caused by 24 h cold ischemia (CI) at 40 µmol·L⁻¹. Moreover, compound 2 could improve CI-induced disruption of redox homeostasis via activation of the PI3K/AKT signaling pathway, representing the first fungal polyketide with such cardioprotective activity.

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.

Colorectal cancer is considered to be a highly immune-related disease, and the severe chronic inflammatory stress in the tumor microenvironment (TME) greatly impedes the effective prognosis and treatment of colorectal cancer. Based on a dual strategy, anti-proliferation and inhibition of inflammatory factor HMGB1, a series of GN-derivatives were synthesized and screened for their anticancer efficacy, and compound 22 showed the strongest anti-proliferative activity against HCT116 cells, with IC₅₀ value 13.1 μmol·L⁻¹. To improve the solubility, compounds 23−40 were synthesized and then evaluated for activities against colon cancer cells. Finally, compounds 23 and 24 with good water solubility were screened as target molecules. In anti-proliferation tests, both displayed the strongest activity on CT26 cells, with IC₅₀ value 1.1 and 1.4 μmol·L⁻¹, respectively; in the cloning tests, they also showed a strong anti-proliferative activity against CT26 cells; moreover, they promoted apoptosis, and blocked cells in G₂/M phase in a concentration-dependent manner; in Western Blot tests, they decreased the levels of cyclin A2, cyclin B1 and CDK1 in a concentration-dependent manner. In anti-inflammation aspect, both them displayed strong anti-inflammation activity; compound 23 reduced the levels of NO in both RAW264.7 cells and CT26 cells in the anti-inflammatory tests, and the IC₅₀ values were 10.3 and 1.1 µmol·L⁻¹, respectively; Western Blot showed 23 decreased the levels of HMGB1, RAGE, TNF-α, IL-6, IL-1 and COX-2 in a dose-dependent manner. In animal tests, compound 23 reduced the volume and weight of tumor more obviously than compound 24 and 5-FU, and its effect was a dose-dependent. In summary, compound 23 has therapeutic effect for the treatment of colorectal cancer in some degree, and it has potential to be a candidate for treatment of colorectal cancer.

The rapid emergence of multidrug-resistant bacterial pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), underscores the critical discovery for new antibiotics with novel scaffolds. We identified lead compound LXW933, which exhibits promising anti-MRSA activity and features a unique 1,2,4-oxadiazole scaffold, from our phidianidine-based compound library. Based on this structure, a Function-Oriented Synthesis (FOS) strategy had been conducted to afford a series of phidianidine derivatives for their antibacterial activity evaluation. Compounds 24a exhibited excellent anti-MRSA efficacy with an MIC value of 1.5 μg/mL and low toxicity against HeLa cells. Further mechanistic study showed that 24a effectively inhibits biofilm formation and exerts its antibacterial effect by disrupting the bacterial cell membrane. This research provides valuable insights for the discovery of antibacterial drug leads derived from oxadiazole-containing marine alkaloids, paving the way for new strategies to combat antimicrobial resistance.