Chronic renal failure (CRF) is a progressive disease characterized by a sustained loss of kidney function, for which current therapies remain insufficient. Growing evidence closely links the CRF pathogenesis to renal aging; therefore, targeting aging processes might have therapeutic promise. Herein, we implemented a novel strategy to identify potential anti-CRF agents from anti-aging Chinese herbal medicines. Phenotypic screening indicated that the 75% ethanol extract of Stellaria yunnanensis Franch (JM11002) exhibited marked anti-aging activity, by prolonging the lifespan of Caenorhabditis elegans and decreasing the proportion of SA-β-gal-positive senescent MRC-5 cells. Importantly, JM11002 also ameliorated renal dysfunction, inflammation, and fibrosis in both unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction (UUO) mouse models. Phytochemical investigation identified 20-hydroxyecdysone (JM11201), a major active component of JM11002 , which recapitulated the renoprotective effects in both the UUO model and unilateral ischemia-reperfusion injury with contralateral nephrectomy (UIRIx) model. Mechanistically, 20-hydroxyecdysone suppressed the TGF-β1/Smad3 signaling pathway and decreased the expression of fibrosis-related proteins in UUO kidneys. In summary, through an aging-intervention strategy, we discovered the renoprotective effect of Stellaria yunnanensis Franch extract and its active component, 20-hydroxyecdysone, two promising candidates for the development of novel CRF therapies.
Vicatia thibetica de Boiss (V. thibetica), a traditional medicinal and edible plant used by the Bai ethnic group in China, is known for its effects in tonifying qi, nourishing the blood, dispelling dampness, and relieving itching. Previous studies have shown that its root extract (JM02001) exerts anti-aging effects by promoting collagen expression and antioxidant potential. However, its anti-skin aging efficacy in vivo and its bioactive constituents have been largely unexplored. Herein, JM02001 was found to mitigate extracellular matrix (ECM) loss, restore superoxide dismutase-1 (SOD-1) expression, suppress matrix metalloproteinase-9 (MMP-9) expression, and increased the epidermal barrier intensity in D-galactose-treated mice. The ethyl acetate fraction (JM02102) exhibited the most promising anti-glycation, antioxidant, and collagen-promoting activities. Chlorogenic acid (CGA) was identified as an important active compound. Both JM02102 and CGA alleviated ECM degradation and enhanced epidermal barrier function in D-galactose-treated mice. Furthermore, in glucocorticoid-treated mice, they restored dermal and epidermal thickness, suppressed REDD1 and p16 INK4A expression, and enhanced epidermal barrier function. Therefore, our findings indicated that the extract of V. thibetica root and its compound CGA protect against skin aging by preserving ECM, decreasing oxidative stress, and reinforcing the skin barrier, thus validating its traditional use and highlighting its potential as a source of anti-aging therapeutics.
Traditional Chinese medicine has shown therapeutic potential in treating osteoarthritis (OA) by regulating inflammation and maintaining cartilage homeostasis. However, the complex compositions of herbal medicines and the lack of efficient screening strategies have hindered the identification of active compounds and their molecular mechanisms. To address these challenges, this study used graph neural networks (GNNs) for drug discovery and demonstrated their potential in elucidating therapeutic mechanisms. Using an in-house GNN model, we identified Paederia scandens as a promising candidate for OA treatment. Experimental validation confirmed that Paederia scandens improved cartilage metabolic homeostasis and mitigated subchondral bone sclerosis. Further analysis implicated asperuloside, a major constituent of Paederia scandens , as a key bioactive compound contributing to these therapeutic effects. Transcriptomic profiling and protein-protein interaction network analysis identified Integrin Subunit Beta 1 as a potential central regulatory hub. Asperuloside treatment was found to reshape cartilage gene expression; downregulate cytokine and chemokine signaling pathways; and alleviate inflammation, while enhancing cartilage matrix synthesis and decreasing matrix degradation. Further in vivo and in vitro experiments consistently supported these findings. Collectively, our findings indicated that asperuloside is a promising OA therapeutic candidate. Moreover, the GNN-driven framework established in this study provides a novel strategy for modernizing traditional Chinese medicine and accelerating the discovery of bioactive compounds. This work highlights the critical role of GNNs in integrating computational prediction with biological validation to facilitate mechanistic exploration and advance precision drug development for complex diseases such as OA.
S phase kinase-associated protein 2 (SKP2), the rate-limiting substrate receptor of the SKP1-Cullin1-F-box (SCF) E3 ubiquitin ligase complex, is considered a canonical gatekeeper of cell cycle progression. However, accumulating evidence indicates that SKP2 functions as a multifaceted signaling hub that orchestrates metabolic reprogramming, the DNA damage response, stem cell maintenance, and synaptic plasticity. Dysregulation of these processes contributes to the pathogenesis of many types of human diseases, including cancer. This review provides a comprehensive overview of the diverse biological roles of SKP2, beginning with detailed insights into the assembly and substrate-recognition mechanisms of the Cullin1-SKP2-CKS1 protein complex. Moreover, we explore the functional dichotomy of SKP2, expanding its classic role in K48-linked proteasomal degradation to include noncanonical roles in K63-linked signaling activation. Furthermore, we elucidate the pathogenic implications of SKP2 in malignancies such as castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC), as well as neurodegenerative conditions, including Alzheimer’s disease. More importantly, we evaluate therapeutic approaches targeting SKP2, highlighting the shift from first-generation protein-protein interaction (PPI) inhibitors to next-generation degraders, including the novel induced-proximity degrader SKPer1 and emerging PROTACs. Finally, to bridge the gap to clinical translation, we discuss the remaining druggability challenges and future directions for pharmacological optimization.
The pathogenesis of acute lung injury (ALI) and the severe form of ALI, acute respiratory distress syndrome (ARDS), is incompletely understood. We aimed to determine the mechanism of action for non-muscle myosin heavy-chain IIA (NMMHC IIA) and the NMMHC IIA targeting compound in the context of lipopolysaccharide (LPS)-induced pulmonary endothelial barrier dysfunction associated with ALI. Endothelial-specific monoallelic knockout of NMMHC IIA alleviated ALI and reversed alterations in sphingosine-1-phosphate (S1P), a serum metabolite. Inhibition of NMMHC IIA upregulated SPHK1, a key S1P-synthesizing enzyme, and the SPHK1 transcriptional regulator, KLF2. NMMHC IIA directly interacted with FOXO1 in LPS-treated endothelial cells to promote FOXO1 nuclear translocation. Knockdown of MYH9 or FOXO1 restored barrier integrity by activating the KLF2/SPHK1 pathway. Endothelial NMMHC IIA knockdown promoted FOXO1 dephosphorylation and KLF2/SPHK1 activation in vivo, which increased serum S1P levels; NMMHC IIA overexpression exerted opposite effects. Furthermore, DT-13, a steroidal sapogenin derived from Liriope muscari, was confirmed to bind to NMMHC IIA via the cellular thermal shift assay (CETSA) and microscale thermophoresis (MST) assay. DT-13 attenuated LPS-induced endothelial barrier disruption by targeting NMMHC IIA and mediating the FOXO1/KLF2/SPHK1 axis. The findings herein elucidate a new mechanism underlying ALI pathogenesis and suggest promising therapeutic strategies.
Inflammation is a complex biological response essential for tissue repair in acute settings, yet chronic dysregulation contributes to progressive tissue damage and the pathogenesis of numerous diseases. Lonicera japonica Thunb. (honeysuckle), a traditional Chinese medicinal herb renowned for its “heat clearing and detoxifying” properties, exhibits multi-target anti-inflammatory activity through synergistic modulation of inflammatory signaling cascades. This review systematically consolidates current knowledge regarding the anti-inflammatory bioactive components of honeysuckle and provides comprehensive insights into their therapeutic mechanisms. We focus on molecular targets, elucidating how honeysuckle constituents regulate key inflammatory pathways, thus offering a foundation for developing Lonicera japonica-based therapeutics against inflammation-driven pathologies. Additionally, we critically evaluate the challenges and limitations in translating these findings into clinical applications.
Diacerein, an anthraquinone derivative, is emerging as a promising disease-modifying agent in rheumatoid arthritis (RA), because of its potent anti-inflammatory and chondroprotective actions. Unlike nonsteroidal anti-inflammatory drugs, which primarily inhibit cyclooxygenase enzymes, diacerein suppresses interleukin-1β, a central mediator of synovial inflammation and cartilage degradation. It also modulates tumor necrosis factor-alpha and matrix metalloproteinases, thereby alleviating pain, decreasing inflammation, and preserving joint structure. This review of clinical and preclinical studies highlights the therapeutic potential of diacerein in RA management, focusing on its molecular mechanisms, clinical outcomes, and combination strategies with disease-modifying antirheumatic drugs (DMARDs) or biologics. Recent advances in drug delivery, including nanoparticle-based and sustained-release formulations, have further enhanced its bioavailability and efficacy. Diacerein effectively decreases joint swelling and stiffness, while demonstrating a superior gastrointestinal safety profile to nonsteroidal anti-inflammatory drugs. However, its slow onset of action and moderate efficacy as a monotherapy limit its standalone use. Combination therapy with DMARDs or biologics appears to potentiate its therapeutic benefits. Overall, diacerein is a valuable adjunctive agent in RA treatment. Further studies are warranted to optimize dosing regimens and delivery systems to improve clinical outcomes.
Gastrointestinal motility disorders (GIMDs) are characterized by impaired gastrointestinal motility. The prevention and treatment of GIMDs remain challenging, because of their prevalence and complexity. The pathogenesis of GIMDs involves multiple factors, such as dysregulation of the enteric nervous system, smooth muscle dysfunction, neurotransmitter imbalance, chronic inflammation, and gut microbiota dysbiosis, which synergistically contribute to GIMD development and progression. Currently, modern medicine remains the primary approach for treating GIMDs, with prokinetic agents such as mosapride and domperidone. However, traditional Chinese medicine (TCM) has attracted attention as a complementary and alternative therapy that can considerably alleviate GIMDs. Accordingly, this review is aimed at comprehensively summarizing the pathogenesis and current management of GIMDs, on the basis of articles in the PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) databases. Future GIMD research should focus on the discovery of new therapeutic targets and the deep synergies between TCM and modern medicine, to achieve a transition from evidence-based medicine to precision medicine, which may aid in the development of more effective interventions and optimization of GIMD management.
New drug research and development (R&D) faces critical challenges such as drug resistance, ineffectiveness of single-target interventions, “undruggable” targets, long cycles, and high costs. This article analyzes five typical use cases to illustrate breakthrough strategies for addressing these issues. Innovations include the identification of dual-target antibiotics (paenimicin) and phospholipid-targeting antifungals (mandimycin) that overcome microbial resistance via mining silent biosynthetic gene clusters; development of “molecular glue” compounds (D927 and BBO-10203) that regulate protein-protein interactions, thus addressing insulin resistance and tumor drug resistance; AI-driven discovery of the TNIK inhibitor rentosertib for reversing pulmonary fibrosis; use of protein interface remodeling to develop the KRAS G12D inhibitor zoldonrasib for “undruggable” targets; and repurposing of existing drug combinations (letrozole plus irinotecan), on the basis of multi-omics data for Alzheimer’s disease. These use cases demonstrate how interdisciplinary technologies (e.g., AI and structural biology) and strategic innovations (multi-target design and drug repurposing) can drive a transformation from experience-driven to precision and intelligence-driven R&D, and provides a reference for meeting intractable clinical needs.
Geroprotectors that delay aging have substantial potential for preventing and mitigating age-related diseases. Natural products derived from traditional herbal medicines are promising candidates for geroprotector discovery, because of their multi-target mechanisms and preventive health benefits. Through screening of 836 Chinese herbal medicine extracts, we identified that the leaf extract of Caryota maxima (JM13001) significantly extended lifespan and healthspan in Caenorhabditis elegans. JM13001 increased total lipid content and upregulated mono-unsaturated fatty acids (MUFAs), which are known to contribute to longevity. JM13001 exerted its effects through DAF-2 signaling, thereby promoting lipid accumulation and extending lifespan in nematodes. Notably, the lifespan-extending effects of JM13001 were abolished after the loss of key enzymes responsible for converting saturated fatty acids to MUFAs or after oleic acid supplementation; therefore, its geroprotective effects are dependent on MUFAs. Chemical analysis revealed that JM13001 contains flavonoids such as rutin, isoquercitrin, and kaempferol-3-O-rutinoside, among which rutin alone was sufficient to reproduce the anti-aging and lipid accumulation promotion effects of JM13001 through DAF-2 signaling. This study identifies a novel geroprotective herbal extract and its active ingredient, thereby providing insights into the anti-aging mechanisms of natural geroprotectors via MUFA metabolism regulation.
Traditional Chinese medicine (TCM), characterized by multi-component, multi-target, and systemic therapeutic mechanisms, provides unique advantages in managing complex diseases. However, the inherent complexity of TCM formulations, including nonlinear component interactions, elusive compatibility principles, and a lack of quantitative biomarkers, has hindered the systematic elucidation of their efficacy mechanisms and clinical translation. Artificial intelligence (AI) technologies, including machine learning and deep learning, combined with network pharmacology approaches, have emerged as transformative tools to systematically characterize and model TCM’s complexity. Given that TCM and AI share a foundational emphasis on systemic interactions rather than isolated components, AI approaches can facilitate high-throughput prediction of bioactive components, rational design of synergistic formulas, and dynamic modeling of pharmacological effects. Recent interdisciplinary studies have harnessed AI to address TCM challenges including predicting bio-active constituents, optimizing herbal compatibility, and standardizing diagnostic parameters. Whereas prior reviews focused on AI applications in TCM data mining and drug development, this work comprehensively integrates active component prediction, compatibility mechanisms, and pharmacological effect modeling, and additionally discusses emerging applications of large-scale AI models in modern TCM research.
Heart failure (HF) remains a major global health challenge with limited therapeutic options, thus prompting the search for novel cardioprotective agents among traditional Chinese medicines. In this study, screening of 828 herbal extracts in an oxygen glucose deprivation injury H9c2 cardiomyocyte model led to the identification of Euphorbia neriifolia L. extract (JM04) as a promising candidate. JM04 significantly increased cell viability while decreasing lactate dehydrogenase release and reactive oxygen species (ROS) accumulation in both H9c2 and primary cardiomyocytes. In vivo , JM04 ameliorated cardiac function and attenuated myocardial fibrosis in isoproterenol-induced HF mice, as evidenced by echocardiography and histological analysis. Network pharmacology and mechanistic studies revealed that JM04 modulated the Nrf2/ROS/HIF-1α axis by exerting free radical scavenging activity, activating the Nrf2 antioxidant pathway, restoring mTOR phosphorylation, and enhancing HIF-1α expression, thereby protecting against cardiomyocyte apoptosis. Furthermore, UPLC-MS/MS identified six active components consistent with network pharmacology predictions, thus highlighting its multicomponent and multitarget nature. Collectively, these findings demonstrated that JM04 exerts potent cardioprotective effects through integrated antioxidant and signaling modulation, and support its further development as a candidate botanical drug for HF intervention.
The host response to viral infections largely depends on the viral load intensity, and the fluctuating viral kinetics after antiviral treatment should perturb host responses accordingly. Therefore, conventional comparison of individual host factors between virus-infected models with vs without antiviral treatment usually generates biased results that tend to reflect perturbations due to fluctuating viral kinetics. The extent of this bias is predominately determined by the range of viral load fluctuation. Herein, we raised a response regression model to serve as a guiding principle to precisely explore the pharmacological mechanisms of host-targeted antiviral (HTA) agents. The statuses of virus-responsive host factors were estimated to regress toward baseline in accordance with decreased viral load, whereas host factors with regression deviation or regression transcendence statuses were considered potential targets of the pharmacological effects. In a pilot application, we developed a mathematical method for transcriptomic analysis based on the response regression model, to identify the actual differentially expressed genes potentially affected by HTAs. Our study should substantially facilitate future pharmacological mechanistic study of HTAs. Moreover, our adapted strategy could be further expanded to other multi-omics analyses and diverse infectious diseases.
Meroterpenoids, a class of hybrid natural products derived from both terpenoid and non-terpenoid biosynthetic pathways, serve as a prolific source of drug leads, because of their structural complexity and extensive bioactivities. Meroterpenoids have provided many clinical drugs or promising leads, such as mycophenolic acid (an immunosuppressant), territrem B (an acetylcholinesterase inhibitor), and pyripyropene A (a cholesterol acyltransferase-2 inhibitor). Recently, meroterpenoids featuring a benzo-fused ten-membered ring skeleton have attracted considerable attention for their unique scaffolds and diverse post-modifications. Bioactivity evaluations have revealed that nearly half of these compounds (32 of 66) exhibit cytotoxicity with half-maximal inhibitory concentrations below 10 μM, and therefore have great potential as drug development candidates, particularly in cancer therapy. However, a systematic summary of this subclass remains lacking. Herein, we summarize benzo-fused ten-membered ring meroterpenoids reported between 1980 and 2024, including their sources, structural diversity, bioactivities, and biosynthetic pathways, to provide comprehensive insights to guide further studies on meroterpenoids.
Dengue virus (DENV) poses a serious health threat globally for which specific antivirals are not available. Envelope (E) protein and RNA-dependent RNA polymerase (RdRp) from DENV represent the most critical targets for the development of antivirals that inhibit viral adsorption for entry and genome replication, respectively; no dual inhibitors targeting E/RdRp have been reported to date. Vina-ginsenoside R18 (R18), a triterpenoid saponin isolated from Panax notoginseng , was shown to target E protein domain III to inhibit binding of E protein to integrin beta3, thus preventing viral adsorption to the host surface receptor. R18 selectively targets RdRp protein and induces a conformational change, leading to a decrease in enzyme activity. Consequently, R18 represses DENV infection by acting at viral binding, entry, and replication stages, and attenuates the pathologic symptoms of DENV-infected ICR suckling and AG129 mice. These results showed R18 to be a novel dual E/RdRp inhibitor that can serve a potential agent against DENV infection.
