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.
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.
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.
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.
Despite therapeutic advances, long-term psoriasis management remains challenged by cost, immunogenicity, and administration barriers. Although the anti-inflammatory properties of avicularin (AL) are recognized, its direct targeting of IL-17RA and its therapeutic efficacy in psoriasis remain unreported. Here, we established the efficacy of Euphorbia humifusa Willd. (EH) in a psoriasis mouse model, then used an integrated strategy combining network pharmacology, RNA-seq, and surface plasmon resonance-mass spectrometry (SPR-MS) to assess its pharmacodynamic material basis. This systematic approach identified the IL-17 pathway as the primary mechanism, and IL-6, CXCL10, and IL-17RA as key targets. On the basis of these key targets, SPR-MS screened seven candidate compounds from EH, among which AL was confirmed as a key IL-17RA-targeting bioactive compound. Subsequent validation demonstrated that AL dose-dependently ameliorated psoriatic lesions and downregulated key IL-17 pathway effectors, including IL-17RA, IL-6, and CXCL10 ( p < 0.05). Direct binding between AL and IL-17RA was subsequently confirmed through bio-layer interferometry, SPR-MS re-screening, and molecular docking. Our findings not only establish AL as a promising oral IL-17RA-targeted agent but also delineate a robust strategy that may aid in the systematic discovery of active natural compounds.
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.
Accurate repair of DNA double-strand breaks (DSBs) is essential for maintaining genomic integrity. RAD51, the core recombinase in homologous recombination, plays central roles in repairing DNA damage and protecting stalled replication forks. In normal cells, RAD51 helps maintain genomic integrity; however, in cancer, its overexpression often supports replication-stress tolerance, as well as resistance to chemotherapy, radiotherapy, and PARP inhibitors. RAD51 is tightly controlled at multiple levels, including transcriptional, post-transcriptional, and post-translational regulation, which together shape its activity in different biological contexts. This review summarizes the structural features of RAD51, its regulatory networks, and its roles in human disease, with particular emphasis on cancer progression and treatment resistance. Currently available RAD51 inhibitors, their mechanisms of action, and the main challenges that still limit clinical translation are discussed. Together, current findings indicate that RAD51 is a key genome maintenance factor and a promising therapeutic target in precision oncology.
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 p16INK4A 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.
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.