Metastasis is the leading cause of mortality in colorectal cancer (CRC). The hypoxic tumor microenvironment contributes to CRC progression by activating hypoxia-adaptive responses and the Warburg effect. This study investigates the role of transmembrane channel-like protein 7 (TMC7) in CRC metastasis. TMC7 is significantly upregulated in CRC tissues in patients, particularly in metastatic lesions. High TMC7 expression was associated with reduced survival and a higher incidence of metachronous liver metastases. Moreover, TMC7-high tumors exhibited enhanced glucose uptake. In vitro, TMC7 promoted CRC cell proliferation and invasion under hypoxic conditions, accompanied by HIF-1α nuclear translocation and activation of hypoxia-adaptive responses. In vivo, TMC7 significantly accelerated lung metastasis and shortened overall survival in a nude mouse xenograft model. Mechanistically, protein kinase N2 (PKN2) acts as a negative regulator of HIF1α activity, suppressing hypoxia adaptation and glycolysis. TMC7 inhibited PKN2 activity, thereby relieving its repression on HIF1α and facilitating HIF1α nuclear accumulation. This cascade ultimately enhances glycolytic flux and supports metastatic progression. Importantly, ectopic expression of PKN2 reversed the pro-metastatic and metabolic reprogramming phenotypes induced by TMC7. Furthermore, elevated TMC7 predicted inferior outcomes following chemotherapy and immunotherapy. Together, these findings uncover a novel TMC7–PKN2–HIF1α signaling axis that drives CRC metastasis through regulation of hypoxia adaptation and the Warburg effect. This study provides new mechanistic insights into CRC metastasis and highlights TMC7 as a potential therapeutic target for precision treatment of metastatic disease.

Cancer stem cells (CSCs) have been demonstrated to have a close association with cancer initiation, metastasis, drug resistance, and recurrence. Consequently, the exploration and identification of new compounds that target CSCs have become a prominent area in recent drug development. Natural products, characterized by their structural and bioactive variety, offer substantial inspiration for drug design and development. From an innovative vantage point of structure - activity relationship (SAR) investigations, this paper comprehensively reviews various categories of anti-CSCs natural products, all of which share Michael acceptors as a common pharmacophore. This review not only furnishes fresh perspectives for the research on anti-CSCs natural products but also presents alternative strategies for the molecular design and structural modification of potential drug molecules aimed at CSCs.

One unreported eremophilane sesquiterpenoid, 1α-methoxy-3-oxo-8α-hydroxy-10αH- eremophila-7(11)-en-12,8β-olide (1), was isolated from Ligularia fischeri. The structure of 1 was identified by detailed 1D and 2D NMR and HRMS analyses.

Connective tissue growth factor (CTGF) is a key driver in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study presents a groundbreaking supramolecular cryo-shock bone marrow mononuclear cell system for targeted drug delivery in IPF. We incorporated antisense oligonucleotides (ASO) to inhibit CTGF and simultaneously encapsulated nintedanib using the ZMO-E5-NPs carrier for synergistic delivery. The cryo-shock treatment enhances cellular structural integrity and preserves receptor functionality, thereby extending cell viability. By modifying the E5 peptide and conjugating it with DSPE-PEG-MAL, we developed a composite carrier, ZMO-E5-NPs, which demonstrates efficient lung-targeting capability. This system enables rapid nanoparticle capture by fibroblasts through matrix metalloproteinase 2 (MMP2) recognition, ensuring precise delivery of both ASO and nintedanib. In a bleomycin-induced pulmonary fibrosis mouse model, ZMO-E5-NPs-ASO (nintedanib-containing group) significantly attenuated fibrosis progression, improved lung function, and exhibited excellent biocompatibility and safety, highlighting its potential as a novel therapeutic strategy for respiratory diseases.

Quinoa is widely recognized as a high-quality protein source suitable for producing bioactive hydrolysates with significant health-promoting potential. This study compared four proteases (alcalase, trypsin, pepsin, and neutral protease) to identify optimal enzymatic conditions for generating antioxidant quinoa protein hydrolysates (QPHs). Among them, alcalase exhibited the highest degree of hydrolysis (36.15%) and yielded the largest proportion of low-molecular-weight fragments (< 2 kDa, 41.08%). It also produced hydrolysates with the lowest surface hydrophobicity and particle size, reflecting more extensive structural disruption, and demonstrated the highest essential amino acid content (20.72 g/100 g). Functionally, alcalase-derived QPHs showed the strongest DPPH radical scavenging activity (4.30 mg TE/g), the highest reducing power (0.61), and provided the greatest cytoprotection in HepG2 cells (83.43%), significantly enhancing SOD, GPx, and CAT activities while reducing MDA levels by 57.8%. Pepsin hydrolysate exhibited selective enhancement, showing the highest ABTS radical scavenging capacity (7.22 mg TE/g) and the greatest FRAP value (13.26 μmol TE/100 g DW), likely attributable to aromatic-rich fragments generated according to its cleavage specificity. Overall, these findings demonstrate that enzymatically derived QPHs, particularly those produced by alcalase, possess strong antioxidant activity and represent promising natural antioxidant ingredients for functional foods and nutraceutical formulations. The results also offer novel mechanistic insights supporting their application in health-promoting food products.

Signal transducer and activator of transcription 3 (STAT3) drives multiple hallmarks of tumorigenesis, making it a validated therapeutic target for diverse cancers. The 1,4-naphthoquinones, such as plumbagin (PL), exhibit anticancer activity via inhibiting STAT3 phosphorylation and dimerization, but their severe cytotoxicity precludes clinical translation. Here, we screened 23 PL derivatives for STAT3 inhibitory activity and normal cell cytotoxicity, identifying III-1a as the optimal candidate with superior STAT3 inhibition and reduced toxicity compared to PL. Molecular docking and cellular thermal shift assay (CTESA) revealed that III-1a binds to the L244 residue within the coiled-coil domain (CCD) of STAT3. In vitro, III-1a dose-dependently suppressed JAK/STAT3 signaling in oral squamous cell carcinoma (OSCC), particularly STAT3 Ser727 phosphorylation. It inhibited STAT3-mediated epithelial—mesenchymal transition (EMT) and induced ferroptosis, thereby attenuating OSCC proliferation, invasion and migration. STAT3 knockdown abrogated its anti-tumor effects, and in vivo studies further confirmed its efficacy against OSCC growth. Collectively, this study identifies a novel PL-derived STAT3 inhibitor targeting STAT3 CCD to regulate EMT and ferroptosis, providing a promising therapeutic candidate for OSCC.

In the original publication [...].

Leukemia is a malignant clonal disease originating from hematopoietic stem cells. Uncontrolled proliferation, impaired differentiation and maturation, accompanied by reduced apoptosis is the most significant feature of leukemia. It has been suggested that c-Cbl is involved in the development of myeloid leukemia, but the upstream signal regulating its activity remains unclear. FBXO22 is an E3 ubiquitin ligase belonging to the F-box protein family. We constructed stable cell lines of the overexpression of FBXO22 and c-Cbl, the knockdout of c-Cbl as well as FBXO22 + c-Cbl co-transfection. We used CCK-8 and FACS to measure the cell viability, cell cycle and cell differentiation, respectively. After overexpression of FBXO22, the proliferation of U937 and K562 cells was slowed down, the pro-apoptotic proteins were increased, the anti-apoptotic proteins were decreased, and the cells differentiated into the next stage. The result of c-Cbl knockdown was consistent with that of FBXO22 overexpression. Overexpression of c-Cbl showed the opposite result. In vivo experiments also showed that both FBXO22 overexpression and c-Cbl knockdown could inhibit the occurrence and development of leukemia. Immunoprecipitation result showed that FBXO22 interacted with c-Cbl and promoted ubiquitination and degradation of c-Cbl. Moreover, the results of rescue experiments showed that c-Cbl reversed the function of FBXO22 on leukemia cells. We identified that FBXO22 interacts with c-Cbl and promotes its ubiquitination and degradation to act as a tumor suppressor gene in leukemia. Our studies suggested that FBXO22 plays an anticancer role by mediating ubiquitination and degradation of c-Cbl in leukemia.

Sarizotan, a 5-HT1A receptor agonist, has shown efficacy in treating neurodegenerative diseases and may offer a novel approach for managing Inflammatory Bowel Disease (IBD). In this study, we evaluated the therapeutic potential of Sarizotan using a dextran sulfate sodium (DSS)-induced colitis mouse model and in vitro assays. Sarizotan treatment significantly alleviated colitis symptoms in mice, reduced inflammatory infiltration and epithelial apoptosis, and improved colon histology. 16S rRNA sequencing revealed that Sarizotan altered the gut microbiota composition and increased microbial diversity. In vitro, Sarizotan suppressed LPS-induced pro-inflammatory cytokine expression in RAW264.7 macrophages, preserved tight junction proteins in Caco-2 monolayers, and reduced oleic acid–induced apoptosis in HT29 epithelial cells. Furthermore, siRNA-mediated knockdown of 5-HT1A receptor reversed the anti-apoptotic effect of Sarizotan, confirming the role of receptor activation. These results suggest that Sarizotan exerts protective effects against IBD through both anti-inflammatory and anti-apoptotic mechanisms mediated by 5-HT1A receptor signaling. Given its established clinical safety profile, Sarizotan may represent a promising candidate for repurposing as a novel therapeutic agent for IBD.

BackgroundIdiopathic inflammatory myopathy-associated interstitial lung disease (IIM-ILD) is a severe autoimmune condition with limited treatment options. Phosphodiesterase 4B (PDE4B) is a key enzyme in the metabolism of cyclic adenosine monophosphate (cAMP) in lung tissue, and targeting PDE4B has been proposed as a promising therapeutic strategy. This study aimed to evaluate the therapeutic potential of Nerandomilast (a PDE4B inhibitor) in an experimental IIM-ILD model and to investigate its underlying mechanisms.MethodsAn IIM-ILD mouse model was established by immunization with skeletal muscle homogenate. Mice were treated with Nerandomilast (5 or 12.5 mg/kg, twice daily) or Nintedanib (60 mg/kg, once daily) as a positive control. Disease severity was assessed using myositis scores and spleen index. Pulmonary fibrosis and inflammation were evaluated via micro-CT, histopathology, and bronchoalveolar lavage fluid (BALF) analysis. B cell infiltration, activation, and differentiation were examined by flow cytometry, immunofluorescence, and Western blotting. Key signaling pathways were analyzed in lung tissue.ResultsNerandomilast ameliorated muscle inflammation, pulmonary fibrosis, and pulmonary inflammation. Mechanistically, Nerandomilast targeted lung-infiltrating B cells: it inhibited their accumulation and proliferation, downregulated the activation marker BAFF, and suppressed their differentiation into plasma cells by reducing the expression of key transcription factors and the plasma cell marker. Serological testing indicated a significant decrease in anti-Jo-1 autoantibody positivity. At the molecular level, Nerandomilast elevated lung tissue cAMP levels, inhibited the phosphorylation of pro-survival/activation pathways (PI3K/AKT, NF-κB, STAT3) in B cells, and enhanced CREB phosphorylation.ConclusionThe PDE4B inhibitor Nerandomilast demonstrates potent therapeutic effects in a preclinical IIM-ILD model, alleviating both myositis and pulmonary pathology. Its efficacy is mechanistically linked to the direct modulation of B cells, achieved by elevating intracellular cAMP and subsequently reprogramming key signaling networks to inhibit B cell activation, proliferation, and pathogenic differentiation into antibody-producing plasma cells. These findings highlight Nerandomilast as a promising candidate for the treatment of IIM-ILD.

Background/Objectives: Metabolic-dysfunction-associated steatotic liver disease (MASLD) and metabolic-dysfunction-associated steatohepatitis (MASH) arise in the setting of obesity, insulin resistance, type 2 diabetes, and metabolic syndrome. This review examines how mitochondrial dysfunction participates in the transition from lipid accumulation to hepatocyte injury, inflammation, and fibrosis, and how evidence from human, animal, and in vitro studies should be interpreted. Methods: We provide a narrative synthesis of mechanistic, translational, and clinical studies on hepatic mitochondrial metabolism, fatty acid oxidation, oxidative phosphorylation, redox stress, organelle crosstalk, mitophagy, mitochondrial biogenesis and proteostasis, mitochondrial danger signals, the gut-liver-mitochondria axis, and mitochondria-related therapeutic strategies. Results: In early metabolic overload, mitochondrial oxidation may increase as an adaptive response. With persistent substrate pressure, this adaptation can become inefficient, with impaired fatty acid disposal, less efficient oxidative phosphorylation, reactive oxygen species production, redox imbalance, defective mitochondrial quality control, altered mitochondrial biogenesis, mitochondrial unfolded protein response (UPRmt)-related proteostatic stress and mtDNA instability. Mitochondrial DNA and RNA released from damaged organelles may also activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING), inflammasome, and RNA-sensing pathways, linking hepatocyte stress to macrophage activation, stellate cell activation, extracellular matrix deposition, and fibrosis. Conclusions: The current evidence supports mitochondria as a stage-dependent amplifier of metabolic liver injury rather than a uniform initiating event. Clinically, the strongest evidence remains with upstream metabolic unloading and liver-directed metabolic therapy, whereas direct mitochondrial restoration and quality-control targeting remain promising but less mature.

Ferroptosis, a non-apoptotic, iron-dependent form of regulated cell death, is closely related to the pathogenesis of neurodegenerative diseases. Stem cells and their derivatives exhibit remarkable potential in modulating ferroptosis, offering promising therapeutic intervention for neurodegenerative diseases. In this review, we systematically explore neurological aging and its association with cognitive impairment and neurodegenerative diseases, with focus on the molecular mechanisms of ferroptosis in neurodegenerative diseases and the potential therapeutic strategies of stem cell derivatives for neurological diseases.

BACKGROUND:Tissue-nonspecific alkaline phosphatase (TNAP) expression increases after liver injury, but its role in liver fibrosis remains unclear. This study investigated the effect of TNAP on liver fibrosis and its mechanism in regulating TGF-β1 signaling. METHODS:Human liver samples and a CCl4-induced liver fibrosis mouse model with adv-TNAP and a TNAP inhibitor (tetramisole, Tetra) were used to study the function of TNAP in liver fibrosis. Primary HSCs were used to study the mechanism of TNAP in regulating the TGF-β1 signal. RESULTS:Elevated TNAP expression was observed in human and murine fibrotic liver tissues, correlating with increased fibrotic markers. In vivo experiments using TNAP overexpression and inhibition in a CCl4-induced liver fibrosis mouse model demonstrated that TNAP exacerbated, while its inhibition alleviated, liver fibrosis. In vitro studies revealed that TNAP regulated TGF-β1 conversion and HSCs activation through the TGF-β1/SMAD pathway. TNAP facilitated TGF-β1 conversion by promoting the interaction between CD47 and thrombospondin-1 (TSP1). Membrane expression of CD47 modulated by TNAP might contribute to the binding effect of CD47 and TSP1. CONCLUSIONS:TNAP plays a critical regulatory role in TGF-β1-mediated liver fibrosis, probably by promoting the binding of CD47/TSP1. Targeting TNAP-mediated pathways may offer new therapeutic strategies for liver fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung lesion, which is called a "tumor-like disease". Previous studies have confirmed that intratracheal instillation of formononetin-loaded porous microspheres (FMN-PLGA-MSs) can effectively improve bleomycin-induced pulmonary fibrosis. However, the poor lung retention of FMN-PLGA-MSs reduces the therapeutic efficacy of the FMN. Building on this foundation, this study prepared chitosan-coated formononetin porous microspheres (CS-FMN-PLGA-MSs) to enhance the FMN lung retention by leveraging the bioadhesive properties of chitosan. It is expected to prolong the action time of formononetin in lung tissues and enhance the therapeutic efficacy for pulmonary fibrosis. The study results showed that, compared to FMN-PLGA-MSs, CS-FMN-PLGA-MSs could be better taken up by MLG cells and NIH-3T3 cells. In vivo imaging demonstrated that CS-FMN-PLGA-MSs had a prolonged lung retention time, lasting up to 48 h. CS-FMN-PLGA-MSs exhibited a greater deposition in the regions of lung tissue compared to FMN-PLGA-MSs. The in vivo efficacy results in bleomycin-induced pulmonary fibrosis mice showed that, compared to FMN-PLGA-MSs, CS-FMN-PLGA-MSs had a higher anti-pulmonary fibrosis efficacy, significantly reducing hydroxyproline levels in fibrotic lung tissues, decreasing the extent of pulmonary fibrosis, and improving lung function. CS-FMN-PLGA-MSs provide a new reference for the treatment of pulmonary fibrosis.

Salvia miltiorrhiza Bunge (Danshen) is a traditional Chinese medicinal herb that has long been used for its cardiovascular and antioxidant benefits and has a potential role in the treatment of hypertensive disorders associated with pregnancy, such as pre-eclampsia. S-Nitrosoglutathione reductase (GSNOR) has emerged as a promising therapeutic target due to its role in regulating nitric oxide bioavailability and vascular function. Rapid screening and characterization of GSNOR inhibitors with favorable membrane permeability from Danshen by developing a novel magnetic nanoparticle-based ligand fishing method combined with a parallel artificial membrane permeability assay. Functionalized magnetic nanoparticles were synthesized and characterized using transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, and thermogravimetric analysis. GSNOR was immobilized on these nanoparticles, and the immobilization yield and enzyme activity were evaluated. The method was used to screen 17 compounds from Danshen extract, with 9 compounds showing significant binding affinity to GSNOR. Molecular docking and in vitro inhibitory activity assays were performed to validate the binding mechanisms and inhibitory effects of the identified compounds. Molecular docking revealed that these compounds form multiple hydrophobic interactions and hydrogen bonds with GSNOR, effectively inhibiting its activity. Tanshinone I and Tanshinone IIA exhibited the highest enrichment (19.7- and 20.0-fold, respectively) and potent inhibitory activity on GSNOR, with IC50 values of 19.47 μM and 17.99 μM. This study not only identified GSNOR inhibitors from Danshen but also established an efficient strategy for screening bioactive compounds from herbal medicines.

MUC5AC is an important component of mucins, which is often disproportionately increased in response to cigarette smoke and allergens, thereby increasing health problems. As a traditional Chinese medicine, Inula japonica Thunb. is used mainly to treat cough and phlegm. 1-O-Acetylbritannilactone (ABL), one of the main ingredients in I. japonica, may be an anti-inflammatory and anti-MUC5AC drug candidate. ABL significantly decreased the production of NO and the mRNA expression of IL-1β, IL-6, TNF-α, and iNOS in LPS-stimulated RAW264.7 cells. Network pharmacology suggested that ABL might inhibit inflammation and MUC5AC expression, and EGFR, MAPK, SRC, and PKC-α might be key proteins involved. The results of molecular docking, molecular dynamics simulations, CETSA and MST suggested that ABL interacted with PKC-α, indicating that PKC-α was a target of ABL. ABL reduced the expression of the SRC/EGFR/MAPK signaling pathway in PMA-induced NCI-H292 cells and LPS-stimulated RAW264.7 cells. In animal experiments, ABL significantly ameliorated COPD in mice by improving pulmonary function, suppressing oxidative stress, and decreasing inflammatory cell infiltration and mucus production in lung tissue. The results of the phenol red test showed that ABL had a significant expectorant effect. In conclusion, ABL exhibited anti-inflammatory and anti-MUC5AC effects by targeting PKC-α and downregulating the SRC/EGFR/MAPK signaling pathway. This study revealed that ABL is a natural candidate molecule with anti-inflammatory and expectorant effects.

Connective tissue growth factor (CTGF) is notably upregulated in scar tissue, making it a promising target for therapeutic intervention. Here, we have designed and screened an antisense oligonucleotide (ASO) that binds specifically to the exon five sequence of CTGF, with particular emphasis on the use of 2′-O-methoxyethyl (MOE) and locked nucleic acid (LNA) modifications to enhance stability and specificity. In vitro experiments demonstrated that both MOE-ASO#1 and LNA-ASO#1 significantly inhibited fibroblast proliferation and extracellular matrix protein expression. In vivo studies using mouse and rabbit scar models, as well as a nude mouse keloid xenograft model, revealed that these ASOs effectively reduced scar formation and keloid growth while also suppressing IL-6 expression. LNA-ASO#1 showed superior pharmacodynamics compared to MOE-ASO#1. Mechanistic investigations indicated that the ASOs exert their antifibrotic effects by inhibiting the TGF-β1 pathway, myofibroblast activation, and extracellular matrix production. These findings suggest that LNA-ASO#1 is a promising therapeutic strategy for the treatment of scars.