Chemico-Biological Interactions最新文献

{"title":"Mechanisms and targeted prevention of chronic pancreatitis-acinar to ductal metaplasia caused by a low concentration of di-(2-ethylhexyl)-phthalate","authors":"Mengyue Ji ,&nbsp;Xinru Du ,&nbsp;Yue Ma ,&nbsp;Sisi Song ,&nbsp;Zhendong Wang ,&nbsp;Yancheng Gao ,&nbsp;Ye Yang ,&nbsp;Chunxiao Zhou ,&nbsp;Yuan Li","doi":"10.1016/j.cbi.2025.111758","DOIUrl":"10.1016/j.cbi.2025.111758","url":null,"abstract":"<div><div>The impact of long-term exposure to low concentrations of environmental pollutants on pancreatic disorders is a major public health issue. Di-(2-ethylhexyl)-phthalate (DEHP) is a persistent environmental endocrine toxicant present in many products. Despite evidence of the harmful effects of DEHP on pancreatic tissue, the molecular mechanisms underlying its activity in chronic pancreatitis (CP) remain unclear. Acinar to ductal metaplasia (ADM) is a key pathological process in CP. Here, chronic exposure to low concentrations of DEHP elevated the expression of a glucose-regulated protein (GRP75) in mouse acinar cells. GRP75 is a bridge protein for endoplasmic reticulum (ER)-mitochondrial junctions, and the overexpression of GRP75 abnormalizes ER-mitochondrion coupling, shortening the contact distance between them. Such biological processes facilitate Ca²⁺ release from the ER into the mitochondria and cause mitochondrial Ca²⁺ overload, leading to the overproduction of ROS and thereby promoting the development of ADM in acinar cells. These ductal-like cells secrete collagen and activate pancreatic stellate cells through paracrine action, synergistically promoting the development and progression of CP. Finally, we revealed that targeting GRP75 with stearic acid (SA) could prevent DEHP-induced CP-ADM via drug screening and functional analysis. Our present study offers new insights into environmental toxin-induced pancreatic disorders and suggests a potential key intervention target for the prevention of CP-ADM.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111758"},"PeriodicalIF":5.4,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biogenic Ag/AgCl nanocomposites induce apoptosis via mitochondrial pathway and reduce size of 3D HT29 colorectal cancer spheroids","authors":"Gokhan Gorgisen ,&nbsp;Cigdem Aydin Acar","doi":"10.1016/j.cbi.2025.111759","DOIUrl":"10.1016/j.cbi.2025.111759","url":null,"abstract":"<div><div>This study reports the successful green synthesis of silver/silver chloride nanocomposites using <em>Opopanax hispidus</em> extract. Characterization analyses confirmed the formation of Ag/AgCl nanostructures with good stability. A distinct surface plasmon resonance peak at 433 nm and absorbance over 30 days indicated strong colloidal stability. X-ray diffraction analysis revealed the coexistence of metallic silver and silver chloride phases, while transmission electron microscopy images showed polydisperse, spherical to quasi-spherical nanoparticles ranging from 8.02 to 51.68 nm. Energy dispersive spectroscopy further confirmed the elemental composition, including a notable chlorine signal supporting AgCl formation. The cytotoxic effects of the synthesized nanocomposites were assessed using a three-dimensional spheroid model of HT29 colorectal cancer cells. A dose-dependent reduction in both cell viability and spheroid integrity was observed, with significant effects at concentrations of 100 and 200 μg/mL. Western blot analysis revealed apoptosis induction via the mitochondrial pathway, with downregulation of anti-apoptotic Bcl-X_S/L and upregulation of pro-apoptotic Bax and cleaved caspase-3. This study is the first to investigate the anticancer effects of green-synthesized silver/silver chloride nanocomposites in a three-dimensional colorectal cancer spheroid model. The findings demonstrate the therapeutic potential of these nanocomposites and emphasize their molecular specificity within a physiologically relevant tumor microenvironment.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111759"},"PeriodicalIF":5.4,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolomic profiling reveals ADB-BUTINACA-induced long-term hepatotoxicity","authors":"Siyue Zheng ,&nbsp;Yi Zhou ,&nbsp;Xiaoran Song ,&nbsp;Xing Ke ,&nbsp;Hao Wu ,&nbsp;Zhongping Huang ,&nbsp;Yilei Fan","doi":"10.1016/j.cbi.2025.111754","DOIUrl":"10.1016/j.cbi.2025.111754","url":null,"abstract":"<div><div>The multi-organ toxicity of ADB-BUTINACA, a synthetic cannabinoid with high abuse potential, poses a public health risk. However, its long-term toxicological effects and metabolic mechanisms remain unclear. This study aimed to elucidate the hepatotoxic potential and metabolic disruption induced by ADB-BUTINACA through a 30-day oral exposure model in mice at doses of 0.1, 1, and 10 mg kg⁻¹·bw⁻¹. Serum biochemical analysis revealed elevated TNF-α, IL-6, total cholesterol, triglycerides, and LDL-C, indicating systemic inflammation and lipid dysregulation. Histopathological examination showed dose-dependent hepatocellular swelling, lipid droplet accumulation, and inflammatory infiltration. Non-targeted metabolomic profiling identified 60 significantly altered metabolites and 12 perturbed metabolic pathways, including unsaturated fatty acid biosynthesis, taurine metabolism, and the tricarboxylic acid (TCA) cycle. Notably, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and taurine were markedly reduced. RT-qPCR results showed that ADB-BUTINACA induced inhibition of TCA cycle and unsaturated fatty acid synthesis activity in the liver. Molecular docking demonstrated stable and competitive binding of ADB-BUTINACA to key metabolic enzymes: Fatty Acid Desaturase 2 (FADS2) and Elongation of Very Long Chain Fatty Acids Protein 2 (ELOVL2). This suggests interference with endogenous lipid regulatory processes. These findings elucidate the hepatotoxic mechanisms of ADB-BUTINACA and underscore its potential health risks as an emerging synthetic cannabinoid contaminant.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111754"},"PeriodicalIF":5.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The biological potential and health-benefits of flavonoids: A review and development opportunities","authors":"Marco Duarte ,&nbsp;Sílvia Santos Pedrosa ,&nbsp;P Raaj Khusial ,&nbsp;Ana Raquel Madureira","doi":"10.1016/j.cbi.2025.111755","DOIUrl":"10.1016/j.cbi.2025.111755","url":null,"abstract":"<div><div>Flavonoids are a class of polyphenolic phytochemicals, representing an important group of secondary metabolites in plants. They can be divided into seven groups, depending on their chemical features, and, in nature, they can be obtained from various sources, primarily plants. Industrially, and due to the biological potential of flavonoids, there has been a notable effort to develop new methodologies that allow for the efficient and eco-friendly production of these compounds. The growing interest in natural products for various applications, such as the nutraceutical and cosmeceutical industries, lends considerable relevance to these compounds as potential functional ingredients. Further, flavonoids are heavily explored because they present relevant biological activities like antioxidant and anti-inflammatory, which could translate into health benefits at multiple levels of the human body, like cardiac function, metabolism-related diseases (e.g., diabetes, obesity), bone preservation, neuroprotection, among others. This review aims to explore the biological potential of flavonoids, clarifying their most relevant health benefits while providing an update on the current state of the art, simultaneously pointing future research directions.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111755"},"PeriodicalIF":5.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sirtuin 1/3 regulates p53 deacetylation to inhibit iron poisoning-induced alveolar epithelial cell death and contributes to Rapamycin-mediated protection against limb ischemia/reperfusion-induced lung injury","authors":"Dan Huang ,&nbsp;Yong-lin Liang ,&nbsp;Lie-liang Zhang ,&nbsp;Bin Zhou ,&nbsp;Bin Tang","doi":"10.1016/j.cbi.2025.111756","DOIUrl":"10.1016/j.cbi.2025.111756","url":null,"abstract":"<div><h3>Background</h3><div>Acute limb ischemia is a disorder with high morbidity and mortality globally. Unfortunately, the effectiveness of limb ischemia/reperfusion (I/R)-induced acute lung injury (ALI) therapy remains limited.</div></div><div><h3>Methods</h3><div>I/R-induced lung injury (IRLI) rat model and LPS-stimulated cell model were established. The histological changes and collagen deposition in lungs were evaluated by H&amp;E and Masson staining. Lung injury was assessed by pathological scoring, evaluation of arterial PaO₂ and lung water content. qRT-PCR, Western blot, immunohistochemistry, immunofluorescent staining and ELISA assay were employed to detect the expression and secretion of key molecules. The oxidative stress markers were detected using commercial kits, and CCK-8, EdU incorporation, TUNEL assays and flow cytometry were employed to detect cell proliferation and apoptosis, respectively. The interaction between U2AF2 and SIRT1/3 was examined by RIP assay, and the association between SIRT1/3 and p53, as well as the acetylation of p53, were detected by co-IP.</div></div><div><h3>Results</h3><div>Rapamycin induced SIRT1 and SIRT3 expression and deacetylase activities in the lung tissues of IRLI rats. Inhibition of SIRT1 or SIRT3 attenuated the protective effects of Rapamycin on I/R-induced lung injury, pyroptosis, oxidative stress and ferroptosis <em>in vivo</em>. In LPS-stimulated L2 cells, SIRT1 or SIRT3 was involved in Rapamycin-mediated protection in inflammation, pyroptosis, oxidative stress and ferroptosis. Mechanistically, Rapamycin enhanced the mRNA stability of SIRT1 or SIRT3 via recruiting U2AF2, and it also promoted p53 deacetylation by inducing SIRT1 and SIRT3.</div></div><div><h3>Conclusion</h3><div>SIRT1/3 regulated p53 deacetylation to inhibit iron poisoning-induced alveolar epithelial cell death and contributed to Rapamycin-mediated protection against limb I/R-induced ALI.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111756"},"PeriodicalIF":5.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting cuproptosis by FDX1 in acetaminophen-induced liver injury","authors":"Yan Liu ,&nbsp;Ying Yang ,&nbsp;Baizhao Peng ,&nbsp;Zhongyue Ou ,&nbsp;Anna Zuo ,&nbsp;Zihao Jiang ,&nbsp;Chuanghai Wu ,&nbsp;Hiu Yee Kwan ,&nbsp;Ke Ma ,&nbsp;Lin Yu ,&nbsp;Xiaoshan Zhao","doi":"10.1016/j.cbi.2025.111753","DOIUrl":"10.1016/j.cbi.2025.111753","url":null,"abstract":"<div><div>Acetaminophen (APAP) overdose is the most common etiology of acute drug-induced liver injury (DILI) worldwide. Although oxidative stress, apoptosis, and necrosis are well-recognised mechanisms, the involvement of cuproptosis, a newly identified, copper-dependent form of regulated cell death, remains poorly understood. Here, the contribution of cuproptosis to APAP hepatotoxicity is elucidated, identifying ferredoxin 1 (FDX1) as its master regulator. In vivo, the copper chelator ammonium tetrathiomolybdate (TM) markedly attenuated APAP-induced liver damage, as evidenced by decreased serum ALT and AST levels, reduced hepatocyte death, and diminished inflammatory cell infiltration and cytokine release. Transcriptomic mining of GEO datasets revealed significant dysregulation of cuproptosis-associated genes in APAP-exposed hepatocytes, with FDX1 being the most prominently up-regulated. Genetic ablation of FDX1 in mice and FDX1 knockdown in human HepaRG cells both conferred robust protection against APAP-induced lethality, phenocopying the effects of TM. Collectively, our findings establish FDX1-mediated cuproptosis as a critical driver of APAP hepatotoxicity and position copper homeostasis as a tractable therapeutic target for DILI.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111753"},"PeriodicalIF":5.4,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phytosphingosine suppresses gastric cancer through SFRP4/β-catenin axis-mediated Wnt signaling pathway inhibition","authors":"Yanchen Liu ,&nbsp;Rui Guo ,&nbsp;Chi Xue ,&nbsp;Xinwei Zhang ,&nbsp;Fanghao Xiao ,&nbsp;Xiangxuan Zhao ,&nbsp;Zhi Zhu ,&nbsp;Kai Li","doi":"10.1016/j.cbi.2025.111749","DOIUrl":"10.1016/j.cbi.2025.111749","url":null,"abstract":"<div><h3>Introduction</h3><div>Traditional Chinese Medicine (TCM) has historically been employed in the treatment of various diseases, including malignancies such as cancer. Phytosphingosine (PHS), a bioactive natural compound with antitumor properties, has attracted increasing attention in recent oncological studies.</div></div><div><h3>Objectives</h3><div>This study systematically investigates the pharmacological effects and molecular mechanisms of PHS in GC.</div></div><div><h3>Methods</h3><div>The small molecule targeting Secreted Frizzled-Related Protein 4 (<em>SFRP4</em>), identified through transcriptome sequencing, was validated using Cellular Thermal Shift Assay (CETSA). To investigate the pharmacological effects of PHS, we employed Transwell invasion assays, colony formation assays, xenograft tumor models, and flow cytometry-based apoptosis detection. Molecular mechanisms were explored via co-immunoprecipitation (Co-IP), immunohistochemistry (IHC), and Western blotting.</div></div><div><h3>Result</h3><div>The results demonstrate that PHS suppresses GC progression by dual mechanisms: (1) directly inducing apoptosis via a dose-dependent increase in the Bax/Bcl-2 ratio and (2) more importantly, PHS achieves pivotal regulation of the Wnt signaling pathway through suppression of secreted SFRP4 phosphorylation, which promotes <em>β-catenin</em> ubiquitin-proteasomal degradation. Western blot and murine models confirmed reduced expression of Wnt signaling components (<em>β-catenin</em>, <em>Cyclin D1</em>, <em>c-Myc</em>) and significant tumor growth inhibition.</div></div><div><h3>Conclusions</h3><div>These findings reveal the <em>SFRP4</em>-Wnt axis as a central target for PHS, offering novel insights into its molecular action and highlighting its potential as a therapeutic strategy derived from traditional medicine, with clinical implications for targeting Wnt-driven gastric carcinogenesis.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111749"},"PeriodicalIF":5.4,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145126455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erianin reverses 5-FU resistance by targeting CALM1/CAMKK2 and activating autophagy in colorectal cancer","authors":"Fangyuan Zhou ,&nbsp;Luorui Shang ,&nbsp;Jinxiao Li ,&nbsp;Mengqi Zhang ,&nbsp;Shuhan Wang ,&nbsp;Yuju Cai ,&nbsp;Qifeng Lin ,&nbsp;Haiyang Gao ,&nbsp;Shenglan Yang","doi":"10.1016/j.cbi.2025.111750","DOIUrl":"10.1016/j.cbi.2025.111750","url":null,"abstract":"<div><h3>Background</h3><div>Chemoresistance represents a significant factor contributing to the failure of clinical treatments in colorectal cancer (CRC), with resistance to 5-fluorouracil (5-FU) being notably prevalent. Erianin has demonstrated potential in reversing tumor resistance; however, its specific effects and underlying mechanisms in the context of 5-FU-resistant CRC require comprehensive validation.</div></div><div><h3>Methods</h3><div>The half-maximal inhibitory concentration (IC50) of Erianin and 5-FU was determined using the CCK8 assay. CRC cells resistant to 5-FU were induced by progressively increasing concentrations of 5-FU. Cellular proliferation, migration, and invasion were evaluated via 5-ethynyl-2′-deoxyuridine (EdU) assays, wound-healing assays, and Transwell Matrigel invasion assays. The expression levels of protein and mRNA expression levels for various molecules were quantified using Western blotting (WB) and quantitative real-time polymerase chain reaction (qRT-PCR). Immunofluorescence assays were employed to assess the expression of autophagy-related markers. The <em>in vivo</em> therapeutic efficacy of Erianin was assessed using a xenograft tumor model.</div></div><div><h3>Results</h3><div>Erianin effectively reinstated the sensitivity of 5-FU-resistant CRC cells to 5-FU, significantly reducing tumor cell proliferation, migration, and invasion, as well as inhibiting xenograft tumor growth. Mechanistic investigations demonstrated that Erianin targets and binds to the calmodulin 1 (CALM1) protein, enhancing its stability and subsequently increasing the phosphorylation levels of CAMKK2. This interaction facilitates autophagy in 5-FU-resistant CRC cells, ultimately leading to tumor cell death.</div></div><div><h3>Conclusion</h3><div>Erianin sensitized the resistant CRC cells to 5-FU by activating the CALM1/CAMKK2 signaling pathway, thereby inducing autophagy. The combination of 5-FU and Erianin presents a promising therapeutic approach to enhance survival outcomes in patients with refractory CRC.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111750"},"PeriodicalIF":5.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145105782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HTR1D regulates the PI3K/Akt signaling pathway to impact glioblastoma development and resistance to temozolomide","authors":"Huanqi Zhang ,&nbsp;Ziyan Liu ,&nbsp;Jing Cheng ,&nbsp;Yiming Jiang ,&nbsp;Xiaoli Zheng ,&nbsp;Chong Zhang ,&nbsp;Yangling Li","doi":"10.1016/j.cbi.2025.111748","DOIUrl":"10.1016/j.cbi.2025.111748","url":null,"abstract":"<div><div>Glioblastoma (GBM), the most aggressive primary brain tumor, presents significant therapeutic challenges owing to limited treatment options beyond the cornerstone chemotherapy temozolomide (TMZ) and its intrinsic chemoresistance. This study elucidates additional mechanisms of the multimodal antidepressant vortioxetine in GBM, extending beyond the reported PI3K/Akt pathway modulation. RNA-sequencing analysis identified five potential vortioxetine-responsive targets in GBM cells: <em>SCN5A</em>, <em>HTR1D</em>, <em>SLC6A9</em>, <em>KIF11</em>, and <em>ADRB2</em>. Notably, only <em>HTR1D</em> overexpression correlated with poor disease-free survival in GBM patients. Vortioxetine-mediated HTR1D suppression suggests its potential role as an HTR1D inhibitor in GBM progression. HTR1D-overexpressing GBM cells exhibited enhanced proliferative and migratory capacities. LinkedOmics database analysis revealed the HTR1D regulation on PI3K/Akt axis, a dominant signaling pathway showing significant positive correlation with TMZ resistance. Crucially, HTR1D knockdown enhanced TMZ sensitivity in GBM cells. Moreover, the TMZ-vortioxetine combination demonstrated marked synergistic anti-tumor effects concomitant with HTR1D suppression. <em>In vivo</em>, the TMZ-vortioxetine combination more effectively suppressed GBM proliferation than either agent alone. Collectively, these findings identify HTR1D as a novel vortioxetine target in GBM that modulates proliferation, metastasis, and TMZ resistance via PI3K/Akt signaling. This study provides convincing preclinical evidence for TMZ-vortioxetine combination therapy, proposing both a new therapeutic target and a viable strategy to circumvent TMZ resistance in GBM.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111748"},"PeriodicalIF":5.4,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Theaflavin 3,3′-digallate suppresses metastasis and reduces insulin-like growth factor-1-induced cancer stemness and invasiveness in human melanoma cells","authors":"Ju-Pi Li ,&nbsp;Yi-Hsien Hsieh ,&nbsp;Yi-Hsun Lee ,&nbsp;Wen-Yi Tsai ,&nbsp;Shun-Fa Yang ,&nbsp;Yih-Shou Hsieh ,&nbsp;Pei-Ni Chen","doi":"10.1016/j.cbi.2025.111751","DOIUrl":"10.1016/j.cbi.2025.111751","url":null,"abstract":"<div><div>Theaflavin 3,3′-digallate (TF3), a flavonoid compound, exerts antidiabetic effects, induces apoptosis, and suppresses cancer growth. However, its effects on melanoma metastasis and insulin-like growth factor 1 (IGF-1)-induced cancer stemness remain largely unexplored. This study explored key molecular signaling pathways underlying the antitumor and antimetastatic activities of TF3 in melanoma. The antimetastatic potential of TF3, as well as its impact on IGF-1-induced cancer stemness, were evaluated using wound healing assays, gelatin zymography, Matrigel invasion assays, sphere formation assays, and Western blotting. Its antiangiogenic and antimetastatic activities were further examined in vivo using subcutaneous xenograft and tail vein injection mouse models. TF3 significantly inhibited cell migration, invasion, and matrix metalloproteinase (MMP) activity in A 375 and A2058 melanoma cells. It also suppressed sphere formation, self-renewal capacity, and aldehyde dehydrogenase 1 (ALDH1) activity. In sphere-forming melanoma cells, TF3 downregulated key cancer stemness and drug resistance markers, including ABCB1, ABCG2, CD44, and CXCR4. Notably, TF3 reversed IGF-1-induced sphere formation, invasion, and MMP-9 expression. Mechanistically, TF3 suppressed IGF-1-mediated phosphorylation of focal adhesion kinase (FAK) and Src. In vivo, TF3 significantly inhibited tumor growth, reduced angiogenic marker expression, and suppressed lung metastasis. Collectively, these findings demonstrate that TF3 impedes melanoma progression by inhibiting metastasis and suppressing IGF-1-induced cancer stemness and invasiveness.</div></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"421 ","pages":"Article 111751"},"PeriodicalIF":5.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}