International journal of oncology最新文献

{"title":"Overcoming acquired doxorubicin resistance of ovarian carcinoma cells by verapamil‑mediated promotion of DNA damage‑driven cytotoxicity.","authors":"Elvira Mukinovic, Sina Federmann, Larissa Messling, Marlena Sekeres, Julia Mann, Lena Abbey, Matthias U Kassack, Gerhard Fritz","doi":"10.3892/ijo.2026.5861","DOIUrl":"10.3892/ijo.2026.5861","url":null,"abstract":"<p><p>The efficacy of anticancer therapeutics is limited by acquired drug resistance of tumor cells. The present study aimed to characterize and overcome resistance mechanisms to the anthracycline derivative doxorubicin (Doxo). To this end, comparative analyses of Doxo‑induced stress responses of parental A2780 ovarian carcinoma cells and Doxo‑resistant A2780ADR variants were performed. A2780ADR cells revealed cross‑resistance to multiple compounds, including anticancer drugs [cisplatin (CisPt) and etoposide (Eto)] and DNA repair/DNA damage response (DDR) inhibitors (olaparib, niraparib, entinostat, prexasertib and rabusertib). A2780ADR cells formed markedly fewer DNA double‑strand breaks (DSB) following Doxo exposure compared with parental A2780 cells, resulting in a mitigated DDR, reduced proliferation inhibition and attenuated apoptosis. Potential resistance mechanisms identified to contribute to Doxo resistance of A2780ADR cells include increased Doxo efflux due to increased multi‑drug resistance gene 1 (MDR1) expression and reduced topoisomerase IIα protein expression. Substantial resensitization of A2780ADR cells to Doxo was achieved by both the RAC1 GTPase inhibitor EHT1864, the histone deacetylase inhibitor entinostat (EST) and, most effectively, the calcium channel blocker verapamil (Ver). Notably, Ver‑mediated sensitization also pertains to Eto and CisPt. The synergistic effect of Ver in combination with Doxo, which is reflected by low combination index (CI<0.8), probably involves inhibition of MDR1‑mediated drug export, increased intracellular steady state levels of Doxo and elevated DSB formation, eventually promoting pro‑toxic mechanisms of the DDR. However, combination treatment with Doxo and Ver also increased the cytotoxic response of non‑malignant murine cardiomyocytes, murine embryonic stem cells and human induced pluripotent stem cells. Taken together, the present study suggested inhibition of MDR1‑mediated Doxo efflux by Ver a useful approach to overcome acquired drug resistance of A2780ADR cells by stimulating DDR‑related cytotoxicity, yet at the price of a potentially increased risk of normal tissue toxicity.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12945421/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL‑6: A key player in the EGFR‑TKI‑resistant tumor microenvironment and its therapeutic implications (Review).","authors":"Qi Wei, Chengming Huang, Yuanyuan Zhang, Hao Zeng, Chang Qi, Sihan Tan, Weimin Li, Panwen Tian, Yalun Li","doi":"10.3892/ijo.2026.5860","DOIUrl":"10.3892/ijo.2026.5860","url":null,"abstract":"<p><p>IL‑6, a pleiotropic inflammatory cytokine predominantly secreted by fibroblasts, myeloid‑derived suppressor cells, tumor‑associated macrophages and tumor cells, is associated with poor prognosis of and therapeutic resistance in non‑small cell lung cancer (NSCLC). The activation of signaling pathways, including the JAK/STAT3, MAPK and PI3K/AKT pathways, promotes tumor survival. Furthermore, the IL‑6/JAK/STAT3 signaling axis has emerged as a key driver of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‑TKI) resistance, orchestrating intricate crosstalk within the tumor microenvironment (TME) to promote cell survival and immunosuppression. The present review synthesized current evidence on the dual role of IL‑6 in mediating EGFR‑TKI resistance and blunting anti‑tumor immunity. The present review highlights the preclinical rationale for combining IL‑6 blockade with EGFR‑TKI or immune checkpoint inhibitors to overcome refractory disease. The present review also highlights the structure, molecular mechanisms and clinical insights of IL‑6 in the TME of <i>EGFR</i>‑mutant NSCLC and may provide optimized therapeutic strategies for EGFR‑TKI‑refractory NSCLC.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12945417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of SPAG6 in regulating physiological functions and tumorigenesis (Review).","authors":"Yu Luo, Qibing Yan, Pohao Zhang, Hui Xu, Rong Zhang, Ruihe Wang, Yongkang Wu","doi":"10.3892/ijo.2026.5855","DOIUrl":"10.3892/ijo.2026.5855","url":null,"abstract":"<p><p>Sperm‑associated antigen 6 (SPAG6) belongs to the cancer/testis antigen family. It is a microtubule‑binding protein located on chromosome 10p12.2 and it plays an important role in various physiological processes, including ciliary movement, immune synapse formation and neurodevelopment. Abnormal SPAG6 expression occurs in multiple malignancies and developmental disorders; however, its underlying molecular mechanisms in tumorigenesis, tumor progression, clinical outcomes and therapeutic response have not been presented. This review provides a comprehensive overview of the physiological functions of SPAG6 and its mechanisms in disease, with a focus on its expression profile, function and association with disease progression and treatment response in hematologic malignancies (e.g., myelodysplastic syndrome, acute myeloid leukemia and B‑cell acute lymphoblastic leukemia) and solid tumors (e.g., breast cancer, lung cancer and osteosarcoma). SPAG6 promotes tumor progression and drug resistance by attenuating the cell cycle and through epigenetic modifications and remodeling of the tumor immune microenvironment. In addition, it may serve as a diagnostic and prognostic marker for various diseases as well as a therapeutic target.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12945423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146180049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging roles of RNA m⁶A modification in multiple myeloma pathogenesis and treatment resistance (Review).","authors":"Yasen Maimaitiyiming, Shuoyang Hu, Die Bai, Yingchao Guan, Na Bu, Wenhui Hao, Mayila Maimaiti","doi":"10.3892/ijo.2026.5853","DOIUrl":"10.3892/ijo.2026.5853","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable hematologic malignancy characterized by the clonal expansion of plasma cells in the bone marrow. Despite advances in therapeutic agents, including proteasome inhibitors, immunomodulatory drugs and immunotherapies, relapse driven by treatment resistance remains a major clinical challenge. This underscores the critical need to elucidate additional molecular mechanisms that drive MM pathogenesis and therapeutic failure. The emerging field of epitranscriptomics, which studies post‑transcriptional RNA modifications, offers a promising perspective. Among these modifications, N6‑methyladenosine (m⁶A), the most abundant internal mRNA modification, has been implicated in regulating nearly every aspect of RNA metabolism. Growing evidence indicates that dysregulation of the m⁶A modification machinery plays a pivotal role in MM heterogeneity, disease progression and drug resistance. The present review synthesized current knowledge on how specific m⁶A regulators contribute to MM oncogenesis by modulating key signaling pathways, interactions with the bone marrow microenvironment and responses to therapy. It also discussed the potential of targeting m⁶A pathways as a therapeutic strategy to overcome treatment resistance and improve patient outcomes. By highlighting recent advances and future directions, the present review underscored m⁶A modification as an important frontier in the battle against MM.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role and underlying mechanisms of miR‑200 family in breast cancer (Review).","authors":"Jiaqi Liu, Hua Du, Yingxu Shi","doi":"10.3892/ijo.2026.5856","DOIUrl":"10.3892/ijo.2026.5856","url":null,"abstract":"<p><p>Βreast cancer (BC) is the most common malignant tumor among women. Its significant heterogeneity and complex molecular mechanisms pose major clinical challenges, including limited therapeutic efficacy and drug resistance. Recently, microRNAs (miRs) have been recognized as key post‑transcriptional regulators involved in tumorigenesis and tumor progression through multiple pathways. Among these, the miR‑200 family (miR‑200a, miR‑200b, miR‑200c, miR‑429 and miR‑141) has attracted considerable attention due to its pivotal role in BC. The present review systematically summarizes the genomic characteristics, expression regulation mechanisms and biological functions of the miR‑200 family in BC. Special emphasis is given to their roles in epithelial‑mesenchymal transition, cell proliferation, apoptosis, maintenance of stemness, and remodeling of the tumor microenvironment. Furthermore, members of the miR‑200 family have potential as diagnostic and prognostic biomarkers and are closely linked to chemotherapy resistance. The present review aims to provide novel insights and a theoretical foundation for the diagnosis, treatment, and deeper investigation of BC by comprehensively examining the functional mechanisms of the miR‑200.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12945413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146226766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"lncRNA AL445238.2‑USP4 axis regulates cell survival and stemness in colon cancer.","authors":"Hualong Lin, Jieni Feng, Peirui Chen, Jialin Hu, Linjia Zhu, Shaofei Yuan","doi":"10.3892/ijo.2026.5858","DOIUrl":"10.3892/ijo.2026.5858","url":null,"abstract":"<p><p>Local progression and metastasis remain the foremost impediments to long‑term survival among patients with colorectal cancer (CRC). long non‑coding RNAs (lncRNAs) have a pivotal role in the advancement of colorectal malignancies. The aim of the present study was to elucidate the functional role and underlying molecular mechanisms of the lncRNA AL445238.2 in CRC progression. In the present study, overexpression/knockdown lentiviral vectors, protein half‑life assays and co‑immunoprecipitation assays were used to explore the regulatory relationship among AL445238.2, ubiquitin‑specific protease 4 (USP4) and BCL2, combined with Transwell assays, sphere formation assays and subcutaneous xenograft models to demonstrate their effects on colon cancer proliferation and stemness both <i>in vitro</i> and <i>in vivo</i>. The experimental findings revealed that AL445238.2 was highly expressed in CRC cells. AL445238 overexpression significantly enhanced the proliferation of DLD1 and SW480 cells, reduced extracellular lactate dehydrogenase release, diminished apoptotic activity and increased cellular stemness, as evidenced by increased CD133 expression and augmented tumor sphere formation, together with enhanced mitochondrial activity. RNA pulldown and immunofluorescence assays further demonstrated a direct interaction between AL445238.2 and USP4, with the two synergistically modulating the expression of the anti‑apoptotic protein Bcl2 and the pro‑apoptotic protein BAX to suppress apoptosis. Moreover, in <i>in vivo</i> assays, USP4 independently promoted cell proliferation, sustained stemness and enhanced mitochondrial function, thereby increasing tumor growth. Collectively, the findings of the present study revealed that AL445238.2, through its interaction with USP4, orchestrated the regulation of cell proliferation, apoptosis, stemness maintenance and migration in CRC cells, offering novel insights into the role of lncRNAs in cancer progression and highlighting potential therapeutic targets.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12945412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of chemoresistance in diffuse large B‑cell lymphoma and novel therapeutic strategies (Review).","authors":"Mengdi Wan, Xi Wang, Bin Luo, Huangming Hong, Yizhun Zhu, Tongyu Lin","doi":"10.3892/ijo.2026.5859","DOIUrl":"10.3892/ijo.2026.5859","url":null,"abstract":"<p><p>Diffuse large B‑cell lymphoma (DLBCL), the most prevalent subtype of lymphoma, is characterized by rapid growth and a poor prognosis, with the R‑CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) being the standard first‑line therapy. However, 30‑40% of patients experience early relapse or refractoriness to treatment, highlighting the need to understand the mechanisms of chemoresistance. The present review synthesizes the current knowledge on the molecular mechanisms underlying chemoresistance in DLBCL, including genetic mutations, epigenetic modifications, aberrant activation of signaling pathways, alterations in drug metabolism and efflux, and upregulation of anti‑apoptotic proteins. In addition, the role of the tumor microenvironment in mediating therapeutic resistance is discussed and biomarkers associated with chemoresistance are explored. Furthermore, novel therapeutic strategies targeting chemoresistance, such as immunotherapy, metabolic modulators and epigenetic therapies, are examined. Understanding these mechanisms is crucial for developing effective treatment strategies to overcome resistance and improve patient outcomes in DLBCL.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the study of the breast carcinoma exosomal microRNAs: From basic mechanisms to clinical applications (Review).","authors":"Zhi-Min Chen, Peng Huang, Dun-Yang Yang, Shu Lin, Si-Qing Cai","doi":"10.3892/ijo.2026.5851","DOIUrl":"10.3892/ijo.2026.5851","url":null,"abstract":"<p><p>Breast carcinoma remains a major global health burden requiring innovative diagnostic and therapeutic strategies. Exosomal miRNAs have emerged as key factors in breast carcinoma that influence tumor progression, metastasis and treatment resistance. Recent studies have elucidated their mechanisms of action, including their roles in regulating oncogenic and tumor‑suppressive pathways, modulating the tumor microenvironment and promoting chemo‑resistance. Advances in miRNA‑based therapies such as miRNA mimics and inhibitors have shown promise in combination treatments, enhancing their therapeutic efficacy. Furthermore, exosomal miRNAs play a role in breast carcinoma calcification, offering novel insights into tumor progression. Unlike previous reviews that focus on a single function or therapeutic potential of miRNAs, the present review systematically integrated the multilevel role of exosomal miRNAs in breast cancer from the two dimensions of oncogenicity and tumor inhibition and the regulatory mechanism of breast carcinoma calcification and proposes that the exosomal miRNA calcification axis may be a key link connecting tumor metabolism and pathological calcification. Despite the potential of miRNAs, challenges remain in optimizing exosome isolation techniques and standardizing miRNA detection methods for clinical applications. Future research should focus on refining miRNA‑based liquid biopsies, developing delivery systems that target exosomes to enhance therapeutic efficacy and early detection strategies and ultimately improving patient survival and quality of life. The present review comprehensively explored the roles of exosomal miRNAs and highlighted their importance in breast carcinoma research. The present review illustrated the potential of exosomal miRNAs as non‑invasive biomarkers and therapeutic targets in precision medicine.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146085553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"[Corrigendum] Podoplanin‑mediated TGF‑β‑induced epithelial‑mesen‑ chymal transition and its correlation with bHLH transcription factor DEC in TE‑11 cells.","authors":"Yunyan Wu, Qiang Liu, Xu Yan, Yukio Kato, Makiko Tanaka, Sadaki Inokuchi, Tadashi Yoshizawa, Satoko Morohashi, Hiroshi Kijima","doi":"10.3892/ijo.2026.5854","DOIUrl":"10.3892/ijo.2026.5854","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that, for the scratch‑wound assay experiments shown in Fig. 8 on p. 2318, the 'control‑siRNA/24 h' and 'podoplanin‑siRNA/48 h' panels contained an overlapping section of data; such that these data, which were intended to show the results from differently performed experiments, appeared to have been derived from the same original source. Upon analyzing the data independently in the Editorial Office, it came to light that, in addition to control blots, the podoplanin blots were duplicated in Fig. 2A and B, and also in Fig. 3A and B, although it wasn't clear whether this was simply the way in which the authors had chosen to arrange the data in these figures, as the reported experimental conditions were the same in the respective figure parts (note that an Expression of Concern statement was also published for this paper: doi.org/10.3892/ijo.2025.5805). Upon contacting the authors, they confirmed that the data had been included in Figs. 2 and 3 as intended, although they realized that an error had been made during the assembly of the scratch‑wound assay images shown in Fig. 8. However, the authors had retained their original data, and the data for the podoplanin‑siRNA/48 h' panel was shown incorrectly in this Figure. In the first instance, the authors wish to propose the following wording for the figure legend for Fig. 3, to clarify that the same podoplanin and β‑actin bands were intended to have been shown in Figs. 2 and 3 (the added text is highlighted in bold): 'Figure 3. The protein expression of podoplanin and EMT‑related markers was regulated by TGF‑β. TE‑11 cells were treated as indicated in Fig. 2. These cells were then lysed, and the lysates were subjected to western blot analyses of pSmad2, Smad2/3, Slug, podoplanin, vimentin, N‑cadherin, E‑cadherin, Claudin‑4, DEC1, DEC2, and β‑actin. &lt;b&gt;The data of podoplanin and β‑actin used in (A) were shown again in (B) as necessary.&lt;/b&gt; Two representative results of at least four independent experiments with similar outcomes are shown'. Textual corrections should also be noted in this Corrigendum: First, in the figure legend for Fig. 8, the P‑value for significance should have been written as '*P&lt;0.05', not as '*P&lt;0.001'. Secondly, in the Results section, the '&lt;i&gt;Podoplanin was closely involved in the invasion and migration in TE‑11 cells&lt;/i&gt;' subsection on p. 2314, sentences 5-7 in this paragraph should have been written as follows ('at 24 h' should have been included in the sixth sentence): 'In order to evaluate the ability of migration, wound‑healing assay was introduced in podoplanin siRNA‑transfected cells. Remaining wound length was measured after 0, 24 and 48 h of podoplanin siRNA transfection, and a significant difference between the control siRNA‑transfected group and the podoplanin siRNA‑ transfected group at 24 h was attained (Fig. 8). Morphologically, a small amount of the TE‑11","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12920010/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<p>KMO downregulation promotes hepatocellular carcinoma growth via 3‑HAA‑mediated mitochondrial mass and function imbalances</p>.","authors":"Ming Liu, Xintong Zhang, Yanfen Hu, Li Niu, Linzhi Guo, Guoqing Zhao, Fan Lu, Fengfeng Jia, Li Li, Hao Wu, Jianjun Zhu","doi":"10.3892/ijo.2026.5846","DOIUrl":"10.3892/ijo.2026.5846","url":null,"abstract":"<p><p><p>Kynurenine (Kyn) 3‑monooxygenase (KMO) is a key enzyme of the tryptophan (Try)‑Kyn pathway and is located on the outer membrane of mitochondria. Notably, it has not yet been elucidated as to whether KMO is involved in hepatocellular carcinoma (HCC) progression by affecting mitochondria. In the present study, KMO was revealed to be downregulated in HCC patients and this downregulation was associated with a poor prognosis. Notably, the downregulation of KMO promoted the proliferation and migration of HCC cells and increased mitochondrial mass. The levels of the Try metabolite 3‑hydroxyanthranilic acid (3‑HAA) were elevated in HCC cells overexpressing KMO. The results indicated that 3‑HAA may inhibit HCC cell growth promoted by KMO downregulation and reverse the KMO downregulation‑induced increase in mitochondrial mass. Furthermore, KMO and 3‑HAA were shown to regulate the expression of the transcription factor nuclear receptor subfamily 4 group A member 1 (NR4A1) and reduce NR4A1 mitochondrial translocation, thus inhibiting the growth of HCC cells. In summary, the current study elucidated that low KMO expression in HCC affects mitochondrial mass and function by reducing the level of the Try metabolite 3‑HAA, downregulating the expression of NR4A1 and promoting its mitochondrial translocation, which in turn may promote the progression of HCC. These findings provide new insights into the treatment of HCC, potentially targeting the mitochondria and the Try‑Kyn pathway.</p>.</p>","PeriodicalId":14175,"journal":{"name":"International journal of oncology","volume":"68 3","pages":""},"PeriodicalIF":4.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12823061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145989118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}