Clinical and Experimental Medicine最新文献

{"title":"Prognostic implication of six m6A-modulated genes signature in the ferroptosis for hepatocellular carcinoma patients.","authors":"Yu He, Zhilin Zou, Zuyong Lan, Ming Chang, Xiao Zhang, Risheng Lin, Wen Zhang, Guangtao Zhang, Ting Wang, Erbao Chen","doi":"10.1007/s10238-025-01700-4","DOIUrl":"10.1007/s10238-025-01700-4","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains one of the most prevalent and lethal malignancies worldwide, with survival rates still falling short of expectations. Emerging evidence highlights the pivotal roles of both m6A methylation and ferroptosis-related genes (FRGs) in HCC progression. However, the prognostic significance of m6A-modulated FRGs remains largely unexplored. In this study, we developed a novel prognostic signature based on m6A-regulated FRGs, identifying six key genes (VEGFA, FANCD2, ZFP69B, EIF2S1, SLC7A11, and SRXN1) through multivariate and LASSO Cox regression analyses. A high m6A-FRGs score was strongly associated with poor prognosis, and multivariate analysis confirmed it as an independent prognostic factor. Notably, the high-risk group exhibited increased expression of immune checkpoint genes and a higher frequency of gene mutations. Functional assays further demonstrated that silencing ZFP69B significantly suppressed liver cancer cell proliferation, migration, and invasion. Clinical validation in 144 HCC samples revealed that elevated ZFP69B expression correlated with worse patient outcomes. Moreover, qPCR analysis confirmed CLSPN and HNRNPR as downstream targets of ZFP69B. Collectively, our findings establish the m6A-FRGs signature as a powerful prognostic tool for HCC and identify ZFP69B as a promising therapeutic target, warranting further investigation.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"180"},"PeriodicalIF":3.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12116693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of proteostasis workload on sensitivity to proteasome inhibitors in multiple myeloma.","authors":"Jindrich Sedlacek","doi":"10.1007/s10238-025-01713-z","DOIUrl":"10.1007/s10238-025-01713-z","url":null,"abstract":"<p><p>Genomic alterations and enormous monoclonal immunoglobulin production cause multiple myeloma to heavily depend on proteostasis mechanisms, including protein folding and degradation. These findings support the use of proteasome inhibitors for treating multiple myeloma and mantle cell lymphoma. Myeloma treatment has evolved, especially with the availability of new drugs, such as proteasome inhibitors, into therapeutic strategies for both frontline and relapsed/refractory disease settings. However, proteasome inhibitors are generally not effective enough to cure most patients. Natural resistance and eventual acquired resistance led to relapsed/refractory disease and poor prognosis. Advances in the understanding of cellular proteostasis and the development of innovative drugs that also target other proteostasis network components offer opportunities to exploit the intrinsic vulnerability of myeloma cells. This review outlines recent findings on the molecular mechanisms regulating cellular proteostasis pathways, as well as resistance, sensitivity, and escape strategies developed against proteasome inhibitors and provides a rationale and examples for novel combinations of proteasome inhibitors with FDA-approved drugs and investigational drugs targeting the NRF1 (NFE2L1)-mediated proteasome bounce-back response, redox homeostasis, heat shock response, unfolding protein response, autophagy, and VCP/p97 to increase proteotoxic stress, which can improve the efficacy of antimyeloma therapy based on proteasome inhibitors.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"176"},"PeriodicalIF":3.2,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the risk of ibrutinib in combination with R-ICE in patients with relapsed or refractory DLBCL using explainable machine learning algorithms.","authors":"Ni Zhu, Rong-Bin Shen, Jun-Fa Chen, Jian-You Gu, Si-Chun Xiang, Yu Zhang, Li-Li Qian, Qing Guo, Sha-Na Chen, Jian-Ping Shen, Jun Yan, Jing-Jing Xiang","doi":"10.1007/s10238-025-01709-9","DOIUrl":"10.1007/s10238-025-01709-9","url":null,"abstract":"<p><p>Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) poses significant therapeutic challenges due to heterogeneous patient outcomes. This study aimed to evaluate the efficacy of the ibrutinib plus R-ICE regimen and to leverage explainable machine learning models (ML) for predicting treatment risks and outcomes. Retrospective data from 28 patients treated between March 2019 and July 2022 were analyzed. Machine learning models, including CoxBoost + StepCox, were developed and validated using bootstrap methods. Synthetic minority over-sampling combined with propensity score matching (SMOTE-PSM) addressed class imbalances. Prognostic performance was compared against the Cox proportional hazards model using decision curve and calibration analysis, as well as time-dependent ROC curves. The CoxBoost + StepCox model achieved an average C-index of 0.955 for overall survival (OS) and progression-free survival (PFS). Key prognostic indicators included elevated lactate dehydrogenase (LDH), initial treatment response, time to relapse > 12 months, and CD5 + expression. Calibration curves showed a C-index of 0.932 for OS and 0.972 for PFS in the training set. CD5 + was most predictive for OS and LDH for PFS. Machine learning models demonstrated high accuracy and clinical utility, indicating potential for data-driven treatment decisions in DLBCL.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"177"},"PeriodicalIF":3.2,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12106145/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is high IgG level associated with disease activity and organ damage in patients with Sjögren's syndrome? A 3-year follow-up cohort study.","authors":"Yueting Li, Siyun Chen, Li Guo, Chuhan Wang, Yanhong Wang, Jiuliang Zhao, Dong Xu, Mengtao Li, Xiaofeng Zeng, Yan Zhao","doi":"10.1007/s10238-025-01715-x","DOIUrl":"10.1007/s10238-025-01715-x","url":null,"abstract":"<p><p>Hypergammaglobulinemia is prevalent in primary Sjögren's syndrome (pSS) and is considered a marker of disease activity. However, limited data exist regarding its association with disease activity and organ damage. We enrolled patients with pSS from the Chinese Rheumatism Data Centre and categorized them into four groups based on the IgG levels over a 3-year follow-up: consistently high, consistently intermediate, consistently normal, and intermittent. Disease activity and organ damage at the end of the third year were compared across these groups. A total of 351 patients were included in this study, all females with a median age of 45 (IQR 35-53) years. The median baseline IgG was 17.2 (IQR 13.4-21.4) g/L. About 40% of the patients with elevated baseline IgG levels remained in the consistently high or intermediate IgG group. Compared to patients with consistently normal IgG levels, those with consistently high IgG levels had higher median SSDDI scores (2 vs. 1, p = 0.014), higher median ESSPRI scores (2.5 vs. 1.7, p = 0.005), more extra-glandular organ manifestations (IRR 2.34, 95%CI 1.48-3.7, p = < 0.001), and more extra-glandular organ damage (IRR 2.06, 95%CI 1.03-4.12, p = 0.040) at the third-year follow-up. No significant differences in extra-glandular involvement were found between the consistently intermediate IgG group and the consistently normal IgG group. The consistently high IgG level, but not the consistently intermediate level, was associated with a greater number of extra-glandular manifestations and increased extra-glandular organ damage.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"174"},"PeriodicalIF":3.2,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12104097/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage polarization in hepatocellular carcinoma: a lncRNA-centric perspective on tumor progression and metastasis.","authors":"Ahmad Ghorbani Vanan, Mohammad Taha Nami, Farid Ghorbaninezhad, Pooya Eini, Kamyar Bagheri, Maryam Mohammadlou, Fatemeh Mohammadi, Safa Tahmasebi, Elham Safarzadeh","doi":"10.1007/s10238-025-01711-1","DOIUrl":"10.1007/s10238-025-01711-1","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) represents a multifaceted and aggressive cancer frequently associated with chronic inflammation and immune cell activation. The pathogenesis of HCC is influenced by a variety of factors such as long non-coding RNAs (lncRNAs). LncRNAs, a significant class of non-coding RNAs, contribute to the intricate nature of the transcriptome and are extensively distributed across various tissues and cell types in mammals. In HCC, these transcripts are crucial not only for deepening our molecular understanding but also for advancing clinical outcomes, as they serve as both oncogenes and tumor suppressors by dysregulating essential genes and signaling pathways. Additionally, macrophage polarization is crucial in HCC tumor progression. The study explores the role of lncRNAs in hepatocellular carcinoma (HCC) and elucidates the specific molecular mechanisms by which key lncRNAs such as HULC and MALAT1 regulate macrophage polarization in the tumor microenvironment. These lncRNAs modulate cytokine profiles and influence immune regulators including IL-10 and TGF-β, steering macrophages toward an M2-like, pro-tumor phenotype that fosters aggressive tumor characteristics and progression. Mechanistically, these transcripts interact with epigenetic modifiers like EZH2 to alter histone modifications and chromatin accessibility, while also stabilizing mRNAs that encode inflammatory mediators, thereby reinforcing an immunosuppressive response. The clinical implications of these findings are substantial. The detection of such lncRNAs in patient samples offers a minimally invasive diagnostic avenue, while their pivotal role in complex immune cell behavior positions them as promising prognostic biomarkers. Moreover, targeting these lncRNAs may lead to innovative therapeutic strategies aimed at disrupting tumor-supportive inflammatory cascades and restoring an effective antitumor immune response. Understanding the intricate interplay between lncRNA-mediated epigenetic regulation and macrophage polarization not only refines our grasp of HCC progression but also opens new pathways for interventions designed to improve patient outcomes.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"173"},"PeriodicalIF":3.2,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12104118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The diabetic neuropathy and bone mineral density in type 2 diabetes mellitus: a cross-sectional and meta-analytic study.","authors":"Zheng Zhao, Jizhou Liang, Jingrui Kang, Jing He, Min Li, Weiwei Mao, Wenxue Gao, Bin Su, Ran Cui","doi":"10.1007/s10238-025-01710-2","DOIUrl":"10.1007/s10238-025-01710-2","url":null,"abstract":"<p><p>Diabetic neuropathy (DN) is a common complication of type 2 diabetes mellitus (T2DM), yet its impact on bone mineral density (BMD) remains unclear. This study combines cross-sectional and meta-analytic methods to comprehensively explore the relationship between DN and osteoporosis in T2DM patients. The cross-sectional study included 523 T2DM patients, classified into DN and non-DN groups. BMD was measured using dual-energy X-ray absorptiometry (DXA), and multivariate analysis identified osteoporosis-related factors. The meta-analysis included studies published from 1999 to 2021, comparing BMD between patients with and without DN. The results showed that while significant differences in clinical characteristics and biochemical indices (such as age, HbA1c, and 25(OH) vitamin D levels) were observed between the groups, no significant association between DN and osteoporosis was found after adjusting for covariates like body mass index and blood pressure. Additionally, the meta-analysis confirmed no significant impact of DN on BMD across skeletal sites, including the lumbar spine, hip, and femoral neck. These findings suggest that while DN may indirectly affect bone health through alterations in bone metabolism (such as bone formation markers), its direct impact on BMD is limited. The study's limitations include its cross-sectional design, which restricts causal inference, and retrospective data collection, underscoring the need for prospective studies to further elucidate the mechanisms behind DN's effects on bone health. These results highlight the complex interplay of factors influencing osteoporosis risk in T2DM and underscore the importance of a multifactorial approach to bone health management in this population.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"175"},"PeriodicalIF":3.2,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12104114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as predictive biomarkers for treatment response in primary advanced hypopharyngeal squamous cell carcinoma treated with chemoimmunotherapy.","authors":"Yueyue Shi, Xueyan Zhao, Yan Zhou, Xiaomeng Zhang","doi":"10.1007/s10238-025-01675-2","DOIUrl":"10.1007/s10238-025-01675-2","url":null,"abstract":"<p><p>To evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in peripheral blood for assessing the treatment response to chemoimmunotherapy in primary advanced hypopharyngeal squamous cell carcinoma (HPSCC), we retrospectively reviewed the medical records of patients treated with neoadjuvant taxane-platinum (TP) chemotherapy plus an anti-programmed cell death-1 (PD-1) inhibitor at Wuhan Union Hospital from Jan 2020 to Dec 2022. We collected data on absolute neutrophil, lymphocyte, and platelet counts from routine blood tested at baseline and within a week after the first treatment. A total of 35 patients were included in this study. Post-treatment NLR (r_s = - 0.445, p = 0.007) and PLR (r_s = - 0.475, p = 0.004) demonstrated negative correlations with treatment response assessed by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). NLR and PLR were significantly lower in patients achieving a complete response than those not achieving it (with p values of 0.04 and 0.02 for NLR and PLR, respectively). Among the 27 patients who underwent radical surgery following three cycles of chemoimmunotherapy, a high PLR after the first treatment was negatively correlated with attaining a pathological complete response (pCR) (r_s = - 0.424, p = 0.028). For predicting pCR, the receiver operating characteristic (ROC) curve of PLR after the first treatment yielded an area under the curve (AUC) of 0.759 (95% confidence interval [CI]: 0.572-0.946, p = 0.031), with a sensitivity of 77.8% and a specificity of 72.2%. This research underscores the predictive value of the NLR and PLR in appraising not only the treatment response, as gauged by the RECIST 1.1, but also the pathological response to chemoimmunotherapy in patients with HPSCC.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"172"},"PeriodicalIF":3.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12103357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144136053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multidimensional integrated lung protection measures attenuate pulmonary inflammation and improve lung function by inhibiting the NF-κB signaling pathway in elderly patients with lung dysfunction.","authors":"Yan Zhang, Hao Li, Dan Yin, Mandi Wu, Yinghui Cui, Jinhuo Wang, Zhanyu Cheng, Yujia Wang, Huan Wang, Jianrong Guo","doi":"10.1007/s10238-025-01703-1","DOIUrl":"10.1007/s10238-025-01703-1","url":null,"abstract":"<p><p>Elderly patients with lung dysfunction (EPLD) often experience chronic inflammation and impaired immune responses, significantly impacting their health outcomes. Currently, no specific treatment exists to prevent lung dysfunction in elderly patients. The detailed mechanism of lung dysfunction in elderly patients remains elusive, and this study aims to clarify it. General data and blood specimens were obtained from EPLD. A lung dysfunction mouse model was established by anesthetizing and ventilating BALB/c mice at a high tidal volume of 30 mL/kg. Blood samples and lung tissues were collected from all groups for further testing. HE staining, immunofluorescence, Western blot, ELISA, flow cytometry, and qRT-PCR were used to elucidate the molecular mechanisms of multidimensional integrated lung protection measures (MILPM) in lung dysfunction mice by targeting the NF-κB pathway. The results indicated that upregulation of the NF-κB signaling pathway accelerates the lung dysfunction process, while downregulation of the NF-κB signaling pathway can prevent it. Similarly, the upregulation of TNF-α, IL-6, IL-1β, and ROS levels is associated with the lung dysfunction process, whereas reducing their levels can serve as a preventative method against lung dysfunction development. Upregulation of the NF-κB pathway can accelerate the process of lung dysfunction.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"171"},"PeriodicalIF":3.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12098184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification and validation a novel kinase-related gene signature for predicting prognosis and responsiveness to immunotherapy in hepatocellular carcinoma.","authors":"Yaju Qiu, Xitian Wu, Yang Luo, Lianqiang Shen, Anyang Guo, Jing Jiang, Lijuan Zhu, Yuhua Zhang, Fang Han, Enyan Yu","doi":"10.1007/s10238-025-01556-8","DOIUrl":"10.1007/s10238-025-01556-8","url":null,"abstract":"<p><p>Liver cancer research highlights the kinome's critical role in disease initiation and progression. However, comprehensive data analysis on the kinome's impact on hepatocellular carcinoma (HCC) prognosis is limited. We used the TCGA-LIHC mRNA expression profiles, analyzing them with various R packages. Key methods included univariate Cox regression for prognostic gene identification, consensus clustering for subtype classification, Gene Set Enrichment Analysis (GSEA), and immune landscape evaluation. A prognostic model was developed using LASSO Cox regression, and chemotherapy drug sensitivity was assessed using the pRRophetic package. We identified 45 kinases-related differentially expressed genes (DEGs), with 27 linked to HCC prognosis. Cluster analysis divided these genes into two subtypes, with distinct prognoses. We discovered 157 DEGs between kinase-related subtypes, 120 of which were prognostically relevant. A kinase-related gene signature (KRS) was developed for prognostic prediction. The high-KRS group showed poorer survival in TCGA-LIHC and validation cohorts, with notable differences in immune cell infiltration and checkpoint gene expression. This group also showed varying sensitivity to common drugs and anti-PD-L1 treatment. In contrast, the low-KRS group might respond better to anti-PD-1 immunotherapy. Our study introduces a kinase-related gene signature as a novel tool for predicting HCC prognosis. This signature aids in tailoring personalized treatment strategies, potentially improving clinical outcomes in HCC patients.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"170"},"PeriodicalIF":3.2,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12092527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109824","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AHNAK2 confers 5-fluorouracil resistance in colorectal cancer via activation of the AKT/GSK-3β signaling axis.","authors":"Mianjiao Xie, Wanlin Lin, Yongtao Du, Yunlong Li, Shisen Li","doi":"10.1007/s10238-025-01682-3","DOIUrl":"10.1007/s10238-025-01682-3","url":null,"abstract":"<p><p>AHNAK nucleoprotein 2 (AHNAK2) is implicated in tumor progression and survival signaling, yet its role in chemotherapy resistance, particularly in colorectal cancer (CRC), remains under investigation. In the present study, the GEPIA database and Kaplan-Meier Plotter database were employed to uncover the correlation between high AHNAK2 expression and unfavorable prognostic outcomes in CRC patients. The expression of AHNAK2 in 5-fluorouracil (5-FU)-resistant CRC tissues was validated by immunohistochemical staining, quantitative real-time PCR, and western blot analysis. Then, 5-FU-resistant CRC cell lines LoVo/5-FU and HCT116/5-FU were developed through consecutive treatment of cells with 5-FU and then subjected to gene knockdown or overexpression. A series of assays, including CCK-8 assay, colony formation assay, flow cytometry, wound healing assay, transwell assay, and tumor xenograft mouse model, were conducted to evaluate the effects of AHNAK2 on 5-FU resistance. We observed a significantly increased expression of AHNAK2 in 5-FU-resistant tumor tissues compared to 5-FU-sensitive ones. This elevated expression was negatively associated with the prognosis of CRC patients. Knockdown of AHNAK2 in LoVo/5-FU cells reduced 5-FU resistance in CRC, whereas overexpression of AHNAK2 in HCT116/5-FU cells promoted resistance, both in vitro and in vivo. Mechanistically, AHNAK2 knockdown suppressed the expression of proteins such as PCNA, CDK4, p-AKT/AKT, and p-GSK-3β/GSK-3β, while enhancing the expression of cleaved caspase-3 and E-cadherin in LoVo/5-FU cells. Conversely, AHNAK2 overexpression in HCT116/5-FU cells produced the opposite effects. Collectively, these findings demonstrate that AHNAK2 reduces the chemosensitivity of CRC to 5-FU by activating the AKT/GSK-3β signaling pathway, underscoring its potential as a therapeutic target to improve CRC treatment strategies.</p>","PeriodicalId":10337,"journal":{"name":"Clinical and Experimental Medicine","volume":"25 1","pages":"168"},"PeriodicalIF":3.2,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12086122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}