Cellular Oncology最新文献

{"title":"OTUD1-mediated deubiquitination stabilizes SLC7A11 to suppress ferroptosis in hepatocellular carcinoma.","authors":"Runtian Li, Huanye Mo, Lei Zhang, Qingguang Liu, Kangsheng Tu","doi":"10.1007/s13402-026-01282-7","DOIUrl":"10.1007/s13402-026-01282-7","url":null,"abstract":"<p><strong>Background: </strong>Evasion of ferroptosis has been increasingly recognized as an important mechanism underlying lenvatinib resistance in hepatocellular carcinoma (HCC). However, the roles of deubiquitinating enzymes in ferroptosis regulation and the post-translational control of key ferroptosis regulators in HCC remain poorly understood.</p><p><strong>Methods: </strong>Public lenvatinib resistance-related and ferroptosis-related datasets were analyzed to identify candidate deubiquitinating enzymes associated with HCC therapeutic resistance and ferroptotic stress. Loss- and gain-of-function assays were performed to evaluate the effects of OTUD1 on lenvatinib sensitivity, erastin-induced ferroptosis, and HCC cell growth. Subcutaneous xenograft and orthotopic tumor models were used to assess the role of OTUD1 in tumor growth and ferroptosis resistance in vivo. Western blotting, RT-qPCR, co-immunoprecipitation, cycloheximide chase, MG132 rescue, ubiquitination, SLC7A11 rescue, and ERK1/2 pathway modulation assays were conducted to investigate the underlying mechanism. Clinical HCC specimens and public datasets were analyzed to determine OTUD1 expression and its association with patient prognosis.</p><p><strong>Results: </strong>OTUD1 was identified as a gene associated with lenvatinib resistance in HCC. Knockdown of OTUD1 sensitized HCC cells to lenvatinib, and this effect was abolished by ferroptosis inhibition. OTUD1 knockdown enhanced ferroptosis in HCC cells, whereas OTUD1 overexpression suppressed it. Moreover, OTUD1 promoted HCC growth and conferred ferroptosis resistance in mice. Mechanistically, OTUD1 interacted with solute carrier family 7 member 11 (SLC7A11) and removed its K48-linked polyubiquitin chains, thereby stabilizing SLC7A11 protein levels. In addition, ERK1/2-dependent phosphorylation of OTUD1 at Ser216 strengthened its interaction with SLC7A11, further enhancing SLC7A11 stability and promoting ferroptosis resistance. Analysis of clinical samples and public datasets further revealed that OTUD1 was upregulated in HCC tissues and correlated with poor prognosis.</p><p><strong>Conclusions: </strong>Our findings identify the ERK1/2-OTUD1-SLC7A11 axis as a key mechanism mediating ferroptosis resistance in HCC. These results suggest that OTUD1 may serve as a potential therapeutic target for HCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 5","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13615280/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting RPRD1B overcomes chemoresistance in gastric cancer by suppressing the TOPBP1-mediated DNA damage repair pathway.","authors":"Jian Sheng, Jianghua Li, Chenxi Cao, Xiaorong Liu, Chunhua He, Mingjian Fei, Bin Wu, Xiangli Li, Chundong Hu, Shumin Liu, Yahui Lv","doi":"10.1007/s13402-026-01227-0","DOIUrl":"10.1007/s13402-026-01227-0","url":null,"abstract":"<p><strong>Background: </strong>Despite the widespread adoption of 5-fluorouracil (5-FU)-based regimens as first-line therapy for gastric cancer, a substantial number of patients develop innate or acquired resistance, highlighting the critical need to identify its underlying molecular drivers. RPRD1B (CREPT), a gene frequently overexpressed in GC, has been clinically associated with advanced tumor stage and poor prognosis. Functionally, RPRD1B promotes aggressive tumorigenic phenotypes by accelerating cell-cycle progression, potentiating proliferative signaling, and enhancing the migratory and invasive capacities of cancer cells. However, its functional role in mediating chemotherapy resistance has not been elucidated.</p><p><strong>Methods: </strong>We established 5-FU-resistant gastric cancer cell lines (from AGS/MGC803 parents via stepwise drug exposure) to study RPRD1B's mechanism, and developed an AAV-based system to therapeutically target RPRD1B to overcome 5-FU resistance.</p><p><strong>Results: </strong>In this study, we demonstrated that GC patients with high tumor expression of RPRD1B (CREPT) exhibited a poor response to 5-fluorouracil (5-FU)-based chemotherapy. Furthermore, RPRD1B expression was positively correlated with the expression of TOPBP1, a critical DNA damage response and repair effector. Mechanistically, RPRD1B transcriptionally upregulates TOPBP1 by recruiting RNA polymerase II to its promoter, thereby enhancing DNA damage repair. Using an AAV-delivered shRNA to knockdown RPRD1B in a nude mouse xenograft model, we effectively overcame 5-FU resistance in gastric tumors in vivo.</p><p><strong>Conclusions: </strong>Our findings identify RPRD1B as a promising therapeutic target for reversing chemoresistance in gastric cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":"49 3","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148653005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA-binding protein RALYL-mediated BCL11B RNA stability promotes immune escape in small cell lung cancer through transcriptional activation of BUB3.","authors":"Jiayue Shao, Shuangqing Liu, Ling Qin, Ningning Fan, Qi Sun, Qingwei Meng","doi":"10.1007/s13402-026-01261-y","DOIUrl":"10.1007/s13402-026-01261-y","url":null,"abstract":"<p><strong>Purpose: </strong>Small cell lung cancer (SCLC) is marked by rapid tumor growth and poor outcomes and necessitates effective treatments. This paper explores the molecular mechanisms by which BCL11B affects immune escape in SCLC.</p><p><strong>Methods: </strong>Clinical tissues were collected to analyze BCL11B expression in SCLC, and the correlations between BCL11B and prognosis were examined. A co-culture system of SCLC and T cells was constructed to analyze immune escape. A transplanted tumor model was constructed, and the efficacy of PD-L1 immunotherapy was analyzed after BCL11B knockdown. The downstream targets of BCL11B were screened by bioinformatics, and BUB3 expression was verified in clinical tissues. The regulation of BCL11B on BUB3 was examined. Rescue assays were designed to analyze immune escape and tumor immunotherapy after BUB3 overexpression. RNA-binding proteins that regulated BCL11B were predicted, and their expression and prognostic significance in SCLC were analyzed. The effect of RALYL on immune escape was validated in vitro.</p><p><strong>Results: </strong>BCL11B was notably increased in SCLC tissues and was associated with poor prognoses. BCL11B knockdown repressed SCLC cells from CD8⁺ T-mediated cytotoxicity, enhanced the efficacy of PD-L1 immunotherapy, and blocked SCLC progression. BCL11B transcriptionally activated BUB3 and enhanced PD-L1 expression. BUB3 overexpression reversed the impact of BCL11B knockdown on immune escape and the efficacy of immunotherapy. RALYL increased BCL11B mRNA stability to activate BUB3 and enhance PD-L1 expression. RALYL knockdown prevented immune escape in SCLC cells.</p><p><strong>Conclusion: </strong>RALYL increases BCL11B stability and activates BUB3 to induce immune escape in SCLC by enhancing PD-L1 expression.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative machine learning reveals a TLS signature and CCL5-CCR1 axis-associated immune remodeling in breast cancer.","authors":"Chuyi Wang, Pengcheng Ding, Wei Ouyang, Yunhai Ding, Meilin Lu, Tianyi Li, Yunxing Xu, Liangfeng Zheng, Kai Chen, Feiyue Ji, Min Dai, Guiyuan Gu, Xiaomin Lu","doi":"10.1007/s13402-026-01264-9","DOIUrl":"10.1007/s13402-026-01264-9","url":null,"abstract":"<p><strong>Background: </strong>The transition from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) is a critical but poorly understood step in breast cancer progression. This study characterizes the dynamic remodeling of the tumor microenvironment (TME) during this transition, focusing on tertiary lymphoid structures (TLS) and chemokine signaling.</p><p><strong>Methods: </strong>Using an integrated multi-omics approach-including multiplex immunofluorescence of a clinical cohort, public single-cell and spatial transcriptomics data, and a longitudinal syngeneic mouse model (EO771)-we investigated spatiotemporal TME evolution.</p><p><strong>Results: </strong>Our findings reveal that TLS reorganization during the DCIS-to-IDC shift is closely associated with the CCL5-CCR1 axis, which is implicated in macrophage-CD8⁺ T cell interactions and correlates with terminal T-cell exhaustion. Longitudinal modeling confirmed CCL5 network dysregulation alongside progressive CD8⁺ T cell dysfunction. Through an integrative machine-learning framework, we developed a robust 21-gene TLS signature that independently predicted patient outcomes in multiple cohorts, even after adjusting for clinical confounders. Finally, molecular docking identified cucurbitacin derivatives as candidate compounds nominated by exploratory in silico analysis targeting the CCL5 network.</p><p><strong>Conclusions: </strong>This work highlights CCL5-CCR1 axis-related TLS dysregulation as a key spatiotemporal feature of invasion, provides a clinically applicable prognostic signature for early risk stratification, and nominates actionable targets to intercept invasive progression.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13650226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of DLX6 sensitizes lung adenocarcinoma to cisplatin via GPX4-dependent ferroptosis.","authors":"Zedong Sun, Minmin Zhou, Can Wang, Mingrui Liu, Ningdan Song, Simian He, Feifan Ji, Jiayu Chen, Lin Xu, Xiufen Zheng, Binhui Ren","doi":"10.1007/s13402-026-01263-w","DOIUrl":"10.1007/s13402-026-01263-w","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality worldwide, with limited treatment options due to inherent chemotherapy resistance. Ferroptosis, an iron-dependent form of regulated cell death, has recently emerged as a promising strategy to overcome this resistance. Inducing ferroptosis may sensitize LUAD cells to chemotherapy, but its molecular regulators and therapeutic potential remain largely unexplored. This study aims to investigate the role of Distal-less homeobox 6 (DLX6) in regulating ferroptosis and its contribution to LUAD progression.</p><p><strong>Methods: </strong>To elucidate the function of DLX6 in LUAD, we employed a multi-omics approach, integrating TCGA data analysis, in vitro cell culture models, and in vivo xenograft experiments. Transcriptome sequencing, chromatin immunoprecipitation (ChIP) assays, and dual-luciferase reporter assays were utilized to uncover the underlying molecular mechanisms.</p><p><strong>Results: </strong>We found that DLX6 is significantly upregulated in LUAD and associated with poor patient prognosis. Functional studies showed that silencing DLX6 suppressed cell proliferation, triggered ferroptosis, and sensitized LUAD cells to chemotherapy. Mechanistically, DLX6 acted as a transcriptional activator of Glutathione Peroxidase 4 (GPX4), a central regulator of ferroptosis, by directly binding to its promoter region. Inhibition of DLX6 triggered ferroptosis in LUAD cells, enhancing treatment sensitivity to cisplatin.</p><p><strong>Conclusions: </strong>Our findings highlight DLX6 as a key regulator of ferroptosis and cisplatin sensitivity in LUAD. By promoting GPX4 expression and inhibiting ferroptosis, DLX6 plays a crucial role in LUAD progression. This study provides valuable insights into the molecular mechanisms driving LUAD and offers a potential therapeutic target for sensitizing cisplatin treatment and improving chemotherapy resistance.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13654923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monomethyl phthalate promotes hepatocellular carcinoma progression through MMP9 upregulation.","authors":"Tianming Liu, Yong Yang","doi":"10.1007/s13402-026-01265-8","DOIUrl":"https://doi.org/10.1007/s13402-026-01265-8","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) is recognized as the third leading cause of cancer-related death worldwide, and its epidemiological features are shifting from viral to non-viral etiologies. Phthalates (PAEs) are widely used plastic additives and major indoor environmental pollutants. Monomethyl phthalate (MMP), the primary hepatic metabolite of dimethyl phthalate, possesses endocrine-disrupting and immunosuppressive properties; however, whether a causal association exists between MMP and HCC remains unclear. Two-sample Mendelian randomization (MR) analysis with stringent instrumental variable selection criteria was performed to explore the association between MMP exposure and HCC. In addition, network toxicology, molecular docking, molecular dynamics simulations, together with TCGA database-based differential expression and survival analyses were conducted to identify core targets through which MMP promotes HCC. The specific mechanisms by which MMP facilitates HCC progression were investigated using CCK-8 assays, wound healing assays, and Western blot. MR analysis provided preliminary genetic evidence for a positive association between MMP exposure and elevated HCC risk, with no significant heterogeneity or horizontal pleiotropy detected. MMP promoted the proliferation and migration of HuH-7 cells in a dose-dependent manner. Six core targets were further identified, among which MMP9 was highly expressed in HCC and associated with poor prognosis. Inhibition of MMP9 significantly reversed the MMP-induced pro-carcinogenic effects, indicating that MMP promotes HCC by upregulating MMP9 expression. This study is the first to demonstrate that MMP contributes to HCC pathogenesis through the upregulation of MMP9, providing a novel biomarker and therapeutic target for HCC prevention and environmental risk control.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419180","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":"RNF114-PACSIN3 signaling axis promotes hepatocellular carcinoma progression by enhancing GLUT1 membrane retention and glucose uptake.","authors":"Yue Song, Yilu Lu, Qixiang Liu, Lan Yin, Wen Zheng, Ge Liang, Xinyi Hu, Xinyu Lin, You Zhang, Yongxin Ma","doi":"10.1007/s13402-026-01259-6","DOIUrl":"10.1007/s13402-026-01259-6","url":null,"abstract":"<p><strong>Purpose: </strong>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, with current therapies often limited by significant drug resistance. Owing to the Warburg effect, targeting cancer-specific metabolic vulnerabilities is a promising therapeutic strategy. This study aims to investigate the role of RNF114 in HCC progression and its regulatory mechanism, as well as its clinical translational potential as a therapeutic target.</p><p><strong>Methods: </strong>We evaluated the clinical significance of RNF114 using tissue microarrays and database analysis. RNF114 function in promoting HCC progression by regulating glucose uptake was investigated using knockdown experiments in cell lines and subcutaneous xenograft models. Furthermore, a therapeutic xenograft model was employed to assess the potential of RNF114 knockdown in overcoming Sorafenib resistance.</p><p><strong>Results: </strong>RNF114 was highly expressed in HCC and correlated with poor prognosis. Knockdown of RNF114 significantly suppressed HCC cell proliferation, migration, invasion, and glycolysis. Co-immunoprecipitation identified PACSIN3 as a key substrate of RNF114. RNF114 interacted with the SH3 domain of PACSIN3, promoting its ubiquitination and proteasomal degradation. Subcellular fractionation revealed that the F-BAR domain of PACSIN3 facilitated GLUT1 vesicular trafficking. Consequently, RNF114 impaired this process, leading to increased plasma membrane retention of GLUT1 and enhanced glycolytic flux. Consistently, in both HCC cells and subcutaneous xenograft models, RNF114 knockdown sensitized tumors to Sorafenib treatment.</p><p><strong>Conclusions: </strong>Collectively, our findings reveal that the RNF114-PACSIN3-GLUT1 axis regulates glucose uptake and metabolic reprogramming in HCC, thereby promoting tumor progression and contributing to therapy resistance. Targeting this signaling axis provides a novel insight into metabolic therapy for HCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13638890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNF149/RBM25/MYC/PD-L1 axis promotes CD8⁺ T cell dysfunction in microenvironment of clear cell renal cell carcinoma.","authors":"Xuefei Liu, Xingming Qu, Yuanhua Zou, Yu Chen","doi":"10.1007/s13402-026-01262-x","DOIUrl":"10.1007/s13402-026-01262-x","url":null,"abstract":"<p><strong>Background: </strong>Renal cell carcinoma (RCC) is a common kidney cancer, and clear cell RCC (ccRCC) represents the most common pathological type. CD8⁺ T cells are the most primary killing cells in tumor microenvironment (TME). Ring finger protein 149 (RNF149) played tumor-promoting roles in several tumors, and its roles in ccRCC remained unclear. This study aims to investigate the role of RNF149 in ccRCC.</p><p><strong>Methods: </strong>The expression of RNF149 in clinical ccRCC specimens was determined with western blot and immunohistochemistry staining, and the overexpression or knockdown of RNF149 in ccRCC cells were realized via lentivirus infection. CD8⁺ T cells were co-cultured with tumor cells, and the exhaustion-associated markers were assessed with ELISA and flow cytometry. Xenograft experiment was performed in wild type and nude mice to measure the CD8⁺ T cell infiltration in tumors.</p><p><strong>Results: </strong>RNF149 was upregulated in ccRCC specimens, compared with the para-carcinoma normal kidney tissues, and its expression was associated with tumor size and TNM stage. Gain- and loss-of-function experiments revealed that RNF149 promoted the colony formation, and inhibited apoptosis of ccRCC cells, in the presence of co-culture with CD8⁺ T cells. The RNF149-overexpressed ccRCC induced CD8⁺ T cells an exhaustion-associated phenotype, evidenced by the decreased production of interferon-γ, tumor necrosis factor-α, granzyme B and perforin-1, and the expression of PD-1, lymphocyte activating 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3) and T cell immunoreceptor with Ig and ITIM domain (TIGIT). Xenograft experiments displayed that knockdown of RNF149 delayed tumorigenesis of ccRCC cells in wild type mice, and accelerated CD8⁺ T cell infiltration in tumors. As an E3 ligase, RNF149 bound to RNA binding motif protein 25 (RBM25), and mediated its ubiquitination and degradation. RNF149 facilitated programmed cell death 1 ligand 1 (PD-L1) expression by destabilizing RBM25 and promoting MYC transcription activity.</p><p><strong>Conclusion: </strong>RNF149 promoted ccRCC growth in vivo and in vitro, and induced CD8⁺ T cells an exhaustion-associated phenotype in TME by catalyzing RBM25 ubiquitination and activating PD-L1 transcription. These findings may provide novel insights for clinical immunotherapy of ccRCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419104","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":"PDIA6 exacerbates hepatocellular carcinoma via enhancing proteasome-dependent degradation of AKAP12.","authors":"Rucheng Yao, Yuhan Yin, Xiaosong Li, Xinyu Yang, Wenzhi He, Yufeng Yuan, Jun Hu","doi":"10.1007/s13402-026-01258-7","DOIUrl":"10.1007/s13402-026-01258-7","url":null,"abstract":"<p><p>The continuously rising incidence and persistently high mortality of hepatocellular carcinoma (HCC) have created an urgent need for a deeper understanding of the molecular mechanisms underlying this disease. In the present study, leveraging multiple HCC transcriptome databases, we employed expression analysis, correlation analysis, Gene Set Variation Analysis (GSVA), and cox regression analysis to identify that aberrant upregulation of PDIA6 represents a promising prognostic biomarker associated with adverse clinical outcomes in HCC. Using a series of in vitro oncology research approaches, as well as nude mouse models of subcutaneous tumor formation and lung metastasis, we experimentally validated that PDIA6 promotes the proliferation and metastasis of HCC cells. Through transcriptome sequencing analysis and subsequent rescue experiments, we further confirmed that PDIA6 enhances HCC cell proliferation and migration by activating the Wnt signaling pathway. Combined analysis via immunoprecipitation-mass spectrometry and proteomics revealed that PDIA6 significantly downregulates the expression of the tumor suppressor gene AKAP12. Subsequent rescue experiments demonstrated that PDIA6 drives HCC progression in a manner dependent on the reduced expression of AKAP12. Utilizing protein half-life assays, ubiquitination assays, and co-IP experiments, we uncovered the underlying mechanism: PDIA6 competitively binds to the UCH domain of USP24, which impairs the deubiquitinating activity of USP24 towards AKAP12. This ultimately leads to enhanced K48-linked ubiquitination of AKAP12 and its subsequent proteasomal degradation. We further verified, using specific activators, that AKAP12 inhibits the Wnt signaling pathway in a PKA-dependent manner. In vivo, targeted inhibition of PDIA6 exhibited a more potent therapeutic effect on Wnt-positive HCC tumors.Conclusion Collectively, our study demonstrates the HCC-promoting mechanism of the PDIA6-AKAP12-Wnt signaling axis and highlights its great potential for the development of therapeutic targets in HCC.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410511","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactylation shields S100A11 from degradation to promote gastric cancer metastasis.","authors":"Qingrui Zhang, Yuhang Zhou, Fangning Wang, Jingrui Yan, Jiayu Liu, Lin Zhang, Shiyu Du","doi":"10.1007/s13402-026-01255-w","DOIUrl":"10.1007/s13402-026-01255-w","url":null,"abstract":"<p><strong>Background: </strong>Protein lactylation, a novel post-translational modification utilizing lactate as the substrate, has emerged as a key mechanism linking metabolic alterations to cancer progression. This study aims to investigate the role and underlying mechanism of S100A11 lactylation in gastric cancer progression and metastasis.</p><p><strong>Methods: </strong>Lactylome profiling, site-directed mutagenesis, co-IP, cycloheximide chase, ubiquitination assays, and in vitro/in vivo functional experiments were performed to dissect the regulatory effect of S100A11 lactylation.</p><p><strong>Results: </strong>S100A11 was identified as a hyperlactylated protein in gastric cancer tissues, with lysine 27 (K27) and lysine 55 (K55) serving as the primary modification sites. Mechanistically, lactylation at K27 and K55 disrupted the interaction between S100A11 and its E3 ubiquitin ligase FBXW11, thereby inhibiting polyubiquitination and proteasomal degradation of the protein. The K27R/K55R double mutation, which abolished both lactylation and ubiquitination at these residues, resulted in constitutive stabilization of S100A11. The stabilized S100A11 hyperactivated the PI3K-AKT and ERK1/2 signaling cascades and upregulated the downstream oncogenic effectors Cyclin D1 and c-Myc. Functionally, S100A11 stabilization significantly enhanced the proliferation, colony formation, migration and invasion of gastric cancer cells in vitro, and markedly promoted lung metastasis in vivo. Clinically, higher lactylation levels of S100A11 were observed in patients with advanced TNM stages.</p><p><strong>Conclusion: </strong>This study reveals a lactylation-ubiquitination competitive regulatory mechanism that governs S100A11 protein stability, which directly links Warburg effect-derived lactate to oncogenic protein stabilization and metastatic progression in gastric cancer.</p>","PeriodicalId":9690,"journal":{"name":"Cellular Oncology","volume":" ","pages":""},"PeriodicalIF":4.8,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}