Cancer Science最新文献

{"title":"Selinexor Reduces the Immunosuppression of Macrophages and Synergizes With CD19 CAR-T Cells Against B-Cell Lymphoma.","authors":"Wenjing Luo, Jia Xu, Chenggong Li, Lu Tang, Yingying Li, Xindi Wang, Zhuolin Wu, Yinqiang Zhang, Heng Mei, Yu Hu","doi":"10.1111/cas.70123","DOIUrl":"https://doi.org/10.1111/cas.70123","url":null,"abstract":"<p><p>CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved high response rates in patients with B-cell lymphoma. However, treatment failure and relapse can be attributable to CAR-T cell dysfunction and the immunosuppression of the tumor microenvironment. Combination therapy emerges as a solution strategy, and selinexor might be a potential candidate. In this study, we first established the ex vivo tumor microenvironment model by coculturing tumor cells and macrophages, followed by coculture with CAR-T cells, and identified that selinexor decreased CAR-T cell exhaustion and enhanced its cytotoxicity. Moreover, selinexor upregulated NGFR expression and boosted CAR-T cell proliferation. The ex vivo and in vivo results showed that selinexor prevented macrophages from polarizing to M2 populations. In the xenograft animal model, the sequential use of selinexor and CAR-T cells significantly reduced the tumor burden compared with selinexor or CAR-T cell monotherapies. In summary, our findings suggest that selinexor mitigates the immunosuppression of macrophages and improves CAR-T cell functionality, and the combination of selinexor and CAR-T cells may be a promising therapeutic strategy for B-cell lymphoma.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318427","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":"Engineered EVs-Mediated miR-222 Targeting PTEN/FN1 Axis Reverses Anthracycline Resistance in HER2-Negative Breast Cancer.","authors":"Sujin Yang, Mei Yang, Quanfeng Shao, Dandan Wang, Shanliang Zhong, Suyu Yang, Haiyan Gao, Xihu Qin, Weixian Chen","doi":"10.1111/cas.70118","DOIUrl":"https://doi.org/10.1111/cas.70118","url":null,"abstract":"<p><p>Anthracycline resistance represents a critical therapeutic challenge in breast cancer treatment, wherein alterations in the tumor immune microenvironment and enhanced cellular resistance mechanisms facilitate chemoresistance progression. Transcriptome analysis of 142 HER2-negative breast cancer patients undergoing anthracycline-based chemotherapy revealed four distinct tumor-infiltrating cell subtypes, with subtype D exhibiting elevated M1 macrophage infiltration and superior prognostic outcomes. Differential expression analysis identified miR-222 as the predominantly upregulated microRNA in adriamycin-resistant cells, while Tandem Mass Tag mass spectrometry-based quantitative analysis elucidated PTEN as its direct target and FN1 as a crucial downstream mediator. Engineered extracellular vesicles (EVs) carrying a miR-222 inhibitor were developed to reverse adriamycin resistance via PTEN/FN1 signaling modulation. Molecular docking analysis found specific PTEN-FN1 protein interactions characterized by stable hydrogen bonds at ARG142-ASP23 and ARG15-GLU95. In xenograft models, EVs-mediated delivery of the miR-222 inhibitor significantly attenuated MCF-7/ADR tumor progression through miR-222 suppression and PTEN restoration, with concordant molecular alterations observed in serum-derived EVs. Our findings establish a novel mechanism of EVs-mediated drug resistance through the microRNA-222/PTEN/FN1 axis and present Engineered EVs as a promising therapeutic strategy for anthracycline resistance in breast cancer, while highlighting circulating EVs profiles as potential treatment monitoring biomarkers.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276397","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":"Implication of KLHL Gene Family Member KLHL5 in Colorectal Cancer Progression and Prognosis.","authors":"Konomu Uno, Hirotada Nishie, Hiromi Hiyoshi, Kyosuke Habu, Jun Nakayama, Sota Tate, Tomohisa Sakaue, Eiji Kubota, Mamoru Tanaka, Takaya Shimura, Hiromi Kataoka, Takashi Joh, Shigeki Higashiyama","doi":"10.1111/cas.70107","DOIUrl":"https://doi.org/10.1111/cas.70107","url":null,"abstract":"<p><p>The KLHL gene family member KLHL5, which is a constituent factor of the RING E3 ubiquitin ligase complex, is expressed in various types of cancers and plays a role in cancer pathophysiology. In this study, we identified KLHL5 as a potential biomarker for predicting the prognosis of colorectal cancer (CRC) from 42 KLHL family genes using transcriptome profiles generated by RNA-seq analysis of The Cancer Genome Atlas colorectal adenocarcinoma (TCGA-COAD). We further investigated the implication of KLHL5 in CRC using pathological examination and bioinformatics analyses. Clinicopathological analyses revealed that KLHL5 was more highly expressed in CRC than in adjacent normal mucosa, and its expression level increased concomitantly with the CRC stage (p < 0.05). KLHL5 expression was associated with poor prognostic factors such as depth of invasion (p < 0.001), lymphovascular invasion (p = 0.029), and lymph node metastasis (p = 0.025). Notably, KLHL5 exhibited heterogeneous expression within the tumor, with pronounced expression observed at the invasive front of the tumor (p < 0.0001). Through bioinformatics analyses, we determined that elevated KLHL5 expression in CRC is significantly associated with poor prognosis. Furthermore, analysis from the Gene Expression Omnibus database indicated that KLHL5 expression was more pronounced in the common molecular subtype (CMS) 4 CRC, which is characterized as highly advanced, and the overall and recurrence-free survival rates were poor compared to other CMS groups. Our findings indicate that KLHL5 plays a pivotal role in the progression and development of CRC, and can be used as a potential biomarker and therapeutic target for CRC treatment.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144276398","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":"Gastric Signet Ring Cell Carcinoma in a Helicobacter pylori-Positive 10-Year-Old Boy: A Case Report and Literature Review.","authors":"Xiaoxuan Li, Xinchi Luan, Wenjuan Yu, Shibo Wang, Xiangxue Li, Lihua Zhang, Siyi Zhang, Jialin Song, Jing Guo, Shasha Wang, Wensheng Qiu, Jing Lv","doi":"10.1111/cas.70112","DOIUrl":"https://doi.org/10.1111/cas.70112","url":null,"abstract":"<p><p>Gastric cancer is rare in pediatric populations, with gastric signet ring cell carcinoma (GSRCC) being an exceptionally infrequent subtype. We report a case of GSRCC in a 10-year-old Chinese boy with no family history of cancer. The diagnosis was established via gastroscopy, endoscopic ultrasound, and imaging examinations. Early detection allowed a successful distal gastrectomy with D2 lymph node dissection. Postoperative whole-exome sequencing (WES) revealed no clinically significant mutations but identified some somatic alterations. Notably, gastric biopsy pathology demonstrated strong positivity for Helicobacter pylori (H. pylori) infection. Additionally, we comprehensively reviewed the existing pediatric GSRCC cases, suggesting the potential role of H. pylori infection in the pathogenesis of pediatric gastric cancer.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267693","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":"PC4 Potentially Predicts Chemoradiation-Induced Antitumor Immunity in Esophageal Squamous Cell Carcinoma.","authors":"Jieyong Tian, Xiaoying Wei, Huiquan Liu, Qingsong Pang, Dong Qian, Haiming Dai","doi":"10.1111/cas.70117","DOIUrl":"https://doi.org/10.1111/cas.70117","url":null,"abstract":"<p><p>Chemoradiotherapy (CRT) induces an antitumor immune response in esophageal squamous cell carcinoma (ESCC), and thereby has enormous potential by itself and in combination with immune checkpoint inhibitors (ICI). Our previous studies indicated that human positive cofactor 4 (PC4) was an independent predictor of poor survival in patients with ESCC or lung cancer who were treated with definitive chemoradiation, with a mechanism involving the enhancement of nonhomologous end joining (NHEJ)-mediated DNA repair. Due to the important role of double-strand DNA (dsDNA) in the antitumor immune response, the present study aims to investigate PC4 as a predictor of pathological response and antitumor immune response in ESCC patients who underwent neoadjuvant CRT. In ESCC, low PC4 expression levels have significant power to predict pCR. In particular, pCR is 61.2% in patients with low PC4 expression, but only 23.4% in patients with high PC4. Both disease-free survival (DFS) and overall survival (OS) are significantly longer for patients with low PC4 than for those with high PC4. In agreement with our previous finding that PC4 participates in NHEJ-mediated DNA repair, our further analysis indicates that the expression of PC4 is not only significantly negatively correlated with cyto-free dsDNA in postoperative specimens, but also with tumor-infiltrating CD8⁺T lymphocytes (CD8⁺TILs) and GZMB⁺CD8⁺TILs, suggesting a possible mechanism that high PC4 negatively regulates the antitumor response and therefore results in poor prognosis. Together, our findings demonstrate that low expression of PC4 is a potential biomarker for predicting the antitumor immune response to chemoradiation in patients with operable locally advanced ESCC.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259133","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":"Dauricine Overcomes Osimertinib Resistance in Lung Cancer by Inducing Ferroptosis via Stabilizing SAT1.","authors":"Biying Men, Zhijie Chen, Haotian Ge, Zhuoying Yang, Liang Yun, Jianjun Jiang, Meijuan Dian, Yujing He, Zehao Zhou, Ruihao Zhang, Tianbao Yan, Zichao Li, Yingxin Zhang, Yongjie He, Junming He, Xuguang Rao, Shuan Rao","doi":"10.1111/cas.70113","DOIUrl":"https://doi.org/10.1111/cas.70113","url":null,"abstract":"<p><p>Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) widely used to treat advanced nonsmall cell lung cancer (NSCLC) with EGFR mutations. However, resistance to osimertinib frequently develops, limiting its long-term effectiveness. In this study, we used osimertinib-resistant lung cancer cell lines and lung cancer patient-derived organoids to demonstrate the potential of dauricine, a bioactive compound derived from menispermum dauricum, to overcome osimertinib resistance in lung cancer cells. Mechanistic studies reveal that dauricine, when combined with osimertinib, efficiently induces ferroptosis in resistant lung cancer cells. Notably, RNA interference and pharmacological inhibition assays identify SAT1, a key enzyme involved in polyamine metabolism and oxidative stress regulation, as a critical mediator of the synergistic effects observed with the dauricine-osimertinib combination therapy. Furthermore, we show that dauricine can directly interact with and stabilize SAT1 to enhance its activity. In vivo, when administered with osimertinib, dauricine significantly suppresses tumor growth in osimertinib-resistant lung cancer models. These findings provide novel insights into the role of SAT1 in overcoming osimertinib resistance and suggest that combining dauricine with osimertinib could be a promising therapeutic strategy to improve the efficacy of EGFR-TKI therapy in resistant NSCLC.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250516","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 Role of Histone Methyltransferase SETDB1 in Normal and Malignant Hematopoiesis.","authors":"Yu-Hsuan Chang, Susumu Goyama","doi":"10.1111/cas.70116","DOIUrl":"https://doi.org/10.1111/cas.70116","url":null,"abstract":"<p><p>SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase, functioning in transcriptional silencing of the transposable elements (TEs), endogenous retroviruses (ERVs), interferon-stimulated genes (ISGs), and immune cell-related molecules. SETDB1 collaborates with cofactors such as ATF7IP and TRIM28 and functions in concert with DNA methylation to maintain gene repression in both stem cells and differentiated somatic cells. Given its gene targets, recent studies have shown that SETDB1 is a critical immune checkpoint gene in both solid and hematological tumors. In this review, we first discuss the role of SETDB1 in gene regulation through its histone methyltransferase activity, including an overview of its structural features and key cofactors. We then highlight the lineage-specific roles of SETDB1 in both normal hematopoietic processes and hematological malignancies, emphasizing its function as an immune checkpoint molecule that suppresses natural killer (NK) cell-mediated antileukemia responses.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144217349","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":"Genetic Profiling Reveals the Distinctions Among MTX-Associated DLBCL, EBV-Positive Mucocutaneous Ulcer, and EBV + DLBCL.","authors":"Takumi Takahashi, Keisuke Sawada, Takahisa Yamashita, Wataru Yamamoto, Yosuke Iijima, Akiko Adachi, Makoto Kashimura, Takayuki Tabayashi, Masahiro Kizaki, Takahiro Kaneko, Jun-Ichi Tamaru, Morihiro Higashi, Shuji Momose","doi":"10.1111/cas.70111","DOIUrl":"https://doi.org/10.1111/cas.70111","url":null,"abstract":"<p><p>The WHO recently changed the outline of immunodeficiency/dysregulation (IDD)-associated lymphoproliferative disorders (LPDs)/lymphomas from underlying IDD settings to an overarching framework and accommodates commonalities in histology, the involvement of various oncogenic viruses, and specific clinical/therapeutic consequences. A mutational analysis has been performed on post-transplantation and HIV-positive lymphomas, but not on other iatrogenic immunodeficiency (OII)-associated LPDs mainly caused by methotrexate (MTX) to treat rheumatoid arthritis. We herein conducted next-generation sequencing (NGS) to examine the genetic spectrum along with a fluorescence in situ hybridization analysis of 9p24.1 and PD-L1 expression in 37 MTX-associated diffuse large B-cell lymphoma (DLBCL) cases, 17 Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) cases, and 26 EBV-positive DLBCL (EBV + DLBCL) cases. Targeted NGS identified 177 mutations. The mutation frequency was significantly higher in EBV^- MTX-DLBCL than in EBV-positive LPDs/lymphomas (EBVMCU, EBV⁺ MTX-DLBCL, and EBV + DLBCL). Regrowth or resistance to spontaneous regression after MTX withdrawal was more likely in EBV^- MTX-DLBCL than in EBV⁺ MTX-DLBCL. Therefore, accumulated gene mutations, sustained by the restored immune status in EBV^- MTX-DLBCL, may affect clinical outcomes after MTX discontinuation. Several unique genetic findings were obtained for each category. Fewer TET2/DNMT3A and CD58 mutations in OII-LPD/lymphomas (EBVMCU and MTX-DLBCL) than in EBV + DLBCL indicate that clonal hematopoiesis and an immune evasion-related background contributed less to lymphomagenesis in OII-LPDs. MYD88^L265P/CD79B^Y196 mutations were only detected in EBV^- MTX-DLBCL. SOCS1 mutations were significantly more frequent in EBV-positive LPD/lymphoma categories, irrespective of the immune status, than in EBV^- MTX-DLBCL. These results reveal distinct genetic features among MTX-DLBCL (EBV+/-), EBVMCU, and EBV + DLBCL.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210007","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":"Landscape Analysis of CLDN18 Expression and Isoform Distribution in Solid Tumors: Insights From MONSTAR-SCREEN-2 Study.","authors":"Tadayoshi Hashimoto, Naoko Iida, Yoshiaki Nakamura, Norio Nonomura, Chigusa Morizane, Hiroji Iwata, Susumu Okano, Wataru Yamagami, Naoya Yamazaki, Shigenori Kadowaki, Makoto Ueno, Shogen Boku, Eiji Oki, Yoshito Komatsu, Satoshi Yuki, Akitaka Makiyama, Takatsugu Ogata, Naoki Takahashi, Naohiro Okano, Tomohiro Nishina, Naoya Sakamoto, Takeshi Kuwata, Riu Yamashita, Taro Shibuki, Mitsuho Imai, Takao Fujisawa, Hideaki Bando, Kohei Shitara, Takayuki Yoshino","doi":"10.1111/cas.70100","DOIUrl":"https://doi.org/10.1111/cas.70100","url":null,"abstract":"<p><p>Claudin 18.2 (CLDN18.2), a tight junction protein isoform, is an emerging therapeutic target in oncology. CLDN18 is well-characterized in gastric cancer, but its pan-cancer expression profiles and isoform distributions are poorly documented. In the present study, we analyzed CLDN18 expression in patients with solid tumors enrolled in the MONSTAR-SCREEN-2 study using immunohistochemistry (IHC, n = 349) and whole-transcriptome sequencing (WTS, n = 2191). A splice junction analysis algorithm characterized isoform distribution patterns in WTS data and evaluated temporal changes using paired pre- and postchemotherapy specimens. IHC detected CLDN18.2 (≥ 40% of tumor cells showing any staining intensity) in 16.3% of patients, with highest prevalence in gastric (54.5%), biliary tract (21.7%), pancreatic (20.7%), and small intestinal (18.2%) cancers. WTS and IHC findings were significantly correlated (p < 0.001). WTS analysis with optimized transcript thresholds (n = 2191) demonstrated the CLDN18-high population to be 13.8%, with highest proportions in gastric (64.5%), small intestinal (40.0%), pancreatic (37.8%), and biliary tract (20.0%) cancers. Isoform analysis of 364 patients revealed CLDN18.2 predominance (mean 18.2/18.1 proportion 0.945), with CLDN18.1 predominance observed in only 4.9% of patients. Longitudinal analysis of 27 paired gastric cancer samples revealed a significant reduction in CLDN18 expression and a nonsignificant decrease in the CLDN18.2 proportion following chemotherapy. This analysis validates WTS as a complementary approach to IHC for CLDN18 assessment and demonstrates significant CLDN18 expression across multiple cancer types. The predominance of CLDN18.2 supports the expansion of targeted therapeutic approaches beyond gastric cancer and indicates the potential of RNA-based screening.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210008","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":"ACSM5 Regulates Ferroptosis in Hepatocellular Carcinoma by Up-Regulating POR and Modulating Lipid Metabolism.","authors":"Zhengqiang Wu, Xiaofeng Xiong, Mingyi Dong, Linfei Luo, Zixiang Huang, Kedong Xu, Lianwu Zhao, Fenfen Wang, Zhili Wen","doi":"10.1111/cas.70115","DOIUrl":"https://doi.org/10.1111/cas.70115","url":null,"abstract":"<p><p>The medium-chain fatty acyl-CoA synthetase-5 (ACSM5) plays a crucial role in the development of some cancers. However, its impact on liver cancer is still not clear. In this study, we found that the proliferation ability of LM3 and HepG2 cells was significantly inhibited after ACSM5 was overexpressed, and this change was blocked by the ferroptosis inhibitor deferoxamine. ACSM5 increased the levels of malondialdehyde (MDA) and lipid reactive oxygen species (ROS), reduced the level of glutathione (GSH), and thus triggered ferroptosis. Furthermore, ACSM5 promoted the upregulation of cytochrome P450 oxidoreductase (POR). Knocking down POR blocked the promoting effect of ACSM5 on ferroptosis in HCC. Moreover, ACSM5 promoted the generation of arachidonic acid and thus increased the sensitivity to ferroptosis. In summary, our findings indicate that ACSM5 induces ferroptosis in hepatocellular carcinoma (HCC) by upregulating POR. The metabolic transformation of linoleic acid to arachidonic acid was also promoted by ACSM5; therefore, sensitivity to ferroptosis was increased.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144210006","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}