Apoptosis最新文献

{"title":"The GPX1-OSBPL8 axis: integrating ER ferroptosis and apoptotic signaling","authors":"Renin Chang,&nbsp;Chen-Yueh Wen,&nbsp;Su-Boon Yong,&nbsp;Chia-Jung Li","doi":"10.1007/s10495-026-02355-6","DOIUrl":"10.1007/s10495-026-02355-6","url":null,"abstract":"<div><p>The classification of regulated cell death (RCD) has evolved from discrete, siloed pathways into an integrated network of metabolic and proteostatic checkpoints. For over a decade, the glutathione peroxidase 4 (GPX4)-dependent neutralization of lipid hydroperoxides on the plasma membrane was considered the primary defense against ferroptosis. However, the landmark discovery by Xia et al. [1] in <i>Cell</i> has identified a “non-canonical” ferroptosis pathway governed by the GPX1-OSBPL8 axis, which operates specifically at the endoplasmic reticulum (ER). By elucidating how the lipid transfer protein OSBPL8 recruits GPX1 to reduce peroxidized phosphatidic acid (PA-OOH), this research provides a definitive organelle-specific mechanism for lipid-driven cell death. For the field of apoptosis, this discovery is pivotal: it positions the ER as a central decision-making hub where ferroptotic lipid damage converges with intrinsic apoptotic signals via ER stress, the Unfolded Protein Response (UPR), and unregulated calcium dynamics. This commentary evaluates the mechanistic underpinnings of this non-canonical axis and explores the synergistic potential of targeting ER-localized death programs in oncology.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 6","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic insights into ferroptosis in thyroid cancer and its therapeutic implications","authors":"Wenjie Chen,&nbsp;Xingyue Lai","doi":"10.1007/s10495-026-02322-1","DOIUrl":"10.1007/s10495-026-02322-1","url":null,"abstract":"<div><p>Thyroid cancer (TC), the most common endocrine malignancy, presents significant clinical challenges due to the risk of recurrence, metastasis, and treatment resistance, particularly in advanced cases. Driven by lipid peroxidation, ferroptosis is an iron-dependent, regulated cell death pathway increasingly implicated in cancer biology. This review comprehensively summarizes the mechanistic basis of ferroptosis, encompassing iron metabolism, amino acid regulation, lipid peroxidation, and key regulators such as p53, Nrf2, heat shock proteins and its specific implications in thyroid cancer. This study delineates the contribution of both coding and non-coding ferroptosis-related genes as critical modulators of thyroid cancer progression, thereby influencing patient prognosis. The interplay between ferroptosis and the tumor immune microenvironment is also discussed, emphasizing how immune cells like CD8( +)T cells and macrophages influence and respond to ferroptotic signals. Furthermore, we explore the therapeutic potential of targeting ferroptosis using both natural compounds and synthetic agents, which have shown promise in inducing ferroptosis and suppressing tumor growth in preclinical models. Notably, emerging evidence suggests that activating ferroptosis may help overcome radioiodine resistance and improve survival outcomes, particularly in aggressive subtypes such as anaplastic thyroid cancer (ATC). Therefore, the exploitation of ferroptosis offers a promising avenue to address therapeutic resistance and improve prognosis in thyroid cancer, which merits further clinical investigation.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925798","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic ecosystems of tumor drug resistance mechanisms: from molecular heterogeneity to systemic interventions","authors":"Qiaohong Bao,&nbsp;Hang Chen,&nbsp;Jiali Wu,&nbsp;Yahui Wang,&nbsp;Xinmei Chen,&nbsp;Zhizhe Lin,&nbsp;Youfa Xu,&nbsp;Jianming Chen","doi":"10.1007/s10495-026-02347-6","DOIUrl":"10.1007/s10495-026-02347-6","url":null,"abstract":"<div><p>Tumor drug resistance remains a significant challenge in the failure of cancer treatments, rooted in the complex dynamic adaptive evolution of tumors within the triad of “cell-microenvironment-host.” Previous research methodologies have often concentrated on single-level mechanisms, such as gene mutations or alterations in specific signaling pathways, while neglecting the intricate interactions among tumors, their microenvironments, and the host. This paper proposes a novel theoretical framework—the “Dynamic Ecosystem of Tumor Resistance”—which integrates three levels: intrinsic tumor cell heterogeneity and plasticity, microenvironment interactions, and host systemic regulatory factors. The objective is to systematically explore key resistance mechanisms and their dynamic interactions across these levels, thereby elucidating the complex nature of resistance. This framework aims to stimulate further research into therapeutic strategies targeting tumor resistance and to provide novel insights for the development of clinical approaches to treating malignant tumors.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis, orchestrated by GPX4 downregulation, serves as a critical mediator of neutrophil extracellular trap-driven pathology in hypoxic pulmonary edema","authors":"Yanli Sun,&nbsp;Xiaolong Shu,&nbsp;Hongrui Yuan,&nbsp;Boyi Qin,&nbsp;Fei Guo","doi":"10.1007/s10495-026-02331-0","DOIUrl":"10.1007/s10495-026-02331-0","url":null,"abstract":"<div><p>This study explores the contribution of ferroptosis, a tightly regulated form of cell death, to the development of high-altitude pulmonary edema (HAPE) under hypoxic conditions. We focused on the central ferroptosis regulator glutathione peroxidase 4 (GPX4) and its interaction with neutrophil extracellular trap (NET) formation. Utilizing a murine model of high-altitude hypoxia and in vitro hypoxia/reoxygenation models, we employed a multi-omics approach to map the molecular landscape of HAPE. Transcriptomic and metabolomic analyses of lung tissues confirmed a significant downregulation of GPX4 and a marked activation of ferroptosis-related pathways. Single-cell RNA sequencing identified pulmonary endothelial cells as a key site for this dysregulation, showing decreased GPX4 alongside upregulation of pro-ferroptotic factors. Functional validation demonstrated that GPX4 deficiency in human pulmonary microvascular endothelial cells exacerbated reactive oxygen species accumulation, ferroptosis, and subsequent NET formation. Conversely, GPX4 overexpression effectively mitigated these cytotoxic effects. Furthermore, we elucidated that GPX4 modulates NET formation through key signaling pathways, including Nrf2 nuclear translocation, ERK1/2 and NF-κB phosphorylation, and the HMGB1-TLR4/MyD88 axis. In vivo, therapeutic augmentation of GPX4 levels attenuated pulmonary edema, improved lung function, and suppressed markers of both ferroptosis and NETosis. Our findings establish a novel pathogenic cascade in HAPE where hypoxia-induced GPX4 suppression promotes ferroptotic cell death, which in turn drives NET-associated inflammation, identifying GPX4 as a critical therapeutic target for preventing this condition.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div><div><p>Under high-altitude hypoxia, ROS-mediated GPX4 signaling regulates ferroptosis to drive NET formation, ultimately contributing to the development of pulmonary edema.</p></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147872749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy-lysosomal dependency defines a vulnerable physiological state in drug-tolerant persister cells of triple-negative breast cancer","authors":"Essha Chatterjee,&nbsp;Biswajit Dey,&nbsp;Anamika Sharma,&nbsp;Anil Dharavath,&nbsp;Aliva Naik,&nbsp;Hoshiyar Singh,&nbsp;Santanu Basak,&nbsp;Bhavna Pratyusha,&nbsp;Vigneshwar Reddy Ashireddygari,&nbsp;Prasad Tammineni,&nbsp;Harikrishna Adicherla,&nbsp;Ira Bhatnagar,&nbsp;Nandkumar Doijad,&nbsp;Rahul Kumar,&nbsp;Santosh Kumar Guru","doi":"10.1007/s10495-026-02310-5","DOIUrl":"10.1007/s10495-026-02310-5","url":null,"abstract":"<div><p>Triple-negative breast cancer (TNBC), a subtype of aggressive breast cancer, has limited treatment options. Recurrent disease caused by drug-tolerant persister cells (DTPs) that evade chemotherapeutic agents (e.g., doxorubicin hydrochloride (DOX) and paclitaxel (PTX)) is a significant challenge in treating TNBC. Recent studies highlight both autophagy and lysosomal function as key mechanisms supporting cancer cell survival; however, their precise roles in mediating drug tolerance in TNBC remain largely unexplored. This study aimed to elucidate the mechanisms by which autophagic and lysosomal activities support the survival of TNBC DTPs following exposure to DOX and PTX. Compared with parental cells in both 2D and 3D cellular topologies, our results showed that treatment with DOX and PTX produced a fraction of latent DTPs that exhibited increased autophagic induction and improved lysosomal protein expression. The results revealed that pharmacological inhibition of autophagy (hydroxychloroquine) or lysosomal activity (bafilomycin A1) compromised DTPs’ survival. Similarly, disrupting lysosomal integrity with L-leucyl-L-leucine methyl ester (LLOME) decreased DTPs’ viability. Additionally, knockdown of the lysosomal protein <i>LAMP1</i> (lysosomal-associated membrane protein 1) significantly reduced persister cells’ viability and enhanced the cytotoxic effects of DOX and PTX. In a xenograft model, depleting LAMP1 in TNBC cells slowed tumor proliferation and delayed tumor initiation. Our results demonstrated that increased autophagy-lysosomal process renders DTP cell survival in TNBC by maintaining mitochondrial reactive oxygen species (mROS) generation, which, in turn, contributes to chemotherapy resistance. A potential treatment strategy for eradicating DTP cells and preventing tumor recurrence in TNBC involves targeting these mechanisms.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota-tryptophan-serotonin axis drives anxiety-like behavior via NLRP3-mediated neuronal pyroptosis in the medial prefrontal cortex","authors":"Guiqiang Zhou,&nbsp;Xing Wang,&nbsp;Tongzhou Qin,&nbsp;Ling Guo,&nbsp;Jiajin Lin,&nbsp;Zhaowen Zhang,&nbsp;Peng Gao,&nbsp;Yan Zhou,&nbsp;Wei He,&nbsp;Jing Li,&nbsp;Guirong Ding","doi":"10.1007/s10495-026-02356-5","DOIUrl":"10.1007/s10495-026-02356-5","url":null,"abstract":"<div><p>The gut–brain axis plays a critical role in anxiety disorders, yet the underlying mechanisms remain incompletely understood. Using a mouse model of radiofrequency radiation (RFR)-induced anxiety-like behaviors, we employed gut microbiota intervention, regulation of tryptophan metabolites, and other methods to investigate the impact of the gut–brain axis on brain function changes. It was found that gut microbiota dysbiosis disrupts tryptophan metabolism, leading to reduced serotonin (5-HT) levels and NLRP3 inflammasome-mediated neuronal pyroptosis in the medial prefrontal cortex (mPFC). Probiotic intervention restored microbial homeostasis, normalized central 5-HT metabolism, suppressed neuronal pyroptosis, and partially alleviated anxiety-like behaviors. Similarly, treatment with the selective serotonin reuptake inhibitor (SSRI) paroxetine increased brain 5-HT, attenuated NLRP3 activation and pyroptosis, and improved behavioral outcomes. These findings reveal that perturbations in gut–brain tryptophan metabolism are strongly correlated with anxiety-like behaviors via neuroinflammatory pyroptotic pathways, offering new mechanistic insights and potential therapeutic targets for anxiety disorders.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div><div><p>After exposure to radiofrequency radiation, the gut microbiota of mice became disrupted, leading to impaired tryptophan metabolism in the intestines, resulting in the accumulation of tryptophan and a reduction in its secondary metabolites. This caused a decrease in the levels of tryptophan and its secondary metabolites transported to the medial prefrontal cortex (mPFC) of the brain via the bloodstream. Specifically, the reduction in 5-HT (serotonin) triggered the activation of the NLRP3 inflammasome, which led to an increase in GSDMD (gasdermin D), mediating neuronal pyroptosis. Ultimately, these changes contributed to the development of anxiety-like behaviors in the mice.</p></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147863502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ablation of FBXO38 triggers lysosome-dependent STING degradation to drive chemotherapy resistance in cervical cancer","authors":"Xihua Shen,&nbsp;Qi Liu,&nbsp;Yan Li,&nbsp;Xiaoping Ma,&nbsp;Cengceng Lu,&nbsp;Rongyan Ma,&nbsp;Rui Han,&nbsp;Zhiyi Lin,&nbsp;Hu Han","doi":"10.1007/s10495-026-02350-x","DOIUrl":"10.1007/s10495-026-02350-x","url":null,"abstract":"<div><p>Chemotherapy resistance remains a major obstacle in cervical cancer (CC) treatment. Protein degradation systems, particularly F-box proteins, attracted growing interest in this context. However, the key regulators and their underlying mechanisms in CC remain poorly understood. This study aimed to investigate the functional significance and underlying mechanism of FBXO38 in cisplatin resistance and malignant phenotype of CC. Clinical samples were analyzed to assess the association between FBXO38 and clinicopathological features. Parental HeLa and SiHa cell lines, as well as their cisplatin-resistant sublines, were subjected to FBXO38 overexpression or knockdown. Cell viability, apoptosis, colony formation, tumorsphere ability, lysosomal and STING-related marker expressions were conducted to evaluate FBXO38’s function and potential regulation pathway. In vivo experiments were assessed using xenograft models. NH₄Cl was used for lysosomal inhibition. FBXO38 downregulation was correlated with poor differentiation, lymph node metastasis, and reduced cisplatin sensitivity in clinical samples. Cisplatin-resistant CC cells exhibited progressive FBXO38 loss, whereas FBXO38 reintroduction restored drug sensitivity and suppressed colony formation, induced apoptosis, and reduced cancer stem–like phenotypes. Conversely, FBXO38 silencing enhanced chemoresistance, stemness, and tumor-initiating capacity. In vivo, FBXO38 depletion enhanced tumor-initiating capacity, reduced cisplatin-induced tumor suppression and apoptosis. Furthermore, FBXO38 ablation promoted lysosome-dependent STING degradation, leading to attenuated signaling. Treatment with lysosomal inhibitors restored STING activation and reversed cisplatin resistance. FBXO38 functions as a tumor suppressor by maintaining cisplatin sensitivity in CC through regulation of the lysosome-dependent STING pathway. Targeting FBXO38 and its regulatory axis may represent a promising strategy to overcome treatment failure.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147937922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKCβ II antagonizes O-GlcNAcylated FOXO4 and inhibits lipid synthesis","authors":"Hua Fu,&nbsp;Yuqin Li,&nbsp;Pengzhou Li,&nbsp;Liyong Zhu,&nbsp;Shaihong Zhu,&nbsp;Guohui Wang","doi":"10.1007/s10495-026-02348-5","DOIUrl":"10.1007/s10495-026-02348-5","url":null,"abstract":"<div><h3>Background</h3><p>Obesity and associated metabolic disorders remain major public health challenges worldwide. The regulation of lipid synthesis represents a promising therapeutic target, yet the precise mechanisms remain elusive.</p><h3>Methods</h3><p>RT-qPCR and western blot measured gene expression. Lipid droplets were evaluated by Nile Red staining. TC, HDL-C, LDL-C, TG and NEFA levels were detected by ELISA kits. The interaction between proteins or genes was analyzed by ChIP, Dual-luciferase reporter, and Co-IP assays. Subcellular localization was analyzed by nuclear/cytoplasmic fractionation and immunofluorescence.</p><h3>Results</h3><p>FOXO4 was downregulated after bariatric surgery and directly decreased the transcription of lipogenic enzymes ACACA and HMGCR. Nuclear localization of FOXO4 was regulated by a previously uncharacterized interplay between O-GlcNAcylation and phosphorylation. Specifically, O-GlcNAcylation at S261 promoted FOXO4 nuclear translocation and enhanced lipogenic gene expression, while PKCβII-mediated phosphorylation at T451 antagonized this modification. Functionally, FOXO4 deletion suppressed lipid synthesis under HFD conditions. OGA or PKCβII knockdown promoted lipid synthesis by regulating FOXO4.</p><h3>Conclusion</h3><p>Elevated OGA inhibited FOXO4’s nuclear translocation via O-GlcNAcylation, and subsequent PKCβII-mediated phosphorylation-induced degradation. This process decreased ACACA and HMGCR expression, thereby attenuating lipid synthesis.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multi-targeted therapeutic strategy for triple-negative breast cancer: the tumor-targeting peptide p28 enhances chemotherapy, induces apoptosis, crosses the blood–brain barrier, and suppresses metastasis","authors":"Haniyeh Abuei,&nbsp;Pei Pei Chong,&nbsp;Mohammad Hossein Malekzadeh,&nbsp;Anahita Mojiri,&nbsp;Mohammad Amin Mosleh Shirazi,&nbsp;Sedigheh Sharifzadeh,&nbsp;Ali Farhadi","doi":"10.1007/s10495-026-02346-7","DOIUrl":"10.1007/s10495-026-02346-7","url":null,"abstract":"<div><p>Triple-negative breast cancer (TNBC) is an aggressive and molecularly heterogeneous subtype of breast cancer characterized by limited targeted treatment options, frequent chemoresistance, and a strong propensity for metastasis, particularly to the central nervous system (CNS). These challenges highlight the need for multi-targeted therapeutic strategies. The tumor-targeting peptide p28, which exhibits antitumor activity and potential blood–brain barrier (BBB) penetration, represents a promising candidate for enhancing therapeutic efficacy in TNBC through distinct mechanisms of action. In this study the effects of p28, five standard chemotherapeutic agents, and their low-dose combinations with p28 were systematically evaluated in TNBC models in vitro and in vivo. Cellular responses, including BBB permeability, viability, proliferation, apoptosis, cell cycle distribution, oxidative stress, DNA damage, and metastatic potential, were assessed. Integrated transcriptomic and systems biology analyses were performed to identify dysregulated pathways, and selected targets were subsequently evaluated at the transcript and protein levels. In xenograft models, tumor growth, apoptosis, metastasis-related features, histopathology, toxicity, and overall survival were comprehensively assessed. p28 reduced TNBC cell viability while sparing normal cells, demonstrated favorable BBB permeability, and significantly enhanced the antitumor activity of chemotherapeutic agents at reduced doses. These combinations showed synergistic effects, resulting in markedly enhanced tumor suppression, increased apoptosis, reduced invasion and metastasis, reduced toxicity, and prolonged survival. Collectively, these findings support p28 as a promising preclinical combination strategy in TNBC, distinguished by its synergistic interaction with chemotherapy, and justify further investigation of its therapeutic potential in metastatic breast cancer.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"QD394 induces ferroptosis and suppresses the proliferation of colorectal cancer via the SP1/JNK pathway","authors":"Ruixue Zhang,&nbsp;Haiyan Quan,&nbsp;Wenjing Xiao,&nbsp;Zhenhua Lin,&nbsp;Aihua Jin","doi":"10.1007/s10495-026-02290-6","DOIUrl":"10.1007/s10495-026-02290-6","url":null,"abstract":"<div><p>Lipid peroxidation triggers ferroptosis, a type of regulated cell death that is iron-dependent. Owing to its important role in tumor suppression, ferroptosis represents an extremely promising therapeutic target for cancer. QD394, a quinazolinone-based compound, was recently identified as a novel redox regulator with demonstrated cytotoxic and proapoptotic effects in pancreatic and breast cancer models. Preliminary RNA sequencing analysis suggested potential associations between QD394 treatment and ferroptosis, mitogen-activated protein kinase (MAPK) signaling, and angiogenic pathways. Cell Counting Kit-8 (CCK-8), colony formation assay, and 5-ethynyl-2'-deoxyuridine (EdU) assays, as well as annexin V/PI staining, revealed that QD394 inhibited cell proliferation and induced apoptosis. Microtubule assembly, chick chorioallantoic membrane (CAM), and scratch assays demonstrated that QD394 suppressed angiogenesis. Notably, QD394-treated colorectal cancer (CRC) cells exhibited decreased levels of glutathione (GSH), solute carrier family 7 member 11 (xCT), and glutathione peroxidase 4 (GPX4), and increased levels of malondialdehyde (MDA) and lipid reactive oxygen species (ROS), suggesting that QD394 induces ferroptosis. Mechanistically, QD394 treatment reduced specific protein 1 (SP1) levels through ubiquitin-mediated proteolysis. Notably, overexpression of SP1 counteracted QD394-induced ferroptosis. Moreover, QD394 treatment significantly increased the ratio of p-JNK to total JNK in CRC cells, whereas SP1 overexpression effectively reversed this effect. In a xenograft model, QD394 significantly inhibited tumor growth and decreased tumor weight, and the expression of Ki-67, GPX4, and SP1. In contrast, 4-hydroxynonenal (4-HNE) and p-JNK levels were markedly elevated. Collectively, our findings reveal that QD394 triggers ferroptosis in CRC through the SP1/JNK signaling axis, highlighting its potential as a novel anticancer agent.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture><span>The alternative text for this image may have been generated using AI.</span></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 5","pages":""},"PeriodicalIF":8.1,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147829224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}