Cell Death Discovery最新文献

{"title":"Targeting the PBX1-BCL2L1 axis as a therapeutic strategy in colorectal cancer.","authors":"Hao Lin, Ting Su, Ying Liu, Ruilan Deng, Jie Li, Xuanhao Lin, Qiaoling Ke, Yijing Luo, Lele Meng, Bin Liang, Xuhong Song, Dongyang Huang, Lingzhu Xie","doi":"10.1038/s41420-026-03139-2","DOIUrl":"https://doi.org/10.1038/s41420-026-03139-2","url":null,"abstract":"<p><p>Pre-B-cell leukemia homeobox 1 (PBX1) is a transcription factor involved in diverse cellular processes, but its role in colorectal cancer (CRC) remains incompletely understood. In this study, we show that PBX1 is downregulated in CRC tissues and cell lines. Functional experiments revealed that PBX1 overexpression inhibits proliferation, migration, and invasion, but paradoxically suppresses apoptosis, suggesting a dual regulatory role. Transcriptome and CUT&Tag profiling identified BCL2L1 as a direct transcriptional target of PBX1. PBX1 binds the BCL2L1 promoter and enhances Bcl-xL expression, contributing to apoptotic resistance. BCL2L1 knockdown reversed the anti-apoptotic effects of PBX1 and restored apoptosis levels. Upon 5-fluorouracil (5-FU) treatment, PBX1 overexpression reduced cell viability, while concurrent BCL2L1 knockdown significantly enhanced drug sensitivity. In vivo, xenograft experiments demonstrated that PBX1 overexpression suppressed tumor growth, which was further augmented by BCL2L1 knockdown. These results support the dual role of PBX1 in simultaneously inhibiting tumor growth while promoting cell survival through the BCL2L1-Bcl-xL axis. This regulatory interaction may influence tumor persistence and therapeutic response in CRC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834058","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":"Targeting the OTU family: a core therapeutic strategy for reshaping the immunosuppressive microenvironment and reversing drug resistance in HCC by coordinating the autophagy-ferroptosis balance.","authors":"Pengcheng Zhao, Ping Zhang","doi":"10.1038/s41420-026-03148-1","DOIUrl":"https://doi.org/10.1038/s41420-026-03148-1","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) treatment faces dual challenges: resistance to targeted therapy and low response rates to immunotherapy. These issues are rooted in the immunosuppressive tumor microenvironment (TME). Ferroptosis and autophagy, two critical cellular processes, play complex and paradoxical roles in HCC drug resistance and immunoregulation, and they interact closely. This review explores how the OTU deubiquitinase family, especially OTUB1, acts as a central hub coordinating the autophagy-ferroptosis balance. Additionally, other OTU family members, such as OTUD3, OTULIN, and OTUD6B, contribute to HCC progression by modulating similar pathways, highlighting the need for a broader therapeutic approach. Specifically, OTUD3 suppresses HIF-1α-driven angiogenesis, OTULIN inhibits NF-κB-mediated inflammation, and OTUD6B stabilizes pVHL to impede metastasis, collectively demonstrating their synergistic or antagonistic interactions with OTUB1 in reshaping the TME. This coordination drives HCC drug resistance and remodels the immune microenvironment. OTUB1 suppresses ferroptosis and maintains tumor cell survival by deubiquitinating and stabilizing key proteins like SLC7A11, GPX4, and p62. It also promotes immune escape by modulating PD-L1 stability and immune cell function. Consequently, therapeutic strategies targeting the OTU family-such as developing selective inhibitors for multiple members, using intelligent nanodelivery systems, and combining them with ferroptosis inducers or immune checkpoint inhibitors-show significant potential for reversing drug resistance and improving immunotherapy efficacy. Expanding these strategies to include other OTU members could enhance efficacy and reduce resistance. Addressing how the OTU family precisely modulates the intersection of autophagy and ferroptosis, and how it reshapes immune cell metabolism and function within the TME, is critical for developing novel combination therapies. This article provides a crucial theoretical foundation for developing novel combination strategies targeting metabolism-immune crosstalk.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834113","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":"ZNF473 promotes colorectal cancer progression and chemoresistance by destabilizing p53 protein to upregulate Survivin.","authors":"Yunhua Xu, Guang Fu, Qing Fang, Lan Liao, Xiangwen Tan, Xiong Li, Shuxiang Li, Kai Fu, Shuai Xiao","doi":"10.1038/s41420-026-03145-4","DOIUrl":"https://doi.org/10.1038/s41420-026-03145-4","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. The classic development of CRC is a process from normal colonic mucosa to polyp to eventually adenocarcinoma. However, the critical genes regulating this process and the underlying molecular mechanisms remain elusive. Here, we identified ZNF473 as an upregulated and key functional gene in CRC progression. Specifically, comprehensive bioinformatics analyses were performed to explore the expression of ZNF473 in CRC samples and to investigate its correlation with clinicopathological characteristics, prognosis, and potential biological functions. In vitro experiments were performed to elucidate the potential role and molecular mechanisms of ZNF473 in CRC progression. Results demonstrate that ZNF473 is highly expressed in CRC and correlates with poor prognosis. Functionally, ZNF473 knockdown significantly inhibits cell viability and proliferation. Furthermore, gene function enrichment analyses reveal an association between ZNF473 and pathways related to drug metabolism (Cytochrome P450) and chemotherapy resistance. Mechanistically, ZNF473 physically interact with p53 to promote its protein degradation, consequently upregulates the Survivin expression. In summary, this study reveals the role and molecular function of ZNF473 in CRC progression, uncovering a potential novel ZNF473/p53/Survivin axis and providing a hint for targeting ZNF473 to suppress tumor growth and potential chemoresistance.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834148","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":"RBM14 drives prostate cancer metastasis via stabilizing HK2 mRNA to activate glycolysis and H3K18 lactylation.","authors":"Zhenhong Liu, Haixin Guo, Zhijiao You, Haichao Lin, Weihui Liu, Jiabi Chen, Qingliu He, Wei Zhuang","doi":"10.1038/s41420-026-03131-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03131-w","url":null,"abstract":"<p><p>Metastasis is a leading cause of poor prognosis in prostate cancer (PCa), yet its underlying regulatory mechanisms remain incompletely understood. Following the establishment of highly invasive PC-3M cell lines, RBM14 expression was found to be significantly elevated in highly invasive cells. Furthermore, RBM14 was upregulated in PCa tissues and positively correlated with adverse clinicopathological features. Functional assays demonstrated that RBM14 significantly promoted PCa cell metastasis in vitro and in vivo. Mechanistically, RBM14 bound HK2 mRNA via its RRM1/2 domains to enhance HK2 stability, thereby upregulating HK2 expression. This increased HK2 level boosted PCa cells' glycolytic capacity, which in turn led to increased global lactylation, especially in histone H3 lysine 18 lactylation (H3K18la). The elevated H3K18la preferentially enriched at the promoters of metastasis-related genes, further upregulating their expression. Importantly, combining RBM14 knockdown with 2-DG exerted a synergistic inhibitory effect on PCa metastasis. Collectively, this study identifies RBM14 as a key regulator of PCa metastasis via the HK2-glycolysis-H3K18la axis, providing a potential therapeutic target for combating PCa metastasis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147811683","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":"Echinocandins have an alternative mode of action on biomimetic membranes that is not directly related to the functioning of (1,3) beta-glucan synthase.","authors":"Anna I Malykhina, Svetlana S Efimova, Natalia E Grammatikova, Anna N Tevyashova, Andrey E Shchekotikhin, Olga S Ostroumova","doi":"10.1038/s41420-026-03133-8","DOIUrl":"https://doi.org/10.1038/s41420-026-03133-8","url":null,"abstract":"<p><p>Echinocandins are the preferred agents for treating invasive candidiasis; however, rising resistance in Candida species poses a significant challenge for patient care. This study aimed to improve the efficacy of echinocandins against clinical Candida isolates by enhancing their noncanonical membrane activity. The mechanisms of action of anidulafungin, caspofungin, and micafungin on lipid membranes were investigated using a range of biophysical methods and molecular dynamics approaches. Antifungal activity was assessed using a panel of clinical Candida isolates. The results indicated that echinocandins exhibit greater selectivity for ergosterol-containing membranes than for cholesterol-enriched membranes. Echinocandins caused differential phase disordering, leading to a significant increase in the size of sterol-rich ordered domains, induced membrane stress/perturbation, and promoted the formation of ion-permeable transmembrane pores. The membrane activity of echinocandins was enhanced upon incorporation into liposomes. Echinocandin liposomes exhibited reduced MICs against clinical Candida isolates (down to 0.002 µg/mL) compared with conventional echinocandins. This reduction in MIC was observed regardless of the strain's susceptibility to standard echinocandins. Enhancing the membrane activity of echinocandins through their incorporation into liposomal formulations represents a promising strategy to improve antifungal efficacy and address the increasing resistance observed in clinical Candida isolates.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763663","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":"AURKA/PHB2 signaling drives acquired resistance to KRAS ^G12C inhibitors in KRAS ^G12C-mutant NSCLC.","authors":"Jinrong Liao, Xin Lan, Zeng Chen, Dan Hu, Doudou Luo, Huocong He, Zhiyi Huang, Hongyu Yu, Yunpeng Bai, Xingguang Luo, Xiandong Lin","doi":"10.1038/s41420-026-03080-4","DOIUrl":"https://doi.org/10.1038/s41420-026-03080-4","url":null,"abstract":"<p><p>Patients with non-small cell lung cancer (NSCLC) who initially respond to Sotorasib, a drug targeting the KRAS ^G12C mutation, eventually develop acquired resistance. However, the mechanisms driving this acquired resistance remain largely unclear. This study explored the role of AURKA in mediating resistance to Sotorasib in NSCLC. The expression levels of AURKA mRNA and protein in NSCLC cell lines (H358 and Calu-1) were assessed using qPCR and Western blot. To further elucidate the role of AURKA in the biological alterations of Sotorasib-resistant cells and its association with the PI3K/AKT signaling pathway, a comprehensive set of assays was conducted, including MTS, colony formation, Transwell migration, luciferase reporter assays, fluorescent in situ hybridization (FISH), molecular docking analyses, and immunoprecipitation. The key findings include: (1) Long-term Sotorasib treatment led to upregulation of AURKA; (2) Overexpression of AURKA induced Sotorasib resistance, suppressed apoptosis and promoted migratory potential in Calu-1 and H358 cells, while AURKA knockdown increased the sensitivity, enhanced apoptosis and inhibited migratory capacity of H358-SR and Calu-1-SR cells to Sotorasib; (3) Immunoprecipitation and luciferase reporter assays demonstrated a physical interaction between AURKA and PHB2, establishing a positive feedback loop that sustained malignant behaviors, potentially explaining how Sotorasib-resistant cells survived despite KRAS pathway inhibition; (4) AURKA stabilizes PHB2, activating the PI3K/AKT pathway and allowing cancer cells to bypass the KRAS blockade, thus restoring malignant behavior. (5) The combination of AURKA inhibitor and Sotorasib alleviates the acquired drug resistance in vitro and in vivo. These data suggest that resistance to Sotorasib in NSCLC is associated with a positive feedback loop involving AURKA, PHB2, and PI3K/AKT signaling. AURKA may serve as a biomarker for predicting the therapeutic efficacy of Sotorasib in KRAS G12C-targeted therapies and as a potential therapeutic target to overcome Sotorasib resistance in NSCLC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763701","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":"TRPV4 mediates aminoglycoside trafficking and ototoxicity without compromising antimicrobial efficacy.","authors":"Lingshuai Kong, Takaomi Kurioka, Sachiyo Mogi, Yoshihiro Nitta, Kengo Yamamoto, Taku Yamashita","doi":"10.1038/s41420-026-03132-9","DOIUrl":"https://doi.org/10.1038/s41420-026-03132-9","url":null,"abstract":"<p><p>Aminoglycoside (AG) antibiotics remain essential for treating life-threatening infections; however, their clinical use is limited by irreversible ototoxicity. The mechanisms of AG entry into the cochlea and its role in cochlear degeneration remain unclear. This study identified the transient receptor potential vanilloid 4 (TRPV4) channel as a key mediator of AG trafficking and ototoxicity. In an AG-induced ototoxicity mouse model, TRPV4 pharmacological inhibition reduced cochlear AG accumulation, preserving hearing, hair cell (HC) survival, and cochlear synaptic integrity. Conversely, TRPV4 pharmacological activation accelerated cochlear AG influx, exacerbating AG-induced ototoxicity. Cochlear explant experiments showed that TRPV4 agonists and antagonists modulated Texas Red-labeled gentamicin uptake and HC survival, suggesting that TRPV4 directly contributes to the regulation of HC permeability and survival in the explant preparation. Notably, TRPV4 modulation did not compromise AG antimicrobial activity in bacterial-killing assays, uncoupling therapeutic efficacy from ototoxicity. Collectively, these findings identify TRPV4 as a molecular gateway for AG trafficking into cochleae and demonstrate that its inhibition offers a strategy to protect hearing while maintaining antimicrobial potency. Thus, targeting TRPV4 may provide a clinically translatable approach to prevent AG-induced ototoxicity without undermining their life-saving benefits.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763716","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":"Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.","authors":"Alojzija Brcic, Hrvoje Lalic, Tomislav Smoljo, Klara Bardač, Vilma Dembitz, Romana Penker, Giovanny Rodriguez Blanco, Antonio Bedalov, Dora Visnjic","doi":"10.1038/s41420-026-03105-y","DOIUrl":"https://doi.org/10.1038/s41420-026-03105-y","url":null,"abstract":"<p><p>Differentiation therapy offers a promising approach in acute myeloid leukemia (AML) by overcoming the developmental block that maintains leukemic blasts. Increasing evidence indicates that DNA replication stress can promote differentiation rather than cytotoxicity; however, the metabolic mechanisms linking replication stress to differentiation remain poorly defined. Here, we investigated how perturbations in nucleotide metabolism regulate replication stress-driven differentiation. Using metabolomic and functional analyses in AML cell lines, we show that agents inducing differentiation through replication stress, including 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), dihydroorotate dehydrogenase (DHODH) inhibition, and low-dose cytarabine, converge on disruption of nucleotide pool balance. Low-dose AICAr induced a pyrimidine-purine imbalance, S phase arrest, and enhanced differentiation, whereas high-dose reduced these effects. Although brequinar and cytarabine altered nucleotide metabolism through distinct mechanisms, differentiation induced by all agents was abolished by supplementation with high levels of ribo- and deoxyribonucleosides, confirming that nucleotide imbalance is a central driver. We further identify ribonucleotide reductase (RNR) as a critical modulator of this process. Replication stress induced context-dependent regulation of RNR subunits, with RRM2 upregulated in p53-mutant U937 cells and the p53-responsive RRM2B isoform predominating in p53-wild-type MOLM-13 cells. Consistent with these differences, RRM2 depletion enhanced differentiation in U937 cells without affecting viability but impaired differentiation and survival in MOLM-13 cells. These findings position nucleotide metabolism as a key regulator of AML differentiation and suggest that combining RNR-targeted and checkpoint-modulating strategies could optimize therapeutic responses.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763676","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":"Deletion of exocyst component 5 suppresses repair of injured kidney by limiting cell proliferation.","authors":"Hui Jae Lim, Min Jung Kong, Mira Noh, You Ri Park, Yong Kwon Han, Joshua H Lipschutz, Kwon Moo Park","doi":"10.1038/s41420-026-03127-6","DOIUrl":"https://doi.org/10.1038/s41420-026-03127-6","url":null,"abstract":"<p><p>Impaired cell proliferation causes fibrotic changes in tissues, leading to loss of function. Although exocyst component 5 (Exoc5), a central component of the eight-protein exocyst complex, regulates the targeting and docking of intracellular vesicles which are essential for cell proliferation, its role in tissue regeneration remains to be defined. Here, we investigated the role of Exoc5 in the repair of kidney injury induced by ischemia-reperfusion (I/R) using proximal tubule cell (PTC)-specific Exoc5 knockout (Exoc5^KO) mice generated by crossing Exoc5^f/f with PEPCK-cre mice. Exoc5^KO and wild-type (Exoc5^WT) mice were subjected to either bilateral kidney I/R or sham surgery. I/R induced functional and structural kidney damage in both Exoc5^KO and Exoc5^WT mice, as evidenced by increased plasma creatinine and BUN, decreased glomerular filtration rate, and histological damage. Kidney function and structure gradually improved in both Exoc5^KO and Exoc5^WT mice over time; however, neither group fully recovered normal function, and the recovery was less pronounced in Exoc5^KO than in Exoc5^WT mice. Twenty-one days after I/R, Exoc5^KO mice showed greater collagen deposition and α-smooth muscle actin (α-SMA) and vimentin expression compared to Exoc5^WT mice, whereas E-cadherin expression was lower. Post-I/R PTC proliferation in Exoc5^KO mice was significantly lower than in Exoc5^WT mice. In contrast, post-I/R induction of paired box 2 (Pax2) was greater in Exoc5^KO than in Exoc5^WT mice. In HK-2 cells, a human PTC line, Exoc5 downregulation by siRNA increased Pax2 expression and further increased N-cadherin, phosphorylated-Smad3 (p-Smad3), and α-SMA expression compared to control cells following TGF-β treatment. Collectively, these findings indicate that loss of Exoc5 impairs PTC regeneration and exacerbates fibrosis in the injured kidney, suggesting its therapeutic potential in preventing the transition from acute kidney injury (AKI) to chronic kidney disease (CKD).</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763731","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":"Trifluoperazine causes mast cell apoptosis through a secretory granule-mediated pathway.","authors":"Marianthi Vraila, Jun Mei Hu Frisk, Animamalar Mayavannan, Mirjana Grujic, Erik Stigare, Adnan Lidian, Jenny Hallgren, Gunnar Pejler","doi":"10.1038/s41420-026-03122-x","DOIUrl":"https://doi.org/10.1038/s41420-026-03122-x","url":null,"abstract":"<p><p>Mast cells contribute to the pathology of various diseases, in particular allergic conditions. Therefore, it is essential to develop strategies that efficiently prevent their harmful effects under such circumstances. Here, we sought to evaluate the possibility of cell death induction as a potential means of selectively depleting mast cells. Previous work has suggested that mast cells are sensitive to regimes that target their acidic secretory granules, and the aim of this study was therefore to identify novel anti-mast cell compounds that act via a granule-mediated pathway. To this end, we evaluated trifluoperazine, an antipsychotic drug known to present lysosomotropic properties. We demonstrate that trifluoperazine is cytotoxic for mast cells, whereas multiple other cell types were resistant. Trifluoperazine induced mainly apoptotic cell death in mast cells. Further, our data indicate that trifluoperazine acts on mast cells by inducing secretory granule permeabilization. In support of this, trifluoperazine caused granule deacidification, accompanied by cytosolic acidification as well as translocation of tryptase from the secretory granules into the cytosol. Trifluoperazine-induced cell death and subsequent DNA degradation were profoundly abrogated when granule acidification was inhibited by the V-ATPase inhibitor bafilomycin A1, suggesting that the granule acidity has a key role in the cell death mechanism. Moreover, mast cell death in response to trifluoperazine was largely caspase-independent, whereas serine protease activity was shown to promote apoptosis-like vs. necrosis-like cell death. Overall, these findings introduce trifluoperazine as a novel anti-mast cell agent that induces cell death through granule permeabilization. Trifluoperazine may thus be evaluated for therapeutic intervention to ameliorate mast cell-mediated detrimental effects.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}