Cell Death & Disease最新文献

{"title":"ACTL6A depletion induces KLF4-mediated anti-tumorigenic effects in colorectal cancer.","authors":"Hye-Ju Yang, Eun-Ju Kim, Yeonsoo Kim, Youngwon Cho, Younghee Choi, Sang-Hyun Song, Tae-You Kim","doi":"10.1038/s41419-025-07946-w","DOIUrl":"https://doi.org/10.1038/s41419-025-07946-w","url":null,"abstract":"<p><p>ACTL6A, a subunit of the SWI/SNF and INO80 chromatin remodeling complexes, is frequently overexpressed in various cancers, and its depletion attenuates cell proliferation in colorectal cancer (CRC). However, the epigenetic mechanisms underlying ACTL6A function remain poorly understood. Here, we aimed to elucidate how ACTL6A regulates chromatin accessibility and gene expression in CRC. Integrated multi-omics analyses revealed that ACTL6A deficiency alters chromatin accessibility and upregulates P53 pathway-related genes, accompanied by the recruitment of SWI/SNF and INO80 complexes. Mechanistically, ACTL6A depletion enhances KLF4 binding at newly accessible regions, where it cooperates with these chromatin remodeling complexes to activate P53 pathway-related genes and induce apoptosis. ACTL6A contributes to CRC cell proliferation by inhibiting the KLF4-mediated transcriptional activation of tumor-suppressive genes. Thus, our findings highlight that targeting ACTL6A may serve as a promising therapeutic strategy in CRC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"653"},"PeriodicalIF":9.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HUMANIN produced by human efferocytic macrophages promotes the resolution of inflammation.","authors":"Mélissa Maraux, Mathieu Vetter, Ludivine Dal Zuffo, Francis Bonnefoy, Audrey Wetzel, Alexis Varin, Baptiste Lamarthée, Olivier Tassy, Didier Ducloux, Philippe Saas, Thomas Cherrier","doi":"10.1038/s41419-025-07909-1","DOIUrl":"https://doi.org/10.1038/s41419-025-07909-1","url":null,"abstract":"<p><p>Elimination of apoptotic neutrophils by macrophages, a process called efferocytosis, is a critical step in the resolution of inflammation. Efferocytosis induces the reprogramming of macrophages towards a pro-resolving phenotype and triggers the secretion of pro-resolving factors. While mouse efferocytic macrophages are well-described, less is known about human efferocytic macrophages. Here, using RNA sequencing analysis of three different types of in vitro-derived human efferocytic macrophages, we observed a common modulation of mitochondrial metabolism-related genes in human M0, M1, and M2a-like macrophages, thus correlating with some previous results obtained in other non-human models. These results led us to identify for the first time some particular genes regulated in humans like PLIN5 and MTLN. We also shed light on a mitochondrial gene (MT-RNR2) coding a secreted factor called HUMANIN. Mainly known for its antioxidant and neuroprotective effects, we found that HUMANIN was also associated with pro-resolving properties in human and mouse models. Indeed, HUMANIN was produced early during the resolution of inflammation in an acute peritonitis mouse model. Preventive HUMANIN administration in this model reduced leukocyte infiltration and pro-inflammatory cytokine secretion. These anti-inflammatory properties were accompanied by the early acquisition of a CD11b^low non-efferocytic phenotype by mouse macrophages and by an enhanced expression of pro-resolving genes including Alox15 and Retnla. The ability of HUMANIN to dampen pro-inflammatory cytokine secretion was also confirmed in primary human neutrophils. Finally, HUMANIN was also detected in gingival crevicular fluids of patients suffering from periodontitis after the onset of inflammation, suggesting a role of HUMANIN in the control of inflammation. Overall, our data shed light on new aspects of efferocytosis in humans and identify the pro-resolving potential of HUMANIN. This illustrates its prospective therapeutic interest in inflammatory disorders.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"656"},"PeriodicalIF":9.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12394407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial quality control in diabetes mellitus and complications: molecular mechanisms and therapeutic strategies.","authors":"Yanling Chen, Xun Liu, Yixuan Liu, Yujia Li, Dingxiang Li, Zhigang Mei, Yihui Deng","doi":"10.1038/s41419-025-07936-y","DOIUrl":"https://doi.org/10.1038/s41419-025-07936-y","url":null,"abstract":"<p><p>Diabetes mellitus (DM), a metabolic disease of globally health concern, is pathologically attributed to mitochondrial dysfunction, an essential component in disease progression. Mitochondrial quality control (MQC) acts as a critical defense mechanism for metabolic homeostasis, yet its implications in DM and its complications remain incompletely understood. This study thoroughly summarizes emerging evidence that delineates the molecular processes of MQC, with an emphasis on effector protein post-translational regulation, upstream signaling hubs, and interactions with other metabolic processes including ferroptosis and lipid metabolism. We highlight newly discovered processes involving mitochondrial-derived vesicles, licensed mitophagy, and mitocytosis that broaden the regulatory landscape of MQC, going beyond the traditionally recognized process including biogenesis, dynamics and mitophagy. MQC imbalance exacerbates insulin resistance, while impaired insulin signaling reciprocally compromises mitochondrial function, creating a vicious cycle of metabolic deterioration. Despite tissue-specific pathophysiology, diabetic complications exhibit identical MQC impairment including suppressed biogenesis, fission-fusion imbalance, and deficient mitophagy. Emerging therapies including clinical hypoglycemic agents and bioactive phytochemicals demonstrate therapeutic potential by restoring MQC. However, current strategies remain anchored to classical pathways, neglecting novel MQC mechanisms such as mitocytosis. Addressing this gap demands integration of cutting-edge MQC insights into drug discovery, particularly for compounds modulating upstream regulators. Future studies must prioritize mechanistic dissection of MQC novel targets and their translational relevance in halting metabolic collapse of diabetes progression. Since mitochondrial function is a cornerstone of metabolic restoration, synergizing precision MQC modulation with multi-target interventions, holds transformative potential for refine diabetic complications therapeutics.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"652"},"PeriodicalIF":9.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Irgm1 to combat osteoporosis: suppressing ROS and restoring bone remodeling.","authors":"Zichen Cui, Guanghui Gu, Fei Chen, Jianyi Li, Xiaofan Du, Shuqing Chen, Han Zhang, Chenxu Li, Jiale Shao, Jiayi Xi, Yukun Du, Qinghua Zhao, Yongming Xi","doi":"10.1038/s41419-025-07965-7","DOIUrl":"https://doi.org/10.1038/s41419-025-07965-7","url":null,"abstract":"<p><p>The accumulation of reactive oxygen species (ROS) leads to enhanced osteoclast activity, causing severe bone destruction in postmenopausal osteoporosis. Immunity-related GTPase family M member 1 (Irgm1) plays an essential role in affecting the production of intracellular ROS. To detect whether deletion of Irgm1 could suppress osteoclastogenesis through cellular redox regulation, we first evaluated whether the Irgm1 level was significantly elevated in mice bone marrow-derived monocytes/macrophages (BMDMs) from ovariectomy (OVX)-induced osteoporosis mice. Moreover, bioinformatics network analysis was performed to identify Irgm1 as a key upregulated gene during osteoclast differentiation. Next, we found that macrophage-specific Irgm1 knockout (Irgm1-cKO, Lyz2-Cre; Irgm1^flox/flox) in OVX mice resulted in slower bone loss compared with OVX mice from the control group (Irgm1^flox/flox). We then demonstrated that loss of Irgm1 inhibited osteoclast differentiation and bone resorption function via suppressing ROS accumulation. Further mechanism revealed that Irgm1 could endogenously bind to kelch-like ECH-associated protein 1 (Keap1) and keep Keap1 from ubiquitination and degradation. In the absence of Irgm1, Keap1 was downregulated and causing nuclear factor erythroid 2-related factor 2 (Nrf2) to translocate to the nucleus, thereby activating the level of the antioxidant system to combat oxidative stress. Moreover, Irgm1 deficiency in RAW264.7 promoted osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) through inhibiting the M1 phenotype polarization. Taken together, our results revealed that loss of Irgm1 significantly alleviates OVX-induced bone loss, thus laying the foundation for exploring Irgm1 as a novel targeting approach for the treatment of osteoporosis.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"651"},"PeriodicalIF":9.6,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12391319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GFAT1 promotes the progression of hepatocellular carcinoma via enhancing the O-GlcNAcylation of VEZF1.","authors":"Jia-Yao Yang, Rong Zhang, Zhi-Rong Zhang, Shan Li, De-Ao Gong, Chen-Hao Li, Chang Chen, Lu-Yi Huang, Ai-Long Huang, Ni Tang, Kai Wang","doi":"10.1038/s41419-025-07975-5","DOIUrl":"https://doi.org/10.1038/s41419-025-07975-5","url":null,"abstract":"<p><p>Glutamine-fructose-6-phosphate amidotransferase 1 (GFAT1), the first rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), is a pivotal regulator of HBP flux. Despite its established significance, the molecular underpinnings of GFAT1's role in hepatocellular carcinoma (HCC) remain to be elucidated. Here, we found that GFAT1 was upregulated in HCC, and high GFAT1 level was correlated with poor patient prognosis. Our in vitro and in vivo studies demonstrated that GFAT1 facilitated hepatoma cell proliferation and invasion by enhancing HBP and O-GlcNAcylation through its enzymatic activity. Global profiling of O-GlcNAcylation identified vascular endothelial zinc finger protein 1 (VEZF1) as a key substrate heavily O-GlcNAcylated in GFAT1-overexpressing hepatoma cells. Notably, O-GlcNAcylation at specific serine residues (Ser123 and Ser124) within VEZF1 attenuated its proteasomal degradation, thereby enhancing its protein stability and promoting tensin 1 (TNS1) transcription in HCC. In addition, we designed a bioactive VEZF1-derived peptide to competitively inhibit GFAT1-mediated O-GlcNAcylation of VEZF1. This intervention effectively reduced TNS1 expression and suppressed the progression of HCC in a mouse model. Collectively, our findings underscore the therapeutic potential of targeting the GFAT1-VEZF1-TNS1 signaling axis in HCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"647"},"PeriodicalIF":9.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived PRMT1 suppresses macrophage antitumor activity by inhibiting cGAS/STING signaling in gastric cancer cells.","authors":"Hui Wang, He Nie, Xiaoyi Zhao, Ke Chen, Chen Peng, Xuemei Zhang, Huiweng Guo, Yijia Chen, Xiaojing Yang, Dong Wang, Yongbing Yang, Qibin He, Qiang Zhan","doi":"10.1038/s41419-025-07960-y","DOIUrl":"https://doi.org/10.1038/s41419-025-07960-y","url":null,"abstract":"<p><p>Gastric cancer (GC) is a common and aggressive malignancy worldwide. Increasing evidence has shown that epigenetic changes are closely related to the development of cancer and tumor-associated macrophages. Here, we report that PRMT1 is a key immunosuppressive factor in GC. PRMT1 is upregulated in GC and promotes tumor progression. PRMT1 knockdown in GC leads to the activation of the cGAS/STING pathway through the enhancement of dsDNA aggregation, which subsequently increases IFN-β secretion. Notably, after PRMT1 knockdown, M1-like tumor-associated macrophage (TAM) infiltration increased, whereas M2-like TAM infiltration decreased in vivo and in vitro. After the targeted inhibition of STING by siRNA or H151, the improvement in the progression of GC caused by PRMT1 knockdown decreased, and the changes in macrophage polarization were reversed. Furthermore, we found that PRMT1 knockdown in GC affects the STAT pathway in TAMs, inducing changes in their polarization and promoting GC apoptosis by enhancing IFN-β secretion through the cGAS/STING pathway. In summary, our findings revealed that PRMT1 knockdown inhibits the cGAS/STING pathway in GC, which produces type I IFNs to promote the polarization of M1-like macrophages in the tumor microenvironment.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"649"},"PeriodicalIF":9.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACSS2-TFEB axis acts as a critical regulator of the autophagic machinery in head and neck squamous cell carcinoma.","authors":"Danhui Yin, Qian Yang, Shisheng Li, Yongchun Peng, Jianbo Zhang, Zuozhong Xie, Tengfei Fan","doi":"10.1038/s41419-025-07971-9","DOIUrl":"https://doi.org/10.1038/s41419-025-07971-9","url":null,"abstract":"<p><p>Head and neck squamous cell carcinoma (HNSCC) has a high rate of metastasis and recurrence, and poses a considerable threat to patient survival. Autophagy, an intracellular degradation pathway, plays a crucial role in tumor progression; however, the underlying mechanisms of action remain unclear. This study aimed to explore the role of the ACSS2-TFEB axis in the regulation of autophagy and its impact on HNSCC cell proliferation, migration, invasion, and lysosomal function. HNSCC tumor tissues and cell lines were analyzed for ACSS2 protein expression. The effects of the ACSS2 knockdown on cell proliferation, migration, invasion, and autophagic flux were also assessed. The interaction between ACSS2 and transcription factor EB (TFEB) and its influence on lysosomal function were also examined. In this study, we found that ACSS2 protein expression was significantly upregulated and correlated with metastasis and poor prognosis. ACSS2 knockdown inhibited the proliferation, migration, and invasion of HNSCC cells, and disrupted autophagy flux, primarily by impairing lysosomal function. Additionally, ACSS2 was found to sustain autophagic flux through TFEB activation, a key regulator of the autophagy-lysosome pathway. TFEB activation promotes lysosomal function and autophagic flux, thereby facilitating tumor cell growth and metastasis. This study elucidated the molecular mechanism by which ACSS2 enhances HNSCC cell proliferation and invasion via TFEB activation. The ACSS2-TFEB axis is a potential therapeutic target for HNSCC and provides a foundation for the development of targeted therapies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"650"},"PeriodicalIF":9.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRPL12 K163 acetylation inhibits ccRCC via driving mitochondrial metabolic reprogramming.","authors":"Xingzhao Ji, Fuyuan Xue, Ying Wang, Dexuan Gao, Jian Sun, Tianyi Dong, Qian Mu, Quanlin Xu, Shengnan Sun, Yi Liu, Qiang Wan","doi":"10.1038/s41419-025-07896-3","DOIUrl":"https://doi.org/10.1038/s41419-025-07896-3","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC) is a common urological tumor, with clear cell renal cell carcinoma (ccRCC) being the most prevalent subtype. Metabolic reprogramming plays a critical role in ccRCC progression, making it a promising target for therapeutic intervention, though effective treatments remain unavailable. Our previous studies have shown that mitochondrial ribosomal protein L12 (MRPL12) contributes to various metabolic diseases, including diabetic kidney disease and HCC, by regulating mitochondrial biosynthesis. In this study, we demonstrated that MRPL12 is acetylated at lysine 163 (K163) in ccRCC cells, a key modification that influences its regulatory effect on mitochondrial metabolism. Mechanistically, we clarified that acetylation at the K163 site enhances mitochondrial biosynthesis by promoting MRPL12's binding to POLRMT, which subsequently increases mitochondrial metabolism and suppresses cellular glycolysis. Additionally, we found that MRPL12 K163 acetylation levels were significantly downregulated in ccRCC and that restoring this acetylation inhibited ccRCC progression in both in vitro and in vivo models. Furthermore, we demonstrated that the acetyltransferase TIP60 and the deacetylase SIRT5 bind to MRPL12 and regulate its acetylation. These findings highlight K163 acetylation as a critical site for MRPL12-mediated regulation of mitochondrial metabolism and reveal that this modification inhibits renal cancer development by promoting mitochondrial biosynthesis, reducing glycolysis, and driving metabolic reprogramming. This study suggests a potential therapeutic strategy for targeting MRPL12 acetylation in ccRCC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"646"},"PeriodicalIF":9.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: CLPTM1L interacts with ERLIN2 to stabilize SREBP1 and drive tumorigenesis in nasopharyngeal carcinoma.","authors":"Jian Zhang, Shu-Qiang Liu, Xiang-Yu Xiong, Ya-Qing Zhou, Pan-Pan Wei, Xin-Yuan Guan, Jin-Xin Bei, Qian Cui, Chun-Ling Luo","doi":"10.1038/s41419-025-07955-9","DOIUrl":"https://doi.org/10.1038/s41419-025-07955-9","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"648"},"PeriodicalIF":9.6,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High content-imaging drug synergy screening identifies specific senescence-related vulnerabilities of mesenchymal neuroblastomas.","authors":"Sonja Herter, Marta Emperador, Kyriaki Smyrilli, Daniela Kocher, Simay Celikyürekli, Constantia Zeiser, Xenia Gerloff, Sina Kreth, Kai-Oliver Henrich, Kendra K Maaß, Johanna Rettenmeier, Thomas G P Grünewald, Heike Peterziel, Frank Westermann, Anne Hamacher-Brady, Olaf Witt, Ina Oehme","doi":"10.1038/s41419-025-07933-1","DOIUrl":"https://doi.org/10.1038/s41419-025-07933-1","url":null,"abstract":"<p><p>Neuroblastomas encompass malignant cells with varying degrees of differentiation, ranging from adrenergic (adr) cells resembling the sympathoadrenal lineage to undifferentiated, stem-cell-like mesenchymal (mes) cancer cells. Relapsed neuroblastomas, which often have mesenchymal features, have a poor prognosis and respond less to anticancer therapies, necessitating the development of novel treatment strategies. To identify novel treatment options, we analyzed the sensitivity of 91 pediatric cell models, including patient-derived tumoroid cultures, to a drug library of 76 anti-cancer drugs at clinically relevant concentrations. This included 24 three-dimensionally cultured neuroblastoma cell lines representing the range of mesenchymal to adrenergic subtypes. High-throughput ATP-based luminescence measurements were compared to high-content confocal imaging. With machine learning-supported imaging analysis, we focused on changes in the lysosomal compartment as a marker for therapy-induced senescence and assessed the basal lysosomal levels in a subset of untreated mesenchymal versus adrenergic cells. We correlated these findings with pathway activity signatures based on bulk RNA and scRNAseq. Comprehensive image-based synergy screens with spheroid cultures validated the combined effects of selected drugs on proliferation and cytotoxicity. Mesenchymal models presented high basal lysosomal levels correlating with senescence-associated secretory phenotype (SASP) and sphingolipid metabolism pathways. Chemotherapy treatment further increased lysosome numbers, indicative of therapy-induced senescence. Furthermore, the mesenchymal subtypes correlated with MAPK activity and sensitivity to MAPK pathway inhibitors. Lysosomal and SASP signaling is druggable by inhibitors of lysosomal acid sphingomyelinase (SLMi) or senolytics, including BCL2-family inhibitors. Especially the sequential combination of MEK inhibitors (MEKi) with BCL2-family inhibitors was the most effective on relapsed neuroblastoma cell lines. Gene expression analysis of 223 patient samples, drug sensitivity profiling of five patient-derived fresh tissue cultures, and in vivo zebrafish embryo neuroblastoma xenograft models confirmed these findings. Inhibition of MAPK signaling in combination with BCL2-family inhibitors is a novel treatment option for patients suffering from relapsed neuroblastomas.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"644"},"PeriodicalIF":9.6,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}