Yizeng Fan, Yuzhao Wang, Weichao Dan, Yilei Zhang, Li Nie, Zhiqiang Ma, Yanxin Zhuang, Bo Liu, Mengxing Li, Tianjie Liu, Zixi Wang, Leihong Ye, Yi Wei, Yuzeshi Lei, Chendong Guo, Jiale An, Chi Wang, Yulin Zhang, Jin Zeng, Wenyi Wei, Boyi Gan, Lei Li
{"title":"PRMT5-mediated arginine methylation stabilizes GPX4 to suppress ferroptosis in cancer","authors":"Yizeng Fan, Yuzhao Wang, Weichao Dan, Yilei Zhang, Li Nie, Zhiqiang Ma, Yanxin Zhuang, Bo Liu, Mengxing Li, Tianjie Liu, Zixi Wang, Leihong Ye, Yi Wei, Yuzeshi Lei, Chendong Guo, Jiale An, Chi Wang, Yulin Zhang, Jin Zeng, Wenyi Wei, Boyi Gan, Lei Li","doi":"10.1038/s41556-025-01610-3","DOIUrl":"https://doi.org/10.1038/s41556-025-01610-3","url":null,"abstract":"<p>The activation of ferroptosis has shown great potential for cancer therapy from an unconventional perspective, but revealing the mechanisms underlying the suppression of tumour-intrinsic ferroptosis to promote tumorigenesis remains a challenging task. Here we report that methionine is metabolized into <i>S</i>-adenosylmethionine, which functions as a methyl-group donor to trigger symmetric dimethylation of glutathione peroxidase 4 (GPX4) at the conserved arginine 152 (R152) residue, along with a prolonged GPX4 half-life. Inhibition of protein arginine methyltransferase 5 (PRMT5), which catalyses GPX4 methylation, decreases GPX4 protein levels by impeding GPX4 methylation and increasing ferroptosis inducer sensitivity in vitro and in vivo. This methylation prevents Cullin1-FBW7 E3 ligase binding to GPX4, thereby abrogating the ubiquitination-mediated GPX4 degradation. Notably, combining PRMT5 inhibitor treatment with ferroptotic therapies markedly suppresses tumour progression in mouse tumour models. In addition, the levels of GPX4 are negatively correlated with the levels of FBW7 and a poor prognosis in patients with human carcinoma. In summary, we found that PRMT5 functions as a target for improving cancer therapy efficacy, by acting to reduce the counteraction of ferroptosis by tumour cells by means of PRMT5-enhanced GPX4 stability.</p>","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"33 1","pages":""},"PeriodicalIF":21.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bicna Song, Dingyu Liu, Weiwei Dai, Natalie F. McMyn, Qingyang Wang, Dapeng Yang, Adam Krejci, Anatoly Vasilyev, Nicole Untermoser, Anke Loregger, Dongyuan Song, Breanna Williams, Bess Rosen, Xiaolong Cheng, Lumen Chao, Hanuman T. Kale, Hao Zhang, Yarui Diao, Tilmann Bürckstümmer, Janet D. Siliciano, Jingyi Jessica Li, Robert F. Siliciano, Danwei Huangfu, Wei Li
{"title":"Decoding heterogeneous single-cell perturbation responses","authors":"Bicna Song, Dingyu Liu, Weiwei Dai, Natalie F. McMyn, Qingyang Wang, Dapeng Yang, Adam Krejci, Anatoly Vasilyev, Nicole Untermoser, Anke Loregger, Dongyuan Song, Breanna Williams, Bess Rosen, Xiaolong Cheng, Lumen Chao, Hanuman T. Kale, Hao Zhang, Yarui Diao, Tilmann Bürckstümmer, Janet D. Siliciano, Jingyi Jessica Li, Robert F. Siliciano, Danwei Huangfu, Wei Li","doi":"10.1038/s41556-025-01626-9","DOIUrl":"10.1038/s41556-025-01626-9","url":null,"abstract":"Understanding how cells respond differently to perturbation is crucial in cell biology, but existing methods often fail to accurately quantify and interpret heterogeneous single-cell responses. Here we introduce the perturbation-response score (PS), a method to quantify diverse perturbation responses at a single-cell level. Applied to single-cell perturbation datasets such as Perturb-seq, PS outperforms existing methods in quantifying partial gene perturbations. PS further enables single-cell dosage analysis without needing to titrate perturbations, and identifies ‘buffered’ and ‘sensitive’ response patterns of essential genes, depending on whether their moderate perturbations lead to strong downstream effects. PS reveals differential cellular responses on perturbing key genes in contexts such as T cell stimulation, latent HIV-1 expression and pancreatic differentiation. Notably, we identified a previously unknown role for the coiled-coil domain containing 6 (CCDC6) in regulating liver and pancreatic cell fate decisions. PS provides a powerful method for dose-to-function analysis, offering deeper insights from single-cell perturbation data. In two independent studies, Song et al. and Jiang, Dalgarno et al. present computational frameworks, perturbation-response score and Mixscale, respectively, to determine individual cellular variation in response to perturbation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"493-504"},"PeriodicalIF":17.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-025-01626-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495326","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":"Systematic reconstruction of molecular pathway signatures using scalable single-cell perturbation screens","authors":"Longda Jiang, Carol Dalgarno, Efthymia Papalexi, Isabella Mascio, Hans-Hermann Wessels, Huiyoung Yun, Nika Iremadze, Gila Lithwick-Yanai, Doron Lipson, Rahul Satija","doi":"10.1038/s41556-025-01622-z","DOIUrl":"10.1038/s41556-025-01622-z","url":null,"abstract":"Recent advancements in functional genomics have provided an unprecedented ability to measure diverse molecular modalities, but predicting causal regulatory relationships from observational data remains challenging. Here, we leverage pooled genetic screens and single-cell sequencing (Perturb-seq) to systematically identify the targets of signalling regulators in diverse biological contexts. We demonstrate how Perturb-seq is compatible with recent and commercially available advances in combinatorial indexing and next-generation sequencing, and perform more than 1,500 perturbations split across six cell lines and five biological signalling contexts. We introduce an improved computational framework (Mixscale) to address cellular variation in perturbation efficiency, alongside optimized statistical methods to learn differentially expressed gene lists and conserved molecular signatures. Finally, we demonstrate how our Perturb-seq derived gene lists can be used to precisely infer changes in signalling pathway activation for in vivo and in situ samples. Our work enhances our understanding of signalling regulators and their targets, and lays a computational framework towards the data-driven inference of an ‘atlas’ of perturbation signatures. In two independent studies, Song et al. and Jiang, Dalgarno et al. present computational frameworks, perturbation-response score and Mixscale, respectively, to determine individual cellular variation in response to perturbation.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"505-517"},"PeriodicalIF":17.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ewan MacDonald, Alison Forrester, Cesar A. Valades-Cruz, Thomas D. Madsen, Joseph H. R. Hetmanski, Estelle Dransart, Yeap Ng, Rashmi Godbole, Ananthan Akhil Shp, Ludovic Leconte, Valérie Chambon, Debarpan Ghosh, Alexis Pinet, Dhiraj Bhatia, Bérangère Lombard, Damarys Loew, Martin R. Larsen, Hakon Leffler, Dirk J. Lefeber, Henrik Clausen, Anne Blangy, Patrick Caswell, Massiullah Shafaq-Zadah, Satyajit Mayor, Roberto Weigert, Christian Wunder, Ludger Johannes
{"title":"Publisher Correction: Growth factor-triggered de-sialylation controls glycolipid-lectin-driven endocytosis","authors":"Ewan MacDonald, Alison Forrester, Cesar A. Valades-Cruz, Thomas D. Madsen, Joseph H. R. Hetmanski, Estelle Dransart, Yeap Ng, Rashmi Godbole, Ananthan Akhil Shp, Ludovic Leconte, Valérie Chambon, Debarpan Ghosh, Alexis Pinet, Dhiraj Bhatia, Bérangère Lombard, Damarys Loew, Martin R. Larsen, Hakon Leffler, Dirk J. Lefeber, Henrik Clausen, Anne Blangy, Patrick Caswell, Massiullah Shafaq-Zadah, Satyajit Mayor, Roberto Weigert, Christian Wunder, Ludger Johannes","doi":"10.1038/s41556-025-01643-8","DOIUrl":"10.1038/s41556-025-01643-8","url":null,"abstract":"","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"545-545"},"PeriodicalIF":17.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-025-01643-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495834","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":"ER-to-Golgi trafficking through a dynamic intermediate cis-Golgi tubular network in Arabidopsis","authors":"Louise Fougère, Magali Grison, Patricia Laquel, Matheus Montrazi, Fabrice Cordelières, Mónica Fernández-Monreal, Christel Poujol, Tomohiro Uemura, Akihiko Nakano, Yoko Ito, Yohann Boutté","doi":"10.1038/s41556-025-01624-x","DOIUrl":"10.1038/s41556-025-01624-x","url":null,"abstract":"Endoplasmic reticulum (ER)-to-Golgi trafficking is a central process of the secretory system of eukaryotic cells that ensures proper spatiotemporal sorting of proteins and lipids. However, the nature of the ER–Golgi intermediate compartments (ERGICs) and the molecular mechanisms mediating the transition between ERGICs and the Golgi, as well as the universality of these processes among eukaryotes, remain undiscovered. Here we identify a reticulated tubulo-vesicular network, labelled by MEMBRIN proteins, that is mostly independent of the Golgi, highly dynamic at the ER–Golgi interface and crossed by ER-induced released luminal cargos. We find that plant ERGICs become stabilized by the interaction they establish with pre-existing Golgi and gradually mature into Golgi cisternae, this process being dependent on C24-ceramide sphingolipids. Our study is a major twist in the understanding of the Golgi, as it identifies that the ERGICs in plants comprise a Golgi-independent and highly dynamic tubular network from which arise more stable Golgi-associated pre-cisternae structures. Fougère, Grison et al. show that the ER–Golgi intermediate compartment (ERGIC) in plants is a tubulo-vesicular network marked by MEMBRIN proteins that is largely Golgi-independent. The plant ERGIC matures into Golgi cisternae, in a process that depends on sphingolipids.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"424-437"},"PeriodicalIF":17.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143485664","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"A class of large cell-like extracellular vesicles","authors":"Crislyn D’Souza-Schorey, Dolores Di Vizio","doi":"10.1038/s41556-025-01611-2","DOIUrl":"10.1038/s41556-025-01611-2","url":null,"abstract":"Recent discoveries in the field of large extracellular vesicles have revealed a greater diversity in subtypes than was appreciated even only a decade or so ago. A study now describes a cell-autonomous, motile, organelle-rich extracellular vesicle with cell-like functions and the largest one yet — the blebbisome.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"372-374"},"PeriodicalIF":17.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dennis K. Jeppesen, Zachary C. Sanchez, Noah M. Kelley, James B. Hayes, Jessica Ambroise, Emma N. Koory, Evan Krystofiak, Nilay Taneja, Qin Zhang, Matthew M. Dungan, Olivia L. Perkins, Matthew J. Tyska, Ela W. Knapik, Kevin M. Dean, Amanda C. Doran, Robert J. Coffey, Dylan T. Burnette
{"title":"Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties","authors":"Dennis K. Jeppesen, Zachary C. Sanchez, Noah M. Kelley, James B. Hayes, Jessica Ambroise, Emma N. Koory, Evan Krystofiak, Nilay Taneja, Qin Zhang, Matthew M. Dungan, Olivia L. Perkins, Matthew J. Tyska, Ela W. Knapik, Kevin M. Dean, Amanda C. Doran, Robert J. Coffey, Dylan T. Burnette","doi":"10.1038/s41556-025-01621-0","DOIUrl":"10.1038/s41556-025-01621-0","url":null,"abstract":"Cells secrete a large variety of extracellular vesicles (EVs) to engage in cell-to-cell and cell-to-environment intercellular communication. EVs are functionally involved in many physiological and pathological processes by interacting with cells that facilitate transfer of proteins, lipids and genetic information. However, our knowledge of EVs is incomplete. Here we show that cells actively release exceptionally large (up to 20 µm) membrane-enclosed vesicles that exhibit active blebbing behavior, and we, therefore, have termed them blebbisomes. Blebbisomes contain an array of cellular organelles that include functional mitochondria and multivesicular endosomes, yet lack a definable nucleus. We show that blebbisomes can both secrete and internalize exosomes and microvesicles. Blebbisomes are released from normal and cancer cells, can be observed by direct imaging of cancer cells in vivo and are present in normal bone marrow. We demonstrate that cancer-derived blebbisomes contain a plethora of inhibitory immune checkpoint proteins, including PD-L1, PD-L2, B7-H3, VISTA, PVR and HLA-E. These data identify a very large, organelle-containing functional EV that act as cell-autonomous mobile communication centres capable of integrating and responding to signals in the extracellular environment. Jeppesen, Sanchez et al. identify blebbisomes as large membrane-enclosed vesicles containing organelles and secreted by cells. Blebbisomes can both secrete and internalize exosomes and microvesicles.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"438-448"},"PeriodicalIF":17.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41556-025-01621-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462173","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":"Intratumour oxidative hotspots provide a niche for cancer cell dissemination","authors":"Yoshifumi Ueda, Shigeki Kiyonaka, Laura M. Selfors, Keisuke Inoue, Hiroshi Harada, Tomohiro Doura, Kunishige Onuma, Makoto Uchiyama, Ryuhei Kurogi, Yuji Yamada, Jiacheng H. Sun, Reiko Sakaguchi, Yuki Tado, Haruki Omatsu, Harufumi Suzuki, Mike Aoun, Takahiro Nakayama, Taketoshi Kajimoto, Tetsuya Yano, Rikard Holmdahl, Itaru Hamachi, Masahiro Inoue, Yasuo Mori, Nobuaki Takahashi","doi":"10.1038/s41556-025-01617-w","DOIUrl":"10.1038/s41556-025-01617-w","url":null,"abstract":"Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H2O2, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H2O2-rich microenvironments (H2O2 hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H2O2 underwent partial epithelial–mesenchymal transition through p38–MYC axis activation and migrated away from H2O2 hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H2O2 hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation. Ueda et al. develop a sensor targeted to tumour cells that tracks extracellular H2O2. Tumour cells in H2O2 hotspots undergo partial epithelial–mesenchymal transition and migrate away from H2O2 hotspots. This is not seen in NRF2-hyperactivated tumours.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"530-543"},"PeriodicalIF":17.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ewan MacDonald, Alison Forrester, Cesar A. Valades-Cruz, Thomas D. Madsen, Joseph H. R. Hetmanski, Estelle Dransart, Yeap Ng, Rashmi Godbole, Ananthan Akhil Shp, Ludovic Leconte, Valérie Chambon, Debarpan Ghosh, Alexis Pinet, Dhiraj Bhatia, Bérangère Lombard, Damarys Loew, Martin R. Larsen, Hakon Leffler, Dirk J. Lefeber, Henrik Clausen, Anne Blangy, Patrick Caswell, Massiullah Shafaq-Zadah, Satyajit Mayor, Roberto Weigert, Christian Wunder, Ludger Johannes
{"title":"Growth factor-triggered de-sialylation controls glycolipid-lectin-driven endocytosis","authors":"Ewan MacDonald, Alison Forrester, Cesar A. Valades-Cruz, Thomas D. Madsen, Joseph H. R. Hetmanski, Estelle Dransart, Yeap Ng, Rashmi Godbole, Ananthan Akhil Shp, Ludovic Leconte, Valérie Chambon, Debarpan Ghosh, Alexis Pinet, Dhiraj Bhatia, Bérangère Lombard, Damarys Loew, Martin R. Larsen, Hakon Leffler, Dirk J. Lefeber, Henrik Clausen, Anne Blangy, Patrick Caswell, Massiullah Shafaq-Zadah, Satyajit Mayor, Roberto Weigert, Christian Wunder, Ludger Johannes","doi":"10.1038/s41556-025-01616-x","DOIUrl":"10.1038/s41556-025-01616-x","url":null,"abstract":"Glycolipid-lectin-driven endocytosis controls the formation of clathrin-independent carriers and the internalization of various cargos such as β1 integrin. Whether this process is regulated in a dynamic manner remained unexplored. Here we demonstrate that, within minutes, the epidermal growth factor triggers the galectin-driven endocytosis of cell-surface glycoproteins, such as integrins, that are key regulators of cell adhesion and migration. The onset of this process—mediated by the Na+/H+ antiporter NHE1 as well as the neuraminidases Neu1 and Neu3—requires the pH-triggered enzymatic removal of sialic acids whose presence otherwise prevents galectin binding. De-sialylated glycoproteins are then retrogradely transported to the Golgi apparatus where their glycan make-up is reset to regulate EGF-dependent invasive-cell migration. Further evidence is provided for a role of neuraminidases and galectin-3 in acidification-dependent bone resorption. Glycosylation at the cell surface thereby emerges as a dynamic and reversible regulatory post-translational modification that controls a highly adaptable trafficking pathway. MacDonald et al. show that EGF triggers de-sialylation of plasma membrane glycoproteins like integrins in a mechanism that depends on the Na+/H+ antiporter NHE1 and the neuraminidases Neu1 and Neu3. Integrins are trafficked to the Golgi and re-sialylated.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"449-463"},"PeriodicalIF":17.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Theresa Willem, Vladimir A. Shitov, Malte D. Luecken, Niki Kilbertus, Stefan Bauer, Marie Piraud, Alena Buyx, Fabian J. Theis
{"title":"Biases in machine-learning models of human single-cell data","authors":"Theresa Willem, Vladimir A. Shitov, Malte D. Luecken, Niki Kilbertus, Stefan Bauer, Marie Piraud, Alena Buyx, Fabian J. Theis","doi":"10.1038/s41556-025-01619-8","DOIUrl":"10.1038/s41556-025-01619-8","url":null,"abstract":"Recent machine-learning (ML)-based advances in single-cell data science have enabled the stratification of human tissue donors at single-cell resolution, promising to provide valuable diagnostic and prognostic insights. However, such insights are susceptible to biases. Here we discuss various biases that emerge along the pipeline of ML-based single-cell analysis, ranging from societal biases affecting whose samples are collected, to clinical and cohort biases that influence the generalizability of single-cell datasets, biases stemming from single-cell sequencing, ML biases specific to (weakly supervised or unsupervised) ML models trained on human single-cell samples and biases during the interpretation of results from ML models. We end by providing methods for single-cell data scientists to assess and mitigate biases, and call for efforts to address the root causes of biases. This Perspective discusses the various biases that can emerge along the pipeline of machine learning-based single-cell analysis and presents methods to train models on human single-cell data in order to assess and mitigate these biases.","PeriodicalId":18977,"journal":{"name":"Nature Cell Biology","volume":"27 3","pages":"384-392"},"PeriodicalIF":17.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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