Pub Date : 2025-03-03DOI: 10.1016/j.cell.2025.02.002
Zhiguang Chang, Xuan Guo, Xuefei Li, Yan Wang, Zhongsheng Zang, Siyu Pei, Weiqi Lu, Yang Li, Jian-Dong Huang, Yichuan Xiao, Chenli Liu
Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate anti-tumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered Salmonella enterica strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10Rhi state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8+ T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10Rhi state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy’s dual challenge in solid tumors and provides a framework for intratumoral immunomodulation.
{"title":"Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization","authors":"Zhiguang Chang, Xuan Guo, Xuefei Li, Yan Wang, Zhongsheng Zang, Siyu Pei, Weiqi Lu, Yang Li, Jian-Dong Huang, Yichuan Xiao, Chenli Liu","doi":"10.1016/j.cell.2025.02.002","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.002","url":null,"abstract":"Bacterial immunotherapy holds promising cancer-fighting potential. However, unlocking its power requires a mechanistic understanding of how bacteria both evade antimicrobial immune defenses and stimulate anti-tumor immune responses within the tumor microenvironment (TME). Here, by harnessing an engineered <em>Salmonella enterica</em> strain with this dual proficiency, we unveil an underlying singular mechanism. Specifically, the hysteretic nonlinearity of interleukin-10 receptor (IL-10R) expression drives tumor-infiltrated immune cells into a tumor-specific IL-10R<sup>hi</sup> state. Bacteria leverage this to enhance tumor-associated macrophages producing IL-10, evade phagocytosis by tumor-associated neutrophils, and coincidently expand and stimulate the preexisting exhausted tumor-resident CD8<sup>+</sup> T cells. This effective combination eliminates tumors, prevents recurrence, and inhibits metastasis across multiple tumor types. Analysis of human samples suggests that the IL-10R<sup>hi</sup> state might be a ubiquitous trait across human tumor types. Our study unveils the unsolved mechanism behind bacterial immunotherapy’s dual challenge in solid tumors and provides a framework for intratumoral immunomodulation.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"8 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532370","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}
Pub Date : 2025-02-28DOI: 10.1016/j.cell.2025.01.046
Qinqin Jiang, David A. Braun, Karl R. Clauser, Vijyendra Ramesh, Nitin H. Shirole, Joseph E. Duke-Cohan, Nancy Nabilsi, Nicholas J. Kramer, Cleo Forman, Isabelle E. Lippincott, Susan Klaeger, Kshiti M. Phulphagar, Vipheaviny Chea, Nawoo Kim, Allison P. Vanasse, Eddy Saad, Teagan Parsons, Melissa Carr-Reynolds, Isabel Carulli, Katarina Pinjusic, William G. Kaelin
Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.
{"title":"HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy","authors":"Qinqin Jiang, David A. Braun, Karl R. Clauser, Vijyendra Ramesh, Nitin H. Shirole, Joseph E. Duke-Cohan, Nancy Nabilsi, Nicholas J. Kramer, Cleo Forman, Isabelle E. Lippincott, Susan Klaeger, Kshiti M. Phulphagar, Vipheaviny Chea, Nawoo Kim, Allison P. Vanasse, Eddy Saad, Teagan Parsons, Melissa Carr-Reynolds, Isabel Carulli, Katarina Pinjusic, William G. Kaelin","doi":"10.1016/j.cell.2025.01.046","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.046","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the <em>VHL</em> tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"25 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517819","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}
Pub Date : 2025-02-28DOI: 10.1016/j.cell.2025.02.024
Tom Maniatis
NIH’s abrupt decision to cap indirect cost reimbursement at 15% threatens the critical infrastructure supporting groundbreaking biomedical research in the United States. This policy jeopardizes America’s global leadership in science and medicine. Urgent action is needed to advocate for its immediate and permanent reversal to protect the future of science.
{"title":"Safeguarding the future of biomedical science in the United States","authors":"Tom Maniatis","doi":"10.1016/j.cell.2025.02.024","DOIUrl":"https://doi.org/10.1016/j.cell.2025.02.024","url":null,"abstract":"NIH’s abrupt decision to cap indirect cost reimbursement at 15% threatens the critical infrastructure supporting groundbreaking biomedical research in the United States. This policy jeopardizes America’s global leadership in science and medicine. Urgent action is needed to advocate for its immediate and permanent reversal to protect the future of science.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"33 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143526494","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}
Pub Date : 2025-02-28DOI: 10.1016/j.cell.2025.01.041
Maxime Beau, David J. Herzfeld, Francisco Naveros, Marie E. Hemelt, Federico D’Agostino, Marlies Oostland, Alvaro Sánchez-López, Young Yoon Chung, Michael Maibach, Stephen Kyranakis, Hannah N. Stabb, M. Gabriela Martínez Lopera, Agoston Lajko, Marie Zedler, Shogo Ohmae, Nathan J. Hall, Beverley A. Clark, Dana Cohen, Stephen G. Lisberger, Dimitar Kostadinov, Javier F. Medina
High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but fail to reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals and reveal the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetics and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep learning classifier that predicts cell types with greater than 95% accuracy based on the waveform, discharge statistics, and layer of the recorded neuron. The classifier’s predictions agree with expert classification on recordings using different probes, in different laboratories, from functionally distinct cerebellar regions, and across species. Our classifier extends the power of modern dynamical systems analyses by revealing the unique contributions of simultaneously recorded cell types during behavior.
{"title":"A deep learning strategy to identify cell types across species from high-density extracellular recordings","authors":"Maxime Beau, David J. Herzfeld, Francisco Naveros, Marie E. Hemelt, Federico D’Agostino, Marlies Oostland, Alvaro Sánchez-López, Young Yoon Chung, Michael Maibach, Stephen Kyranakis, Hannah N. Stabb, M. Gabriela Martínez Lopera, Agoston Lajko, Marie Zedler, Shogo Ohmae, Nathan J. Hall, Beverley A. Clark, Dana Cohen, Stephen G. Lisberger, Dimitar Kostadinov, Javier F. Medina","doi":"10.1016/j.cell.2025.01.041","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.041","url":null,"abstract":"High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but fail to reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals and reveal the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetics and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep learning classifier that predicts cell types with greater than 95% accuracy based on the waveform, discharge statistics, and layer of the recorded neuron. The classifier’s predictions agree with expert classification on recordings using different probes, in different laboratories, from functionally distinct cerebellar regions, and across species. Our classifier extends the power of modern dynamical systems analyses by revealing the unique contributions of simultaneously recorded cell types during behavior.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"31 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517816","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}
Pub Date : 2025-02-28DOI: 10.1016/j.cell.2025.01.043
Xiadi He, Qiwei Wang, Xin Cheng, Weihua Wang, Yutong Li, Yabing Nan, Jiang Wu, Bingqiu Xiu, Tao Jiang, Johann S. Bergholz, Hao Gu, Fuhui Chen, Guangjian Fan, Lianhui Sun, Shaozhen Xie, Junjie Zou, Sheng Lin, Yun Wei, James Lee, John M. Asara, Jean J. Zhao
Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form “vitcyl-lysine”—a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC’s cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.
{"title":"Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response","authors":"Xiadi He, Qiwei Wang, Xin Cheng, Weihua Wang, Yutong Li, Yabing Nan, Jiang Wu, Bingqiu Xiu, Tao Jiang, Johann S. Bergholz, Hao Gu, Fuhui Chen, Guangjian Fan, Lianhui Sun, Shaozhen Xie, Junjie Zou, Sheng Lin, Yun Wei, James Lee, John M. Asara, Jean J. Zhao","doi":"10.1016/j.cell.2025.01.043","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.043","url":null,"abstract":"Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form “vitcyl-lysine”—a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity <em>in vitro</em> and <em>in vivo</em>. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC’s cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"23 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517818","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}
Pub Date : 2025-02-27DOI: 10.1016/j.cell.2025.01.040
Jonathan Perr, Andreas Langen, Karim Almahayni, Gianluca Nestola, Peiyuan Chai, Charlotta G. Lebedenko, Regan F. Volk, Diego Detrés, Reese M. Caldwell, Malte Spiekermann, Helena Hemberger, Namita Bisaria, Toshihiko Aiba, Francisco J. Sánchez-Rivera, Konstantinos Tzelepis, Eliezer Calo, Leonhard Möckl, Balyn W. Zaro, Ryan A. Flynn
The composition and organization of the cell surface determine how cells interact with their environment. Traditionally, glycosylated transmembrane proteins were thought to be the major constituents of the external surface of the plasma membrane. Here, we provide evidence that a group of RNA-binding proteins (RBPs) is present on the surface of living cells. These cell-surface RBPs (csRBPs) precisely organize into well-defined nanoclusters enriched for multiple RBPs and glycoRNAs, and their clustering can be disrupted by extracellular RNase addition. These glycoRNA-csRBP clusters further serve as sites of cell-surface interaction for the cell-penetrating peptide trans-activator of transcription (TAT). Removal of RNA from the cell surface, or loss of RNA-binding activity by TAT, causes defects in TAT cell internalization. Together, we provide evidence of an expanded view of the cell surface by positioning glycoRNA-csRBP clusters as a regulator of communication between cells and the extracellular environment.
{"title":"RNA-binding proteins and glycoRNAs form domains on the cell surface for cell-penetrating peptide entry","authors":"Jonathan Perr, Andreas Langen, Karim Almahayni, Gianluca Nestola, Peiyuan Chai, Charlotta G. Lebedenko, Regan F. Volk, Diego Detrés, Reese M. Caldwell, Malte Spiekermann, Helena Hemberger, Namita Bisaria, Toshihiko Aiba, Francisco J. Sánchez-Rivera, Konstantinos Tzelepis, Eliezer Calo, Leonhard Möckl, Balyn W. Zaro, Ryan A. Flynn","doi":"10.1016/j.cell.2025.01.040","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.040","url":null,"abstract":"The composition and organization of the cell surface determine how cells interact with their environment. Traditionally, glycosylated transmembrane proteins were thought to be the major constituents of the external surface of the plasma membrane. Here, we provide evidence that a group of RNA-binding proteins (RBPs) is present on the surface of living cells. These cell-surface RBPs (csRBPs) precisely organize into well-defined nanoclusters enriched for multiple RBPs and glycoRNAs, and their clustering can be disrupted by extracellular RNase addition. These glycoRNA-csRBP clusters further serve as sites of cell-surface interaction for the cell-penetrating peptide <em>trans</em>-activator of transcription (TAT). Removal of RNA from the cell surface, or loss of RNA-binding activity by TAT, causes defects in TAT cell internalization. Together, we provide evidence of an expanded view of the cell surface by positioning glycoRNA-csRBP clusters as a regulator of communication between cells and the extracellular environment.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"28 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143507261","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}
Pub Date : 2025-02-27DOI: 10.1016/j.cell.2025.01.039
Rodolfo A. Salido, Haoqi Nina Zhao, Daniel McDonald, Helena Mannochio-Russo, Simone Zuffa, Renee E. Oles, Allegra T. Aron, Yasin El Abiead, Sawyer Farmer, Antonio González, Cameron Martino, Ipsita Mohanty, Ceth W. Parker, Lucas Patel, Paulo Wender Portal Gomes, Robin Schmid, Tara Schwartz, Jennifer Zhu, Michael R. Barratt, Kathleen H. Rubins, Rob Knight
Space habitation provides unique challenges in built environments isolated from Earth. We produced a 3D map of the microbes and metabolites throughout the United States Orbital Segment (USOS) of the International Space Station (ISS) with 803 samples collected during space flight, including controls. We find that the use of each of the nine sampled modules within the ISS strongly drives the microbiology and chemistry of the habitat. Relating the microbiology to other Earth habitats, we find that, as with human microbiota, built environment microbiota also align naturally along an axis of industrialization, with the ISS providing an extreme example of an industrialized environment. We demonstrate the utility of culture-independent sequencing for microbial risk monitoring, especially as the location of sequencing moves to space. The resulting resource of chemistry and microbiology in the space-built environment will guide long-term efforts to maintain human health in space for longer durations.
{"title":"The International Space Station has a unique and extreme microbial and chemical environment driven by use patterns","authors":"Rodolfo A. Salido, Haoqi Nina Zhao, Daniel McDonald, Helena Mannochio-Russo, Simone Zuffa, Renee E. Oles, Allegra T. Aron, Yasin El Abiead, Sawyer Farmer, Antonio González, Cameron Martino, Ipsita Mohanty, Ceth W. Parker, Lucas Patel, Paulo Wender Portal Gomes, Robin Schmid, Tara Schwartz, Jennifer Zhu, Michael R. Barratt, Kathleen H. Rubins, Rob Knight","doi":"10.1016/j.cell.2025.01.039","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.039","url":null,"abstract":"Space habitation provides unique challenges in built environments isolated from Earth. We produced a 3D map of the microbes and metabolites throughout the United States Orbital Segment (USOS) of the International Space Station (ISS) with 803 samples collected during space flight, including controls. We find that the use of each of the nine sampled modules within the ISS strongly drives the microbiology and chemistry of the habitat. Relating the microbiology to other Earth habitats, we find that, as with human microbiota, built environment microbiota also align naturally along an axis of industrialization, with the ISS providing an extreme example of an industrialized environment. We demonstrate the utility of culture-independent sequencing for microbial risk monitoring, especially as the location of sequencing moves to space. The resulting resource of chemistry and microbiology in the space-built environment will guide long-term efforts to maintain human health in space for longer durations.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"10 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143506910","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}
Pub Date : 2025-02-20DOI: 10.1016/j.cell.2025.01.015
Artem Khan, Yuyang Liu, Mark Gad, Timothy C. Kenny, Kıvanç Birsoy
Solute carrier (SLC) proteins play critical roles in maintaining cellular and organismal homeostasis by transporting small molecules and ions. Despite a growing body of research over the past decade, physiological substrates and functions of many SLCs remain elusive. This perspective outlines key challenges in studying SLC biology and proposes an evidence-based framework for defining SLC substrates. To accelerate the deorphanization process, we explore systematic technologies, including human genetics, biochemistry, and computational and structural approaches. Finally, we suggest directions to better understand SLC functions beyond substrate identification in physiology and disease.
{"title":"Solute carriers: The gatekeepers of metabolism","authors":"Artem Khan, Yuyang Liu, Mark Gad, Timothy C. Kenny, Kıvanç Birsoy","doi":"10.1016/j.cell.2025.01.015","DOIUrl":"https://doi.org/10.1016/j.cell.2025.01.015","url":null,"abstract":"Solute carrier (SLC) proteins play critical roles in maintaining cellular and organismal homeostasis by transporting small molecules and ions. Despite a growing body of research over the past decade, physiological substrates and functions of many SLCs remain elusive. This perspective outlines key challenges in studying SLC biology and proposes an evidence-based framework for defining SLC substrates. To accelerate the deorphanization process, we explore systematic technologies, including human genetics, biochemistry, and computational and structural approaches. Finally, we suggest directions to better understand SLC functions beyond substrate identification in physiology and disease.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"50 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463096","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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