Pub Date : 2026-03-11DOI: 10.1016/j.cell.2026.02.014
Suel-Kee Kim, Adriana Cherskov, Aastha Sindhwani, Sang-Hun Choi, Hyojin Kim, Ming-Li Li, Menglei Zhang, Xoel Mato-Blanco, Yuting Liu, Nicola Micali, David M. Young, Mark Estacion, Yueqi Zhang, José Manuel Ruiz-Jiménez, Anandita Nadkarni, Victor Luria, Suvimal Kumar Sindhu, Ipsita Chatterjee, Akemi Shibata, Dan Liang, Nenad Sestan
Understanding the unique features of the human brain compared with non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells (GCs). Experimental data show that ZP2 expression in human GCs is induced by pontine mossy fibers, reducing synaptic proteins at the pontocerebellar glomerular synapses and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.
{"title":"Human-specific features of the cerebellum and ZP2-regulated synapse development","authors":"Suel-Kee Kim, Adriana Cherskov, Aastha Sindhwani, Sang-Hun Choi, Hyojin Kim, Ming-Li Li, Menglei Zhang, Xoel Mato-Blanco, Yuting Liu, Nicola Micali, David M. Young, Mark Estacion, Yueqi Zhang, José Manuel Ruiz-Jiménez, Anandita Nadkarni, Victor Luria, Suvimal Kumar Sindhu, Ipsita Chatterjee, Akemi Shibata, Dan Liang, Nenad Sestan","doi":"10.1016/j.cell.2026.02.014","DOIUrl":"https://doi.org/10.1016/j.cell.2026.02.014","url":null,"abstract":"Understanding the unique features of the human brain compared with non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adaptability and dexterity. To identify shared and divergent features across primates, we conducted single-nucleus transcriptomic and chromatin accessibility profiling of the adult cerebellar cortex in humans, chimpanzees, macaques, and marmosets. We revealed human-specific transcriptomic and regulatory features, particularly those involved in synaptogenesis. Notably, we identified enrichment of the sperm receptor zona pellucida glycoprotein 2 (ZP2) and its potential interactors, known for their roles in gamete interaction, in human granule cells (GCs). Experimental data show that ZP2 expression in human GCs is induced by pontine mossy fibers, reducing synaptic proteins at the pontocerebellar glomerular synapses and decreasing cerebellar neuron electrophysiological activity. This unexpected co-option of ZP2 in human-specific synapse regulation provides insights into the evolutionary specialization of the human cerebellum.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"109 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393447","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 : 2026-03-11DOI: 10.1016/j.cell.2026.02.013
Wei Qian, Xiaoqin Wei, Andrew J Barros, Xiangyu Ye, Haibo Zhang, Qing Yu, Samuel P Young, Eric V Yeatts, Yury Park, Chaofan Li, Sijie Hao, Gislane Almeida-Santos, Jinyi Tang, Harish Narasimhan, Nicole A Kirk, Valeria Molinary, Ying Li, Li Li, Bimal N Desai, Peter Chen, Kwon-Sik Park, Anny Xiaobo Zhou, Jeffrey M Sturek, Wei Chen, In Su Cheon, Jie Sun
The COVID-19 pandemic has highlighted the long-term consequences of viral pneumonia, yet its impact on cancer development remains unclear. Here, we show that patients previously hospitalized with severe COVID-19 have an increased risk of subsequent lung cancer. Across multiple murine models, severe respiratory viral infections accelerated lung cancer growth, whereas vaccination mitigated infection-enhanced tumor progression. Mechanistically, prior viral pneumonia reprogrammed the lung into a pro-tumor microenvironment marked by the sustained accumulation of tumor-associated neutrophils and heightened immunosuppression. We observed persistent chromatin remodeling at key cytokine loci in immune and structural cells, linking inflammatory memory to tumor-promoting signals. Therapeutically, combined blockade of neutrophil recruitment and programmed death-ligand 1 (PD-L1) restored CD8+ T cell function and suppressed tumor growth. Together, these findings establish a causal link between prior viral pneumonia and lung tumorigenesis, underscoring the need for enhanced surveillance and targeted interventions to reduce post-COVID cancer risk.
{"title":"Respiratory viral infections prime accelerated lung cancer growth.","authors":"Wei Qian, Xiaoqin Wei, Andrew J Barros, Xiangyu Ye, Haibo Zhang, Qing Yu, Samuel P Young, Eric V Yeatts, Yury Park, Chaofan Li, Sijie Hao, Gislane Almeida-Santos, Jinyi Tang, Harish Narasimhan, Nicole A Kirk, Valeria Molinary, Ying Li, Li Li, Bimal N Desai, Peter Chen, Kwon-Sik Park, Anny Xiaobo Zhou, Jeffrey M Sturek, Wei Chen, In Su Cheon, Jie Sun","doi":"10.1016/j.cell.2026.02.013","DOIUrl":"10.1016/j.cell.2026.02.013","url":null,"abstract":"<p><p>The COVID-19 pandemic has highlighted the long-term consequences of viral pneumonia, yet its impact on cancer development remains unclear. Here, we show that patients previously hospitalized with severe COVID-19 have an increased risk of subsequent lung cancer. Across multiple murine models, severe respiratory viral infections accelerated lung cancer growth, whereas vaccination mitigated infection-enhanced tumor progression. Mechanistically, prior viral pneumonia reprogrammed the lung into a pro-tumor microenvironment marked by the sustained accumulation of tumor-associated neutrophils and heightened immunosuppression. We observed persistent chromatin remodeling at key cytokine loci in immune and structural cells, linking inflammatory memory to tumor-promoting signals. Therapeutically, combined blockade of neutrophil recruitment and programmed death-ligand 1 (PD-L1) restored CD8<sup>+</sup> T cell function and suppressed tumor growth. Together, these findings establish a causal link between prior viral pneumonia and lung tumorigenesis, underscoring the need for enhanced surveillance and targeted interventions to reduce post-COVID cancer risk.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442766","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 : 2026-03-10DOI: 10.1016/j.cell.2026.02.011
Yue-Chen Liu, Joanne Eakin, Jolie Liston, Rosalind Hunter-Anderson, Calvin Emesiochel, Kiblas Soaladaob, Sunny O. Ngirmang, Olivia Cheronet, Carla S. Hadden, Alexander Cherkinsky, Matthew Spriggs, Keith M. Prufer, Swapan Mallick, Nadin Rohland, Ron Pinhasi, David Reich
The first people reached Remote Oceania 3,000 years before present (BP), arriving roughly simultaneously in the southwest Pacific, the Marianas Archipelago, and Palau. However, no genome-wide ancient DNA data have been available from Palau, a gap we address by reporting 21 individuals from four archaeological sites dating between 2,900 and 500 BP. All had approximately 60% ancestry related to East Asians and 40% to Papuans, similar to present-day Palauans, the longest stretch of population continuity anywhere in Remote Oceania. The lengths of contiguous Papuan ancestry segments in the oldest individuals show that major admixture between Papuans and East Asians in the ancestors of all sampled Palauans began prior to first settlement. This differs from the pattern in the southwest Pacific, where sampled individuals of the Lapita archaeological culture from three different islands had almost entirely East Asian ancestry, with large amounts of Papuan admixture observed only hundreds of years later.
{"title":"Papuan admixture predated the settlement of Palau","authors":"Yue-Chen Liu, Joanne Eakin, Jolie Liston, Rosalind Hunter-Anderson, Calvin Emesiochel, Kiblas Soaladaob, Sunny O. Ngirmang, Olivia Cheronet, Carla S. Hadden, Alexander Cherkinsky, Matthew Spriggs, Keith M. Prufer, Swapan Mallick, Nadin Rohland, Ron Pinhasi, David Reich","doi":"10.1016/j.cell.2026.02.011","DOIUrl":"https://doi.org/10.1016/j.cell.2026.02.011","url":null,"abstract":"The first people reached Remote Oceania 3,000 years before present (BP), arriving roughly simultaneously in the southwest Pacific, the Marianas Archipelago, and Palau. However, no genome-wide ancient DNA data have been available from Palau, a gap we address by reporting 21 individuals from four archaeological sites dating between 2,900 and 500 BP. All had approximately 60% ancestry related to East Asians and 40% to Papuans, similar to present-day Palauans, the longest stretch of population continuity anywhere in Remote Oceania. The lengths of contiguous Papuan ancestry segments in the oldest individuals show that major admixture between Papuans and East Asians in the ancestors of all sampled Palauans began prior to first settlement. This differs from the pattern in the southwest Pacific, where sampled individuals of the Lapita archaeological culture from three different islands had almost entirely East Asian ancestry, with large amounts of Papuan admixture observed only hundreds of years later.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"80 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393448","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 : 2026-03-10DOI: 10.1016/j.cell.2026.02.007
Jérémie Rispal, Jasmine R Garcia, Brisa Palikuqi, Manasa Vegesna, Dedeepya Vaka, Seung Woo Kang, Coralie Trentesaux, Juan Du, Nicola R Realini, Paige N Spencer, James M Gardner, Annika Hausmann, Michael G Kattah, Ken S Lau, Dario Boffelli, Ophir D Klein
The regionalized structure of the intestinal epithelium is critical for its function, and the risk for certain diseases has a regional bias. However, how regionalization is established and how it influences disease susceptibility remain poorly understood. Here, we investigated the role of the gut microbiome-the regionalized community of microorganisms in the intestinal lumen-in promoting regionalization of the colon. We found that the proximo-distal identity of colonocytes along the organ's length is disrupted in mice lacking a microbiome and that the proximal colonic microbiome produces high levels of nicotinic acid, which induces Pparα expression to establish proximal colonocyte identity. Furthermore, we report that microbiome-driven proximal identity confers protection against tissue injury in the mouse. Finally, we determined that the human colon is regionalized and loses its proximal identity during certain disease states.
{"title":"Microbiome-produced nicotinic acid controls colon regional identity and injury susceptibility.","authors":"Jérémie Rispal, Jasmine R Garcia, Brisa Palikuqi, Manasa Vegesna, Dedeepya Vaka, Seung Woo Kang, Coralie Trentesaux, Juan Du, Nicola R Realini, Paige N Spencer, James M Gardner, Annika Hausmann, Michael G Kattah, Ken S Lau, Dario Boffelli, Ophir D Klein","doi":"10.1016/j.cell.2026.02.007","DOIUrl":"10.1016/j.cell.2026.02.007","url":null,"abstract":"<p><p>The regionalized structure of the intestinal epithelium is critical for its function, and the risk for certain diseases has a regional bias. However, how regionalization is established and how it influences disease susceptibility remain poorly understood. Here, we investigated the role of the gut microbiome-the regionalized community of microorganisms in the intestinal lumen-in promoting regionalization of the colon. We found that the proximo-distal identity of colonocytes along the organ's length is disrupted in mice lacking a microbiome and that the proximal colonic microbiome produces high levels of nicotinic acid, which induces Pparα expression to establish proximal colonocyte identity. Furthermore, we report that microbiome-driven proximal identity confers protection against tissue injury in the mouse. Finally, we determined that the human colon is regionalized and loses its proximal identity during certain disease states.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147430451","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 : 2026-03-09DOI: 10.1016/j.cell.2026.02.005
Feng Li, Yuxing Hu, Yan Wang, Xiao Zhang, Shaowei Qiu, Xiaoming Hu, Wenjing Wang, Shuang Wang, Peilin Guo, Cui Song, Huaiji Wang, Changhao He, Jie Sun, Di Yu, Shuhua Yi, Jun Wei, Feifan Liu, Caopei Zheng, Jianxiang Wang, Yuhua Li, Wei Wei
Although promising, chimeric antigen receptor T (CAR T) cell therapy for treating leukemias still faces the critical challenge of antigen modulation, which causes resistance. Building from our clinical insight that both diverse types of leukemia cells and corresponding CAR T cells strongly express CD71 (a ferritin receptor), we designed a ferritin aggregation cell engager (FACE) that can anchor to the CAR T cell surface, guide CAR T cells to face leukemia cells, and facilitate CAR recognition of cognate antigens. In vitro and in vivo experiments with diverse leukemia patient-derived cells and leukemia patient-derived xenograft models show that our FACE-CAR T cells succeed in enhancing therapeutic efficacy with good biosafety, lowering the antigen threshold for overcoming antigen modulation, and even loading chemodrugs in ferritin for combination therapy. This avidity engineering provides a neotype, facile, universal, and flexible approach for improving the efficacy of CAR T cell therapy for diverse refractory leukemias.
{"title":"Ferritin aggregation cell engager for CAR T avidity engineering against refractory leukemias","authors":"Feng Li, Yuxing Hu, Yan Wang, Xiao Zhang, Shaowei Qiu, Xiaoming Hu, Wenjing Wang, Shuang Wang, Peilin Guo, Cui Song, Huaiji Wang, Changhao He, Jie Sun, Di Yu, Shuhua Yi, Jun Wei, Feifan Liu, Caopei Zheng, Jianxiang Wang, Yuhua Li, Wei Wei","doi":"10.1016/j.cell.2026.02.005","DOIUrl":"https://doi.org/10.1016/j.cell.2026.02.005","url":null,"abstract":"Although promising, chimeric antigen receptor T (CAR T) cell therapy for treating leukemias still faces the critical challenge of antigen modulation, which causes resistance. Building from our clinical insight that both diverse types of leukemia cells and corresponding CAR T cells strongly express CD71 (a ferritin receptor), we designed a ferritin aggregation cell engager (FACE) that can anchor to the CAR T cell surface, guide CAR T cells to face leukemia cells, and facilitate CAR recognition of cognate antigens. <em>In vitro</em> and <em>in vivo</em> experiments with diverse leukemia patient-derived cells and leukemia patient-derived xenograft models show that our FACE-CAR T cells succeed in enhancing therapeutic efficacy with good biosafety, lowering the antigen threshold for overcoming antigen modulation, and even loading chemodrugs in ferritin for combination therapy. This avidity engineering provides a neotype, facile, universal, and flexible approach for improving the efficacy of CAR T cell therapy for diverse refractory leukemias.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"406 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380721","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 : 2026-03-09DOI: 10.1016/j.cell.2026.02.009
Zane R. Thornburg, Andrew Maytin, Jiwoong Kwon, Troy A. Brier, Benjamin R. Gilbert, Enguang Fu, Yang-Le Gao, Jordan Quenneville, Tianyu Wu, Henry Li, Talia Long, Weria Pezeshkian, Lijie Sun, John I. Glass, Angad P. Mehta, Taekjip Ha, Zaida Luthey-Schulten
We present a whole-cell spatial and kinetic model for the 100 min cell cycle of the genetically minimal bacterium JCVI-syn3A. We simulate the complete cell cycle in 4D (space and time), including all genetic information processes, metabolic networks, growth, and cell division. By integrating hybrid computational methods, we model the dynamics of morphological transformations. Growth is driven by insertion of lipids and membrane proteins and constrained by fluorescence imaging data. Chromosome replication and segregation are controlled by the essential structural maintenance of chromosome proteins, analogous to condensin (SMC) and topoisomerase proteins in Brownian dynamics simulations, with replication rates responding to deoxyribonucleotide triphosphate (dNTP) pools from metabolism. The model captures the origin-to-terminus ratio measured in our DNA sequencing and recovers other experimental measurements, such as doubling time, mRNA half-lives, protein distributions, and ribosome counts. Because of stochasticity, each replicate cell is unique. We predict not only the average behavior of partitioning to daughter cells but also the heterogeneity among them.
{"title":"Bringing the genetically minimal cell to life on a computer in 4D","authors":"Zane R. Thornburg, Andrew Maytin, Jiwoong Kwon, Troy A. Brier, Benjamin R. Gilbert, Enguang Fu, Yang-Le Gao, Jordan Quenneville, Tianyu Wu, Henry Li, Talia Long, Weria Pezeshkian, Lijie Sun, John I. Glass, Angad P. Mehta, Taekjip Ha, Zaida Luthey-Schulten","doi":"10.1016/j.cell.2026.02.009","DOIUrl":"https://doi.org/10.1016/j.cell.2026.02.009","url":null,"abstract":"We present a whole-cell spatial and kinetic model for the <span><span style=\"\"></span><span data-mathml='<math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow is=\"true\"><mo linebreak=\"goodbreak\" linebreakstyle=\"after\" is=\"true\">&#x223C;</mo></mrow></math>' role=\"presentation\" style=\"font-size: 90%; display: inline-block; position: relative;\" tabindex=\"0\"><svg aria-hidden=\"true\" focusable=\"false\" height=\"1.163ex\" role=\"img\" style=\"vertical-align: 0.307ex; margin-bottom: -0.427ex;\" viewbox=\"0 -449.1 778.5 500.8\" width=\"1.808ex\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"><g fill=\"currentColor\" stroke=\"currentColor\" stroke-width=\"0\" transform=\"matrix(1 0 0 -1 0 0)\"><g is=\"true\"><g is=\"true\"><use xlink:href=\"#MJMAIN-223C\"></use></g></g></g></svg><span role=\"presentation\"><math xmlns=\"http://www.w3.org/1998/Math/MathML\"><mrow is=\"true\"><mo is=\"true\" linebreak=\"goodbreak\" linebreakstyle=\"after\">∼</mo></mrow></math></span></span><script type=\"math/mml\"><math><mrow is=\"true\"><mo linebreak=\"goodbreak\" linebreakstyle=\"after\" is=\"true\">∼</mo></mrow></math></script></span>100 min cell cycle of the genetically minimal bacterium JCVI-syn3A. We simulate the complete cell cycle in 4D (space and time), including all genetic information processes, metabolic networks, growth, and cell division. By integrating hybrid computational methods, we model the dynamics of morphological transformations. Growth is driven by insertion of lipids and membrane proteins and constrained by fluorescence imaging data. Chromosome replication and segregation are controlled by the essential structural maintenance of chromosome proteins, analogous to condensin (SMC) and topoisomerase proteins in Brownian dynamics simulations, with replication rates responding to deoxyribonucleotide triphosphate (dNTP) pools from metabolism. The model captures the origin-to-terminus ratio measured in our DNA sequencing and recovers other experimental measurements, such as doubling time, mRNA half-lives, protein distributions, and ribosome counts. Because of stochasticity, each replicate cell is unique. We predict not only the average behavior of partitioning to daughter cells but also the heterogeneity among them.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"16 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380722","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 : 2026-03-09DOI: 10.1016/j.cell.2026.01.033
Xiaofan Jia, Teng Zhang, Chenxi Yang, Kaiyang Liu, Li Wu, Longfei Diao, Yuting Yang, Jie Wu, Yeyi Li, Weiyan Sun, Kai Zhang, Yuhui Jiang, Yuzheng Zhao, Xu Zhang, Peng Jiang, Yideng Jiang, Qiujing Yu, Song Xiang, Yuan Fu, Ting Wang
The regulation of nicotinamide adenine dinucleotide (NAD+) is crucial for numerous life processes. However, the mechanisms leading to NAD+ degradation in mitochondria remain insufficiently defined. Through in silico screening of potential NAD-binding proteins, we discovered a mitochondrial reaction in which NAD+ is hydrolyzed to nicotinamide mononucleotide (NMN) and AMP by SELENOO (SelO), using Mn2+ as cofactor. Catalysis depends on SelO’s selenocysteine-serine-serine (CSS) C-terminal residues, particularly the selenocysteine 667. In addition to broad metabolic effects, this reaction plays a pronounced role in lipid utilization via SelO directly associating with fatty acid oxidation (FAO) enzymes, and it is conserved in both mammalian cells and bacteria. This reaction is responsive to elevated matrix pH, a signal of enhanced mitochondrial respiration, and protects mitochondria from sustained metabolic overactivation. These findings reveal a conserved mechanism for spatiotemporal NAD+ regulation and highlight its physiological significance in both prokaryotes and eukaryotes.
{"title":"NAD+ hydrolysis catalyzed by SelO is required for mitochondrial homeostasis","authors":"Xiaofan Jia, Teng Zhang, Chenxi Yang, Kaiyang Liu, Li Wu, Longfei Diao, Yuting Yang, Jie Wu, Yeyi Li, Weiyan Sun, Kai Zhang, Yuhui Jiang, Yuzheng Zhao, Xu Zhang, Peng Jiang, Yideng Jiang, Qiujing Yu, Song Xiang, Yuan Fu, Ting Wang","doi":"10.1016/j.cell.2026.01.033","DOIUrl":"https://doi.org/10.1016/j.cell.2026.01.033","url":null,"abstract":"The regulation of nicotinamide adenine dinucleotide (NAD<sup>+</sup>) is crucial for numerous life processes. However, the mechanisms leading to NAD<sup>+</sup> degradation in mitochondria remain insufficiently defined. Through <em>in silico</em> screening of potential NAD-binding proteins, we discovered a mitochondrial reaction in which NAD<sup>+</sup> is hydrolyzed to nicotinamide mononucleotide (NMN) and AMP by SELENOO (SelO), using Mn<sup>2+</sup> as cofactor. Catalysis depends on SelO’s selenocysteine-serine-serine (CSS) C-terminal residues, particularly the selenocysteine 667. In addition to broad metabolic effects, this reaction plays a pronounced role in lipid utilization via SelO directly associating with fatty acid oxidation (FAO) enzymes, and it is conserved in both mammalian cells and bacteria. This reaction is responsive to elevated matrix pH, a signal of enhanced mitochondrial respiration, and protects mitochondria from sustained metabolic overactivation. These findings reveal a conserved mechanism for spatiotemporal NAD<sup>+</sup> regulation and highlight its physiological significance in both prokaryotes and eukaryotes.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"61 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380720","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 : 2026-03-09DOI: 10.1016/j.cell.2026.02.003
Joel Babdor, Ravi K. Patel, Brittany Davidson, Kelvin Koser, Cecilia Noecker, Maha K. Rahim, Jordan E. Bisanz, Iliana Tenvooren, Diana Marquez, Maria Calvo, Vrinda Johri, Elizabeth E. McCarthy, Avneet Shaheed, Christina Ekstrand, Allison M. Weakley, Feiqiao B. Yu, Kristen Krip, Kashif A. Shaikh, Hajera Amatullah, Oliver Fiehn, Matthew H. Spitzer
Human immune systems are highly variable, with most variation attributable to non-genetic sources. The gut microbiome crucially shapes the immune system; however, its relationship with the baseline immune states of healthy humans remains incompletely understood. Therefore, we performed multi-omic profiling of 110 healthy participants through the ImmunoMicrobiome study. A factor-based integrative approach identified coordinated variation, revealing that the interferon response was amongst the most variable immune features in healthy participants. Microbiome composition, pathways, and stool metabolites varied concomitantly with interferon response pathways. Longitudinal data spanning more than a year indicated the significant stability of these parameters within individuals over time. Our study provides extensive data to examine the relationship between the immune states and microbiomes of healthy individuals at steady state, which paves the way for delineating inter-individual differences relevant for disease susceptibility and responses to therapy.
{"title":"Immune-microbiome coordination defines interferon setpoints in healthy humans","authors":"Joel Babdor, Ravi K. Patel, Brittany Davidson, Kelvin Koser, Cecilia Noecker, Maha K. Rahim, Jordan E. Bisanz, Iliana Tenvooren, Diana Marquez, Maria Calvo, Vrinda Johri, Elizabeth E. McCarthy, Avneet Shaheed, Christina Ekstrand, Allison M. Weakley, Feiqiao B. Yu, Kristen Krip, Kashif A. Shaikh, Hajera Amatullah, Oliver Fiehn, Matthew H. Spitzer","doi":"10.1016/j.cell.2026.02.003","DOIUrl":"https://doi.org/10.1016/j.cell.2026.02.003","url":null,"abstract":"Human immune systems are highly variable, with most variation attributable to non-genetic sources. The gut microbiome crucially shapes the immune system; however, its relationship with the baseline immune states of healthy humans remains incompletely understood. Therefore, we performed multi-omic profiling of 110 healthy participants through the ImmunoMicrobiome study. A factor-based integrative approach identified coordinated variation, revealing that the interferon response was amongst the most variable immune features in healthy participants. Microbiome composition, pathways, and stool metabolites varied concomitantly with interferon response pathways. Longitudinal data spanning more than a year indicated the significant stability of these parameters within individuals over time. Our study provides extensive data to examine the relationship between the immune states and microbiomes of healthy individuals at steady state, which paves the way for delineating inter-individual differences relevant for disease susceptibility and responses to therapy.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"79 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147383872","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}
Liver fibrosis is a prominent pathological process contributing to death from hepatic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). There is limited treatment for liver fibrosis. Here, we find that upregulation of Rho-associated coiled-coil containing kinase 2 (ROCK2) in liver endothelial cells (ECs) and perivascular hepatic stellate cells (HSCs) causes vascular niche dysfunction and triggers pro-fibrotic angiocrine signaling. Based on the vascular druggable target ROCK2, we developed its selective inhibitor showing anti-fibrotic potency in preclinical models and human patients. The ROCK2-selective inhibitor TDI01 restored vascular phenotype and alleviated fibrosis in rodent and minipig MASH models. A phase 1 clinical trial (ChiCTR2200058868) of TDI01 demonstrated its favorable pharmacokinetics and safety in humans. An extended clinical trial (ChiCTR2400082056) showed a trend toward reducing liver fibrosis in five of six patients after TDI01 treatment. Thus, we discover vascular ROCK2 as a pro-fibrotic target, and development of an inhibitor selectively targeting angiocrine ROCK2 may provide a treatment of liver fibrosis in human patients.
{"title":"Selective targeting of endothelial and perivascular angiocrine ROCK2 treats liver fibrosis.","authors":"Yan Hu, Biao Yang, Chengju Xiao, Xinchun Yang, Hua Zhang, Pengbo Yang, Xiao Du, Guixiang Zhang, Beibei Liang, Nan Bai, Daoguang Zhang, Dongbo Wu, Qinghua Luo, Yangjing Teng, Yumeng Chen, Zhiqing Guo, Chengjian Zhao, Tinghong Ye, Dong Chai, Xiaolong Qi, Weiting Zhong, Jie Chen, Haohao Dong, Jinhang Gao, Huanhuan He, Junlei Chang, Xuri Li, Liang Peng, Shahin Rafii, Scott L Friedman, Cheng Yi, Yun Cai, Yanping Zhao, Hongjun Wang, Chen Wang, Zhongwei Cao, Bi-Sen Ding","doi":"10.1016/j.cell.2026.02.001","DOIUrl":"https://doi.org/10.1016/j.cell.2026.02.001","url":null,"abstract":"<p><p>Liver fibrosis is a prominent pathological process contributing to death from hepatic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). There is limited treatment for liver fibrosis. Here, we find that upregulation of Rho-associated coiled-coil containing kinase 2 (ROCK2) in liver endothelial cells (ECs) and perivascular hepatic stellate cells (HSCs) causes vascular niche dysfunction and triggers pro-fibrotic angiocrine signaling. Based on the vascular druggable target ROCK2, we developed its selective inhibitor showing anti-fibrotic potency in preclinical models and human patients. The ROCK2-selective inhibitor TDI01 restored vascular phenotype and alleviated fibrosis in rodent and minipig MASH models. A phase 1 clinical trial (ChiCTR2200058868) of TDI01 demonstrated its favorable pharmacokinetics and safety in humans. An extended clinical trial (ChiCTR2400082056) showed a trend toward reducing liver fibrosis in five of six patients after TDI01 treatment. Thus, we discover vascular ROCK2 as a pro-fibrotic target, and development of an inhibitor selectively targeting angiocrine ROCK2 may provide a treatment of liver fibrosis in human patients.</p>","PeriodicalId":9656,"journal":{"name":"Cell","volume":" ","pages":""},"PeriodicalIF":42.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372225","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 : 2026-03-06DOI: 10.1016/j.cell.2026.02.004
Shan Liu, Puneeth Guruprasad, Ranjani Ramasubramanian, Bhoomi Madhu, Luca Paruzzo, Kecheng Han, Andre Kelly, Alexander Shestov, He N. Xu, Alberto Carturan, Chaoting Zhou, Kevin R. Amses, Amichay Afriat, Lev Litichevskiy, Jason Lin, Ezra Dubowitz, Neil Tangal, Jing Zhang, Alana McSween, Melody Tan, Marco Ruella
The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.
{"title":"β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer","authors":"Shan Liu, Puneeth Guruprasad, Ranjani Ramasubramanian, Bhoomi Madhu, Luca Paruzzo, Kecheng Han, Andre Kelly, Alexander Shestov, He N. Xu, Alberto Carturan, Chaoting Zhou, Kevin R. Amses, Amichay Afriat, Lev Litichevskiy, Jason Lin, Ezra Dubowitz, Neil Tangal, Jing Zhang, Alana McSween, Melody Tan, Marco Ruella","doi":"10.1016/j.cell.2026.02.004","DOIUrl":"https://doi.org/10.1016/j.cell.2026.02.004","url":null,"abstract":"The influence of lifestyle factors, such as diet, on the effectiveness of T cell-mediated cancer immunotherapies remains unclear. Here, we demonstrate that the ketogenic diet (KD)-induced ketone metabolite β-hydroxybutyrate (BHB) augments chimeric antigen receptor (CAR) T cell function across multiple preclinical cancer models. Mechanistically, BHB supports the tricarboxylic acid (TCA) cycle in CAR T cells, driving oxidative phosphorylation and energy generation. This metabolic enhancement is associated with CAR T cell proliferation and cytokine production, thereby leading to superior tumor control. Furthermore, BHB induces global transcriptional and epigenetic reprogramming in activated CAR T cells, which promotes an enhanced effector and metabolic profile. Lastly, in a prospective cohort of healthy volunteers, administration of BHB enhanced peripheral T cell oxygen consumption, mitochondrial membrane potential, and ATP production. Our results suggest that metabolite intervention via BHB supplementation is a promising, readily implementable strategy to improve adoptive T cell function against various cancers.","PeriodicalId":9656,"journal":{"name":"Cell","volume":"72 1","pages":""},"PeriodicalIF":64.5,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147368079","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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