Pub Date : 2026-01-13DOI: 10.1038/s41422-025-01207-3
Yaxin Niu, Shengmin Hu, Yanfeng Zhang, Jinbao Yang, Jiarui Zhang, Ruiping He, Li Chen, Lin Xu, Hongfang Zhao, Bing Gan, Ruobing Ren, Ruth J. F. Loos, Haobin Ye, Xingrong Du, Tongjin Zhao, Peng Li, Antonio Vidal-Puig, Linzhang Huang
Insulin-stimulated glucose uptake is central to global carbohydrate metabolism, yet metabolites that enhance glucose uptake independently of insulin remain undefined. Here, we identify L-lactate as an insulin-independent regulator of glucose uptake that mitigates hyperglycemia. Loss of LDHA in muscle reduces lactate production, impairing glucose homeostasis in mice. By contrast, lactate administration or genetic upregulation of lactate production improves glucose control. Knockout of the lactate receptor GPR81 in skeletal muscle worsens glucose tolerance, whereas its ectopic expression or pharmacological activation enhances carbohydrate metabolism. Mechanistically, GPR81 recruits FARP1 to activate RAC1, promoting GLUT4 translocation independently of insulin signaling. Notably, the expression of LDHA, GPR81, and FARP1 is upregulated after exercise, and GPR81 variants are highly correlated with fasting insulin levels in humans, underscoring the synergy of the GPR81-FARP1-GLUT4 axis with insulin in glucose regulation. Our findings suggest that targeting GPR81 represents a potential insulin-independent strategy for the treatment of hyperglycemia.
{"title":"Lactate-activated GPR81/FARP1 signaling drives insulin-independent glucose uptake and metabolic control","authors":"Yaxin Niu, Shengmin Hu, Yanfeng Zhang, Jinbao Yang, Jiarui Zhang, Ruiping He, Li Chen, Lin Xu, Hongfang Zhao, Bing Gan, Ruobing Ren, Ruth J. F. Loos, Haobin Ye, Xingrong Du, Tongjin Zhao, Peng Li, Antonio Vidal-Puig, Linzhang Huang","doi":"10.1038/s41422-025-01207-3","DOIUrl":"10.1038/s41422-025-01207-3","url":null,"abstract":"Insulin-stimulated glucose uptake is central to global carbohydrate metabolism, yet metabolites that enhance glucose uptake independently of insulin remain undefined. Here, we identify L-lactate as an insulin-independent regulator of glucose uptake that mitigates hyperglycemia. Loss of LDHA in muscle reduces lactate production, impairing glucose homeostasis in mice. By contrast, lactate administration or genetic upregulation of lactate production improves glucose control. Knockout of the lactate receptor GPR81 in skeletal muscle worsens glucose tolerance, whereas its ectopic expression or pharmacological activation enhances carbohydrate metabolism. Mechanistically, GPR81 recruits FARP1 to activate RAC1, promoting GLUT4 translocation independently of insulin signaling. Notably, the expression of LDHA, GPR81, and FARP1 is upregulated after exercise, and GPR81 variants are highly correlated with fasting insulin levels in humans, underscoring the synergy of the GPR81-FARP1-GLUT4 axis with insulin in glucose regulation. Our findings suggest that targeting GPR81 represents a potential insulin-independent strategy for the treatment of hyperglycemia.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 2","pages":"137-151"},"PeriodicalIF":25.9,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956283","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 : 2026-01-13DOI: 10.1038/s41422-025-01215-3
Jaiya Randhawa,Luke A J O'Neill
{"title":"Mitochondria target the plasma membrane to cause mitoxyperiosis.","authors":"Jaiya Randhawa,Luke A J O'Neill","doi":"10.1038/s41422-025-01215-3","DOIUrl":"https://doi.org/10.1038/s41422-025-01215-3","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"26 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145961333","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 : 2026-01-09DOI: 10.1038/s41422-025-01214-4
Zhi Cheng, Bryan L. Roth
{"title":"Gz and β-arrestin 1 signaling in the μ-opioid receptor","authors":"Zhi Cheng, Bryan L. Roth","doi":"10.1038/s41422-025-01214-4","DOIUrl":"10.1038/s41422-025-01214-4","url":null,"abstract":"","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 2","pages":"97-98"},"PeriodicalIF":25.9,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01214-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932511","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}
Achieving long-term ex vivo expansion of functional hematopoietic stem cells (HSCs) is essential for advancing HSC-based clinical therapies. Although mechanosensitive ion channels are known to play key roles in the hematopoietic system, their involvement in HSC expansion remains unclear. Here, we show that Piezo1 is highly expressed in HSCs. Both genetic deletion and prolonged chemical activation of Piezo1 impair cultured HSC function, indicating that transient mechanical activation of Piezo1 is required for maintenance of HSCs in culture. To achieve this, we screened various microspheres and found that PS500 (500-nm polystyrene microspheres) significantly enhanced ex vivo expansion of mouse bone marrow HSCs with long-term repopulating capacity. PS500 also expanded human umbilical cord blood HSCs capable of engraftment in immunodeficient mice. Mechanistically, PS500 activates Piezo1, triggering Ca2+-dependent expression of proliferative cytokines and subsequent STAT3 activation, which support HSC self-renewal and proliferation. Together, these findings show that PS500 enables transient Piezo1 activation and efficient, non-toxic expansion of functional HSCs, offering a promising approach for the generation of transplantable HSCs for clinical use.
{"title":"Transient mechanical activation of the Piezo1 channel facilitates ex vivo expansion of hematopoietic stem cells","authors":"Qiwei Wang, Xin Zeng, Haoxiang Yang, Huan Lu, Lingli Jiang, Lizhen Xu, Jinxin Li, Jingyi Li, Yingli Han, Xiaoyan Wu, Yuanhong Zhou, Xiaolan Chen, Yanmin Zhao, Jimin Shi, Yi Luo, Fang Ni, Jie Sun, Qian Zhao, Fan Yang, Peng Xia, Hongyuan Jiang, He Huang, Pengxu Qian","doi":"10.1038/s41422-025-01209-1","DOIUrl":"https://doi.org/10.1038/s41422-025-01209-1","url":null,"abstract":"Achieving long-term ex vivo expansion of functional hematopoietic stem cells (HSCs) is essential for advancing HSC-based clinical therapies. Although mechanosensitive ion channels are known to play key roles in the hematopoietic system, their involvement in HSC expansion remains unclear. Here, we show that Piezo1 is highly expressed in HSCs. Both genetic deletion and prolonged chemical activation of Piezo1 impair cultured HSC function, indicating that transient mechanical activation of Piezo1 is required for maintenance of HSCs in culture. To achieve this, we screened various microspheres and found that PS500 (500-nm polystyrene microspheres) significantly enhanced ex vivo expansion of mouse bone marrow HSCs with long-term repopulating capacity. PS500 also expanded human umbilical cord blood HSCs capable of engraftment in immunodeficient mice. Mechanistically, PS500 activates Piezo1, triggering Ca2+-dependent expression of proliferative cytokines and subsequent STAT3 activation, which support HSC self-renewal and proliferation. Together, these findings show that PS500 enables transient Piezo1 activation and efficient, non-toxic expansion of functional HSCs, offering a promising approach for the generation of transplantable HSCs for clinical use.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"22 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919921","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}
R-loops are pervasive genomic structures that link epigenetic modification and transcriptional regulation. However, the functional roles and regulatory mechanisms of R-loops during preimplantation development in mammals remain unexplored. Here, we reveal that the reprogramming of R-loops across developmental stages depends on CG density, with CG-poor R-loops more stage specific and strongly associated with early embryonic development. Loss of CG-poor R-loops causes severe defects in the maternal-to-zygotic transition (MZT) and preimplantation embryo development. This abnormal maintenance of CG-poor R-loops promotes premature activation of major zygotic genome activation (ZGA) genes. CG-poor R-loops inhibit DDX21 helicase activity on the 7SK/HEXIM1 snRNP complex, restricting CDK9 release and subsequent phosphorylation of Ser2 at the C-terminal domain of RNA polymerase II (RNAPII S2p) — the biochemical hallmark of pause release — thus enforcing RNAPII accumulation at major ZGA gene promoters to ensure productive transcription. These findings establish R-loops as direct modulators of RNAPII pause release, promoting the temporal fidelity of gene expression during the MZT.
{"title":"R-loops orchestrate RNAPII transcriptional reprogramming for the maternal-to-zygotic transition","authors":"Yaoyi Li, Qing Li, Xinxiu Wang, Chao Di, Yingliang Sheng, Ying Ma, Junzhi Liao, Qingqing Cai, Sainan Huang, Jiayu Chen, Guangming Wu, Lingling Zhang, Guangjin Pan, Shaorong Gao, Hongjie Yao","doi":"10.1038/s41422-025-01208-2","DOIUrl":"https://doi.org/10.1038/s41422-025-01208-2","url":null,"abstract":"R-loops are pervasive genomic structures that link epigenetic modification and transcriptional regulation. However, the functional roles and regulatory mechanisms of R-loops during preimplantation development in mammals remain unexplored. Here, we reveal that the reprogramming of R-loops across developmental stages depends on CG density, with CG-poor R-loops more stage specific and strongly associated with early embryonic development. Loss of CG-poor R-loops causes severe defects in the maternal-to-zygotic transition (MZT) and preimplantation embryo development. This abnormal maintenance of CG-poor R-loops promotes premature activation of major zygotic genome activation (ZGA) genes. CG-poor R-loops inhibit DDX21 helicase activity on the 7SK/HEXIM1 snRNP complex, restricting CDK9 release and subsequent phosphorylation of Ser2 at the C-terminal domain of RNA polymerase II (RNAPII S2p) — the biochemical hallmark of pause release — thus enforcing RNAPII accumulation at major ZGA gene promoters to ensure productive transcription. These findings establish R-loops as direct modulators of RNAPII pause release, promoting the temporal fidelity of gene expression during the MZT.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"28 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919920","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 : 2026-01-08DOI: 10.1038/s41422-025-01202-8
Bo Jiang, Wenhui Xing, Xiaocui Xu, Shuqin Chen, Heng Feng, Rui Shao, Jiatong Sun, Yazhuo Zhang, Zaiqi Xie, Wenxiang Wang, Xubin Yin, Yi Wang, Miaomiao Wang, Ling Li, Zhong Zhang, Bo Gao, Jinlong Suo, Xuye Hu, Lijun Wang, Jun Sun, Bin Zhou, Bo O. Zhou, Matthew B. Greenblatt, Rongrong Le, Weiguo Zou
Periosteum contains abundant Ctsk-lineage skeletal stem cells (P-SSCs) that are key drivers of intramembranous ossification during bone development and maintenance. However, P-SSCs regenerate fractured bones by mediating endochondral ossification, raising the question of whether distinct P-SSCs subsets separately mediate steady-state bone formation and fracture repair. Here we uncover the heterogeneity of P-SSCs, identifying an Angptl7-expressing quiescent P-SSCs subset, which is restricted to the fibrous-layer of periosteum and barely contributes to postnatal bone development. After bone fracture, these cells largely contribute to bone healing by dedicating to endochondral ossification, regenerating the entire bone architecture. Dysfunction of Angptl7-lineage P-SSCs strongly impairs the bone healing process but does not affect steady-state bone formation. Multimodal analysis reveals that these cells can be immediately activated under the regulation of TNF-α/NF-κB signaling, subsequently acquiring osteogenic capacity. Together, our findings unravel an injury-specified P-SSCs subpopulation, providing a model that there are tissue-resident stem cells specialized for injury repair, while parallel stem cells maintain homeostasis.
{"title":"Fibrous-layer resident Angptl7+ periosteal stem cells sense injury inflammation to orchestrate fracture repair","authors":"Bo Jiang, Wenhui Xing, Xiaocui Xu, Shuqin Chen, Heng Feng, Rui Shao, Jiatong Sun, Yazhuo Zhang, Zaiqi Xie, Wenxiang Wang, Xubin Yin, Yi Wang, Miaomiao Wang, Ling Li, Zhong Zhang, Bo Gao, Jinlong Suo, Xuye Hu, Lijun Wang, Jun Sun, Bin Zhou, Bo O. Zhou, Matthew B. Greenblatt, Rongrong Le, Weiguo Zou","doi":"10.1038/s41422-025-01202-8","DOIUrl":"10.1038/s41422-025-01202-8","url":null,"abstract":"Periosteum contains abundant Ctsk-lineage skeletal stem cells (P-SSCs) that are key drivers of intramembranous ossification during bone development and maintenance. However, P-SSCs regenerate fractured bones by mediating endochondral ossification, raising the question of whether distinct P-SSCs subsets separately mediate steady-state bone formation and fracture repair. Here we uncover the heterogeneity of P-SSCs, identifying an Angptl7-expressing quiescent P-SSCs subset, which is restricted to the fibrous-layer of periosteum and barely contributes to postnatal bone development. After bone fracture, these cells largely contribute to bone healing by dedicating to endochondral ossification, regenerating the entire bone architecture. Dysfunction of Angptl7-lineage P-SSCs strongly impairs the bone healing process but does not affect steady-state bone formation. Multimodal analysis reveals that these cells can be immediately activated under the regulation of TNF-α/NF-κB signaling, subsequently acquiring osteogenic capacity. Together, our findings unravel an injury-specified P-SSCs subpopulation, providing a model that there are tissue-resident stem cells specialized for injury repair, while parallel stem cells maintain homeostasis.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 2","pages":"121-136"},"PeriodicalIF":25.9,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01202-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908422","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}
Robust mitochondrial ROS production induces extensive double-strand breaks (DSBs) in telomeric DNA of effector T cells, where the DNA repair machinery is rapidly hyper-evoked to sense and ligate DSBs during the respiratory burst. However, whether effector T cells can exploit the DNA repair system to simultaneously potentiate their functional activation remains largely unknown, especially in the context of autoimmunity. Here, we demonstrate that non-homologous end joining (NHEJ), a predominant mechanism of DNA repair, is highly activated in pathogenic T helper 17 (pTh17) cells and exerts a previously unrecognized effect on shaping the pathogenic nature of pTh17s to trigger autoimmunity. Mechanistically, the perception of DSBs by KU proteins facilitates auto-phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which stabilizes RORγt to bind to the promoters of effector-gene loci, thus initiating the pTh17 effector program to induce autoimmunity. Using mass spectrometry and transcriptome analyses, we identified IER2 as a novel NHEJ factor that potentiates DNA-PKcs kinase activity in response to IL-23R stimulation, which is necessary for shaping Th17 pathogenicity. Therefore, targeting the immuno-pattern of the NHEJ system shows potential for the treatment of autoimmune diseases.
{"title":"Sensing of DNA double-strand breaks by the NHEJ system stabilizes RORγt transcriptional activity and shapes Th17 pathogenicity in autoimmunity.","authors":"Guan-Yu Chen,Wen-Jie Zhu,Zhuang Li,Yun-Wei Hu,Xiao-Shuang Luo,Zhi-Qing Mai,Yuan Pan,Yu-Xun Shi,Zuo-Yi Li,Jun Huang,Pei-Dong Yuan,Zhi-Qiang Xiao,Qian Chen,Yan-Yan Xie,Hai-Xiang Huang,Yu-Xi Chen,Yao Lu,Min-Zhen Wang,Yi-Wen Xia,Xiao-Qing Chen,Dong-Ming Kuang,Dan Liang","doi":"10.1038/s41422-025-01204-6","DOIUrl":"https://doi.org/10.1038/s41422-025-01204-6","url":null,"abstract":"Robust mitochondrial ROS production induces extensive double-strand breaks (DSBs) in telomeric DNA of effector T cells, where the DNA repair machinery is rapidly hyper-evoked to sense and ligate DSBs during the respiratory burst. However, whether effector T cells can exploit the DNA repair system to simultaneously potentiate their functional activation remains largely unknown, especially in the context of autoimmunity. Here, we demonstrate that non-homologous end joining (NHEJ), a predominant mechanism of DNA repair, is highly activated in pathogenic T helper 17 (pTh17) cells and exerts a previously unrecognized effect on shaping the pathogenic nature of pTh17s to trigger autoimmunity. Mechanistically, the perception of DSBs by KU proteins facilitates auto-phosphorylation of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which stabilizes RORγt to bind to the promoters of effector-gene loci, thus initiating the pTh17 effector program to induce autoimmunity. Using mass spectrometry and transcriptome analyses, we identified IER2 as a novel NHEJ factor that potentiates DNA-PKcs kinase activity in response to IL-23R stimulation, which is necessary for shaping Th17 pathogenicity. Therefore, targeting the immuno-pattern of the NHEJ system shows potential for the treatment of autoimmune diseases.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"12 1","pages":""},"PeriodicalIF":44.1,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907874","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}
Colorectal cancer (CRC) remains largely refractory to immune-checkpoint blockade, with adenomatous polyposis coli (APC) mutations present in 80%–90% of cases. Loss of APC was previously thought to promote tumor progression mainly through deregulated Wnt/β-catenin signaling. Here, we report that APC loss leads to inhibition of CD8+ T cell infiltration and CRC immune evasion through the dephosphorylation of signal transducers and activators of transcription 1 (STAT1) by protein tyrosine phosphatase non-receptor type 13 (PTPN13), independently of β-catenin. Peptides containing the last 11 C-terminal amino acid (aa) residues of APC (APC11) bind directly to PTPN13 to block PTPN13–STAT1 interactions and facilitate STAT1 phosphorylation, interferon regulatory factor-1 (IRF1) expression, major histocompatibility complex (MHC) class I antigen presentation, and T cell intratumoral infiltration, all of which eventually inhibit tumor progression and enhance the effects of programmed cell death 1 (PD1) blockade. Thus, we have identified a previously unknown APC/PTPN13/STAT1-dependent tumor immune-suppressive mechanism. The potent tumor-suppressing effect of combining anti-PD1 antibodies with APC11 peptides provides a compelling target and rationale for future development of anti-tumor drugs for patients with CRC.
{"title":"Targeting PTPN13 with 11-amino-acid peptides of C-terminal APC prevents immune evasion of colorectal cancer","authors":"Wen-Hui Ma, Wen-Yi Li, Tao Chen, Linqian Jing, Yue-Hong Chen, Kejun Li, Zhuo-Luo Xu, Rong-Fang Shen, Yutong He, Tingyu Mou, Ting-Yue Luo, Xiangnan Sun, Zhao-Kun Wu, Li-Jing Wang, Hong-Juan Liu, Xiaozhong Qiu, Yi Gao, Xiaochun Bai, Wei Wang, Dalei Wu, Guoxin Li, Wei-Jie Zhou","doi":"10.1038/s41422-025-01206-4","DOIUrl":"10.1038/s41422-025-01206-4","url":null,"abstract":"Colorectal cancer (CRC) remains largely refractory to immune-checkpoint blockade, with adenomatous polyposis coli (APC) mutations present in 80%–90% of cases. Loss of APC was previously thought to promote tumor progression mainly through deregulated Wnt/β-catenin signaling. Here, we report that APC loss leads to inhibition of CD8+ T cell infiltration and CRC immune evasion through the dephosphorylation of signal transducers and activators of transcription 1 (STAT1) by protein tyrosine phosphatase non-receptor type 13 (PTPN13), independently of β-catenin. Peptides containing the last 11 C-terminal amino acid (aa) residues of APC (APC11) bind directly to PTPN13 to block PTPN13–STAT1 interactions and facilitate STAT1 phosphorylation, interferon regulatory factor-1 (IRF1) expression, major histocompatibility complex (MHC) class I antigen presentation, and T cell intratumoral infiltration, all of which eventually inhibit tumor progression and enhance the effects of programmed cell death 1 (PD1) blockade. Thus, we have identified a previously unknown APC/PTPN13/STAT1-dependent tumor immune-suppressive mechanism. The potent tumor-suppressing effect of combining anti-PD1 antibodies with APC11 peptides provides a compelling target and rationale for future development of anti-tumor drugs for patients with CRC.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 1","pages":"72-93"},"PeriodicalIF":25.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01206-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894408","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}
Pub Date : 2026-01-05DOI: 10.1038/s41422-025-01203-7
Qi Wang, Yu Sun, Terytty Yang Li, Johan Auwerx
Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy — from receptors and stress-responsive triggers to lysosomal degradation — illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.
{"title":"Mitophagy in the pathogenesis and management of disease","authors":"Qi Wang, Yu Sun, Terytty Yang Li, Johan Auwerx","doi":"10.1038/s41422-025-01203-7","DOIUrl":"10.1038/s41422-025-01203-7","url":null,"abstract":"Mitophagy, an evolutionarily conserved quality-control process, selectively removes damaged mitochondria to maintain cellular homeostasis. Recent advances in our understanding of the molecular machinery underlying mitophagy — from receptors and stress-responsive triggers to lysosomal degradation — illustrate its key role in maintaining mitochondrial integrity and adapting mitochondrial function to ever-changing physiological demands. In this review, we outline the fundamental mechanisms of mitophagy and discuss how dysregulation of this pathway disrupts mitochondrial function and metabolic balance, driving a wide range of disorders, including neurodegenerative, cardiovascular, metabolic, and immune-related diseases, as well as cancer. We explore the dual role of mitophagy as both a disease driver and a therapeutic target, highlighting the efforts and challenges of translating mechanistic insights into precision therapies. Targeting mitophagy to restore mitochondrial homeostasis may be at the center of a large range of translational opportunities for improving human health.","PeriodicalId":9926,"journal":{"name":"Cell Research","volume":"36 1","pages":"11-37"},"PeriodicalIF":25.9,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41422-025-01203-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145896014","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}
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