Pub Date : 2026-01-01Epub Date: 2025-12-11DOI: 10.1016/j.mocell.2025.100308
Dajeong Bong , Hyunwoo C. Kwon , Seung-Jae V. Lee
Aging in Caenorhabditis elegans is regulated by evolutionarily conserved pathways that coordinate cellular maintenance and systemic homeostasis. Here, we review recent advances on four major longevity regimens, including reduced insulin/insulin-like growth factor 1 signaling (IIS), dietary restriction (DR), mild inhibition of mitochondrial respiration, and germline deficiency. Each longevity-promoting regimen enhances protein and RNA quality control, metabolic remodeling, and stress resistance to delay functional declines with age. Reduced IIS strengthens proteostasis and RNA surveillance. DR remodels metabolism and activates autophagy. Mild mitochondrial inhibition elicits adaptive redox signaling and quality control responses. Germline deficiency links reproductive cues to somatic maintenance. We highlight that longevity arises from the integrated regulation of transcriptional, metabolic, and inter-tissue signaling networks. Our review will provide valuable insights obtained from C. elegans into the conserved mechanisms of aging, facilitating the development of interventions that promote healthy longevity in humans.
{"title":"Multilayered regulation of longevity in Caenorhabditis elegans","authors":"Dajeong Bong , Hyunwoo C. Kwon , Seung-Jae V. Lee","doi":"10.1016/j.mocell.2025.100308","DOIUrl":"10.1016/j.mocell.2025.100308","url":null,"abstract":"<div><div>Aging in <em>Caenorhabditis elegans</em> is regulated by evolutionarily conserved pathways that coordinate cellular maintenance and systemic homeostasis. Here, we review recent advances on four major longevity regimens, including reduced insulin/insulin-like growth factor 1 signaling (IIS), dietary restriction (DR), mild inhibition of mitochondrial respiration, and germline deficiency. Each longevity-promoting regimen enhances protein and RNA quality control, metabolic remodeling, and stress resistance to delay functional declines with age. Reduced IIS strengthens proteostasis and RNA surveillance. DR remodels metabolism and activates autophagy. Mild mitochondrial inhibition elicits adaptive redox signaling and quality control responses. Germline deficiency links reproductive cues to somatic maintenance. We highlight that longevity arises from the integrated regulation of transcriptional, metabolic, and inter-tissue signaling networks. Our review will provide valuable insights obtained from <em>C. elegans</em> into the conserved mechanisms of aging, facilitating the development of interventions that promote healthy longevity in humans.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"49 1","pages":"Article 100308"},"PeriodicalIF":6.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145752020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2026-01-07DOI: 10.1016/S1016-8478(26)00005-1
{"title":"Cover and caption","authors":"","doi":"10.1016/S1016-8478(26)00005-1","DOIUrl":"10.1016/S1016-8478(26)00005-1","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"49 1","pages":"Article 100314"},"PeriodicalIF":6.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-11-18DOI: 10.1016/j.mocell.2025.100300
Xinyu Pan , Hui Zhang , Weiwen Huang , Wenbin Ma , Zhou Songyang , Yuanyan Xiong
RNA editing alters mRNA sequences and is linked to aging. We introduce RE-Aging, a platform analyzing age-related RNA editing using GTEx data (259,620 A-to-I and 30,502 C-to-U sites across 27 tissues). Features include site exploration, age correlations, gene annotation, RNA structure analysis, and miRNA binding impact. Supports differential editing analysis (Wilcoxon test) and single-cell RNA editing age mapping for blood cells. Access at http://bioinfo-sysu.com/RE-Aging/.
{"title":"RE-Aging: A functional analysis platform for human RNA editing associated with aging","authors":"Xinyu Pan , Hui Zhang , Weiwen Huang , Wenbin Ma , Zhou Songyang , Yuanyan Xiong","doi":"10.1016/j.mocell.2025.100300","DOIUrl":"10.1016/j.mocell.2025.100300","url":null,"abstract":"<div><div>RNA editing alters mRNA sequences and is linked to aging. We introduce RE-Aging, a platform analyzing age-related RNA editing using GTEx data (259,620 A-to-I and 30,502 C-to-U sites across 27 tissues). Features include site exploration, age correlations, gene annotation, RNA structure analysis, and miRNA binding impact. Supports differential editing analysis (Wilcoxon test) and single-cell RNA editing age mapping for blood cells. Access at <span><span>http://bioinfo-sysu.com/RE-Aging/</span><svg><path></path></svg></span>.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"49 1","pages":"Article 100300"},"PeriodicalIF":6.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145564673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-01Epub Date: 2025-12-02DOI: 10.1016/j.mocell.2025.100303
Shinae Park, Kyungmin Lee, Junsoo Oh, Jung-Shin Lee
Histone H3 lysine 4 trimethylation (H3K4me3) has been associated with active transcription, yet whether it plays a causative role in gene activation remains an open question. In this study, we reveal that the deletion of Paf1 complex subunit Leo1 in Saccharomyces cerevisiae induces robust transcriptional activation at a subset of genes, particularly those involved in sterol transport, without altering global H3K4me3 levels. These induced genes acquire de novo H3K4me3 at promoter-proximal regions, and this transcriptional induction is entirely dependent on Set1, the sole methyltransferase responsible for H3K4me3. Strikingly, loss of Set1 abolishes expression of these genes, even in the presence of previously established H3K4me3, and their expression is fully restored upon Set1 reintroduction. These effects are specific to Leo1 deficiency and not observed in other Paf1C mutants. Furthermore, Set1-dependent gene activation enhances sterol uptake, underscoring its physiological relevance. Our findings provide direct in vivo evidence that Set1-catalyzed H3K4me3 is not merely a transcriptional correlate, but a context-dependent driver of gene expression.
组蛋白H3赖氨酸4三甲基化（H3K4me3）与活性转录有关，但它是否在基因激活中起致病作用仍然是一个悬而未决的问题。在这项研究中，我们揭示了酿酒酵母中Paf1复合物亚基Leo1的缺失诱导了一部分基因的强大转录激活，特别是那些参与固醇运输的基因，而不会改变全球H3K4me3水平。这些诱导基因在启动子-近端区域重新获得H3K4me3，这种转录诱导完全依赖于Set1，这是唯一负责H3K4me3的甲基转移酶。引人注目的是，即使在先前建立的H3K4me3存在的情况下，Set1的缺失也会消除这些基因的表达，并且在Set1重新引入后，它们的表达完全恢复。这些影响仅针对Leo1缺乏症，而在其他Paf1C突变体中未观察到。此外，set1依赖性基因激活增强了甾醇摄取，强调了其生理相关性。我们的研究结果提供了直接的体内证据，证明set1催化的H3K4me3不仅是转录相关的，而且是基因表达的上下文依赖驱动因素。数据可用性：本研究中讨论的ChIP-seq和RNA-seq数据已存储在NCBI的Gene Expression Omnibus （Edgar et al., 2002）中，可通过GEO Series登录号GSE303595 （https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303595）和GSE303407 （https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE303407）访问。
{"title":"Set1-dependent H3K4 methylation is essential for sustained gene expression at newly activated loci","authors":"Shinae Park, Kyungmin Lee, Junsoo Oh, Jung-Shin Lee","doi":"10.1016/j.mocell.2025.100303","DOIUrl":"10.1016/j.mocell.2025.100303","url":null,"abstract":"<div><div>Histone H3 lysine 4 trimethylation (H3K4me3) has been associated with active transcription, yet whether it plays a causative role in gene activation remains an open question. In this study, we reveal that the deletion of Paf1 complex subunit Leo1 in <em>Saccharomyces cerevisiae</em> induces robust transcriptional activation at a subset of genes, particularly those involved in sterol transport, without altering global H3K4me3 levels. These induced genes acquire de novo H3K4me3 at promoter-proximal regions, and this transcriptional induction is entirely dependent on Set1, the sole methyltransferase responsible for H3K4me3. Strikingly, loss of Set1 abolishes expression of these genes, even in the presence of previously established H3K4me3, and their expression is fully restored upon Set1 reintroduction. These effects are specific to Leo1 deficiency and not observed in other Paf1C mutants. Furthermore, Set1-dependent gene activation enhances sterol uptake, underscoring its physiological relevance. Our findings provide direct in vivo evidence that Set1-catalyzed H3K4me3 is not merely a transcriptional correlate, but a context-dependent driver of gene expression.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"49 1","pages":"Article 100303"},"PeriodicalIF":6.5,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145677873","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-12-05DOI: 10.1016/S1016-8478(25)00128-1
{"title":"Cover and caption","authors":"","doi":"10.1016/S1016-8478(25)00128-1","DOIUrl":"10.1016/S1016-8478(25)00128-1","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 12","pages":"Article 100304"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145690342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-11-03DOI: 10.1016/j.mocell.2025.100296
Ravi Shankar Goutam , Neha Kaushik , Basant Kumar , Woochan Jung , Santosh Kumar , Seung-Hwan Lee , Unjoo Lee , Jaebong Kim
The Iroquois (Iro/Irx) gene family encodes transcription factors that belong to the Three-Amino-Acid Loop Extension-class homeodomain group, distinguished by a conserved Iro-box domain. Iroquois signaling is evolutionarily conserved from invertebrates to vertebrates and plays a vital role in embryonic development. In invertebrates, Iro/Irx genes control tissue compartmentalization, whereas in vertebrates, they regulate gastrulation, neural patterning, and organogenesis. These genes are typically organized in conserved genomic clusters under shared regulatory control, reflecting their coordinated expression and common evolutionary origins. Beyond development, dysregulation of Iroquois genes has been implicated in diverse human diseases. Iro/Irx genes are increasingly associated with congenital disorders, including congenital heart disease and neurodevelopmental abnormalities. Moreover, their emerging role in cancer biology has revealed context-dependent behavior, functioning as either tumor suppressors or oncogenes. Recent findings have also highlighted their potential as clinical biomarkers in neurological and neoplastic diseases. Given their broad developmental and pathological roles, Iroquois genes are gaining recognition as promising candidates for therapeutic targeting and molecular diagnostics. This review integrates their developmental functions with their disease associations to provide a comprehensive overview of the biological and clinical significance of Iroquois signaling.
{"title":"Multifaceted role of Iroquois signaling in development and diseases","authors":"Ravi Shankar Goutam , Neha Kaushik , Basant Kumar , Woochan Jung , Santosh Kumar , Seung-Hwan Lee , Unjoo Lee , Jaebong Kim","doi":"10.1016/j.mocell.2025.100296","DOIUrl":"10.1016/j.mocell.2025.100296","url":null,"abstract":"<div><div>The Iroquois (<em>Iro/Irx</em>) gene family encodes transcription factors that belong to the Three-Amino-Acid Loop Extension-class homeodomain group, distinguished by a conserved Iro-box domain. Iroquois signaling is evolutionarily conserved from invertebrates to vertebrates and plays a vital role in embryonic development. In invertebrates, <em>Iro/Irx</em> genes control tissue compartmentalization, whereas in vertebrates, they regulate gastrulation, neural patterning, and organogenesis. These genes are typically organized in conserved genomic clusters under shared regulatory control, reflecting their coordinated expression and common evolutionary origins. Beyond development, dysregulation of Iroquois genes has been implicated in diverse human diseases. <em>Iro/Irx</em> genes are increasingly associated with congenital disorders, including congenital heart disease and neurodevelopmental abnormalities. Moreover, their emerging role in cancer biology has revealed context-dependent behavior, functioning as either tumor suppressors or oncogenes. Recent findings have also highlighted their potential as clinical biomarkers in neurological and neoplastic diseases. Given their broad developmental and pathological roles, Iroquois genes are gaining recognition as promising candidates for therapeutic targeting and molecular diagnostics. This review integrates their developmental functions with their disease associations to provide a comprehensive overview of the biological and clinical significance of Iroquois signaling.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 12","pages":"Article 100296"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-11-12DOI: 10.1016/j.mocell.2025.100298
Weichun Zhu , Zehao Chen , Yunqian Gao , Chungang Zhai , Xia Li , Ning Wang , Kang Fu , Wentao Chen , Jieqiong Peng , Dan Xu , Lei Qiao , Wenqiang Chen
Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy responsible for the degradation of specific cytosolic proteins within lysosomes. Recent research has established a significant correlation between CMA and colorectal cancer (CRC). However, the majority of current research focuses on tumor parenchymal cells, with limited attention paid to the expression and role of CMA in tumor stromal cells, particularly in tumor-associated macrophages (TAMs). In this study, we generated myeloid-specific LAMP2A-knockout and knock-in mice to investigate the role of macrophage CMA in dextran sodium sulfate (DSS)-induced colitis and azoxymethane/dextran sodium sulfate-induced CRC. Our findings indicated that the expression of LAMP2A, the rate-limiting component of CMA, was reduced in tumor-associated macrophages of both human and mouse CRC tissues. The knockout of LAMP2A in macrophages exacerbated experimentally induced colitis and colitis-related CRC, whereas its overexpression in macrophages alleviated the progression of colitis and CRC in mice. Notably, we observed increased angiogenesis within the tumor mass of CRC tissues from LAMP2A-mØKO mice. Mechanistically, LAMP2A deficiency elevated the protein levels of HIF-1α, thereby enhancing the secretion of its target genes, vascular endothelial growth factor A and IL-1β, which are 2 important proangiogenic cytokines. Our study suggests that the activation of CMA in macrophages may represent a promising therapeutic strategy for the treatment of CRC.
{"title":"Deficient chaperone-mediated autophagy in macrophages aggravates colitis and colitis-associated tumorigenesis in mice","authors":"Weichun Zhu , Zehao Chen , Yunqian Gao , Chungang Zhai , Xia Li , Ning Wang , Kang Fu , Wentao Chen , Jieqiong Peng , Dan Xu , Lei Qiao , Wenqiang Chen","doi":"10.1016/j.mocell.2025.100298","DOIUrl":"10.1016/j.mocell.2025.100298","url":null,"abstract":"<div><div>Chaperone-mediated autophagy (CMA) is a highly selective form of autophagy responsible for the degradation of specific cytosolic proteins within lysosomes. Recent research has established a significant correlation between CMA and colorectal cancer (CRC). However, the majority of current research focuses on tumor parenchymal cells, with limited attention paid to the expression and role of CMA in tumor stromal cells, particularly in tumor-associated macrophages (TAMs). In this study, we generated myeloid-specific LAMP2A-knockout and knock-in mice to investigate the role of macrophage CMA in dextran sodium sulfate (DSS)-induced colitis and azoxymethane/dextran sodium sulfate-induced CRC. Our findings indicated that the expression of LAMP2A, the rate-limiting component of CMA, was reduced in tumor-associated macrophages of both human and mouse CRC tissues. The knockout of LAMP2A in macrophages exacerbated experimentally induced colitis and colitis-related CRC, whereas its overexpression in macrophages alleviated the progression of colitis and CRC in mice. Notably, we observed increased angiogenesis within the tumor mass of CRC tissues from LAMP2A-mØKO mice. Mechanistically, LAMP2A deficiency elevated the protein levels of HIF-1α, thereby enhancing the secretion of its target genes, vascular endothelial growth factor A and IL-1β, which are 2 important proangiogenic cytokines. Our study suggests that the activation of CMA in macrophages may represent a promising therapeutic strategy for the treatment of CRC.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 12","pages":"Article 100298"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-10-17DOI: 10.1016/j.mocell.2025.100288
Hoyun Kwak , Wijin Jeon , Nui Ha , Soon-Gu Kwon , Jae Young Seong
{"title":"Response to comments by Kong et al.","authors":"Hoyun Kwak , Wijin Jeon , Nui Ha , Soon-Gu Kwon , Jae Young Seong","doi":"10.1016/j.mocell.2025.100288","DOIUrl":"10.1016/j.mocell.2025.100288","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 12","pages":"Article 100288"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-01Epub Date: 2025-11-06DOI: 10.1016/j.mocell.2025.100297
Seokjun G. Ha, Ji-Hoon Park, Mi-Young Kim, Seung-Jae V. Lee
Western blot is an essential method that detects specific proteins using antibodies, which is one of the most widely applied techniques for protein detection. Here, we present a brief guide to western blot, following the overall procedure from the choice of antibodies to quantification. This guide will provide useful information for researchers who are unfamiliar with western blot assays.
Western blot是一种利用抗体检测特异性蛋白质的重要方法，是目前应用最广泛的蛋白质检测技术之一。在这里，我们简要介绍了western blot，从选择抗体到定量的整个过程。本指南将为不熟悉western blot检测的研究人员提供有用的信息。
{"title":"Brief guide to western blot assays","authors":"Seokjun G. Ha, Ji-Hoon Park, Mi-Young Kim, Seung-Jae V. Lee","doi":"10.1016/j.mocell.2025.100297","DOIUrl":"10.1016/j.mocell.2025.100297","url":null,"abstract":"<div><div>Western blot is an essential method that detects specific proteins using antibodies, which is one of the most widely applied techniques for protein detection. Here, we present a brief guide to western blot, following the overall procedure from the choice of antibodies to quantification. This guide will provide useful information for researchers who are unfamiliar with western blot assays.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 12","pages":"Article 100297"},"PeriodicalIF":6.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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