Molecules and Cells最新文献

{"title":"Cholesterol sulfate as a negative regulator of cellular cholesterol homeostasis","authors":"Le Ba Nam ,&nbsp;Sung-Jin Kim ,&nbsp;Tan Khanh Nguyen ,&nbsp;Chang-Yun Jeong ,&nbsp;June-Yong Lee ,&nbsp;Jun-Seok Lee ,&nbsp;Jeong Taeg Seo ,&nbsp;Seok Jun Moon","doi":"10.1016/j.mocell.2025.100209","DOIUrl":"10.1016/j.mocell.2025.100209","url":null,"abstract":"<div><div>Cholesterol sulfate (CS), one of the most abundant cholesterol derivatives, recently emerged as a key regulatory molecule in several physiological processes. Here, we demonstrate multiple mechanisms by which CS reduces intracellular cholesterol levels. CS promotes the proteasomal degradation of 3-hydroxy-3-methylglutaryl-CoA reductase reductase by enhancing insulin-induced gene-mediated ubiquitination, thereby inhibiting cholesterol synthesis. In addition, CS blocks low-density lipoprotein receptor endocytosis, reducing low-density lipoprotein cholesterol uptake. CS further suppresses the proteolytic activation of sterol regulatory element-binding protein 2, a master transcription factor governing cholesterol synthesis and uptake. Using in vitro and in vivo models, we show that CS lowers cholesterol by targeting both the cholesterol synthesis and uptake pathways, while also modulating an important feedback loop via sterol regulatory element-binding protein 2. These findings highlight the potential of CS as a modulator of cholesterol metabolism, offering new therapeutic insights into cholesterol-related disorders.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 6","pages":"Article 100209"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634082","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}

{"title":"Intestinal bacteria-derived extracellular vesicles in metabolic dysfunction-associated steatotic liver disease: From mechanisms to therapeutics","authors":"Li-Na Qin ,&nbsp;Yun-Feng Yu ,&nbsp;Lie Ma ,&nbsp;Rong Yu","doi":"10.1016/j.mocell.2025.100216","DOIUrl":"10.1016/j.mocell.2025.100216","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disease that affects the health of approximately one-third of the world's population. It is the primary cause of end-stage liver disease, liver malignancy, and liver transplantation, resulting in a great medical burden. No medications have yet been approved by the US Food and Drug Administration for treating MASLD without liver inflammation or scarring. Therefore, the development of specific drugs to treat MASLD remains a key task in the ongoing research objective. Extracellular vesicles (EVs) play an important role in the communication between organs, tissues, and cells. Recent studies have found that intestinal microbiota are closely related to the pathogenesis and progression of MASLD. EVs produced by bacteria (BEVs) play an indispensable role in this process. Thus, this study provides a new direction for MASLD treatment. However, the mechanism by which BEVs affect MASLD remains unclear. Therefore, this study investigated the influence and function of intestinal microbiota in MASLD. Additionally, we focus on the research progress of BEVs in recent years and explain the relationship between BEVs and MASLD from the perspectives of glucose and lipid metabolism, immune responses, and intestinal homeostasis. Finally, we summarized the potential therapeutic value of BEVs and EVs from other sources, such as adipocytes, immunocytes, stem cells, and plants.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 6","pages":"Article 100216"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143906699","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}

{"title":"Decoding SPP1 regulation: Genetic and nongenetic insights into its role in disease progression","authors":"Sungju Jung ,&nbsp;Jiseon Ha ,&nbsp;Jong Hoon Park ,&nbsp;Kyung Hyun Yoo","doi":"10.1016/j.mocell.2025.100215","DOIUrl":"10.1016/j.mocell.2025.100215","url":null,"abstract":"<div><div>Secreted phosphoprotein 1 (SPP1), also known as osteopontin, is a multifunctional glycoprotein that plays a critical role in various physiological processes, including cell adhesion, chemotaxis, immune regulation, and tissue remodeling. Originally identified as a key component of the bone matrix, SPP1 is now recognized for its broad involvement in numerous tissues and significant impact on both normal physiology and disease progression. Dysregulation of SPP1 has been strongly implicated in the pathogenesis and progression of several diseases, including cancer, cardiovascular diseases, autoimmune disorders, and chronic inflammatory conditions. The expression of <em>SPP1</em> is tightly regulated by genetic and nongenetic mechanisms. Genetic alterations, such as single-nucleotide polymorphisms, insertions and deletions, and structural variations within the <em>SPP1</em> gene, have been associated with increased susceptibility to various diseases, influencing disease severity and outcomes. Additionally, nongenetic regulations, including DNA methylation, histone modifications, and long noncoding RNAs, play crucial roles in modulating <em>SPP1</em> expression in response to environmental and cellular signals. This review provides a comprehensive overview of the genetic and nongenetic regulatory mechanisms governing SPP1 and examines their implications in disease pathogenesis. By integrating recent findings, this review highlights the complex interplay between genetic predispositions and nongenetic regulations in determining SPP1 activity and offers new insights into its role as a potential biomarker and therapeutic target. Understanding these regulatory pathways is essential for the development of targeted interventions for diseases in which SPP1 plays a pivotal role.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 6","pages":"Article 100215"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143859233","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}

{"title":"Editorial Board Members/Copyright","authors":"","doi":"10.1016/S1016-8478(25)00053-6","DOIUrl":"10.1016/S1016-8478(25)00053-6","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 6","pages":"Article 100229"},"PeriodicalIF":3.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144099298","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}

{"title":"Phosphorylation of eIF2α suppresses the impairment of GSH/NADPH homeostasis and mitigates the activation of cell death pathways, including ferroptosis, during ER stress","authors":"Hien Thi Le ,&nbsp;Yonghwan Kim ,&nbsp;Mi-Jeong Kim ,&nbsp;Seung Hwa Hyun ,&nbsp;Hyeeun Kim ,&nbsp;Su Wol Chung ,&nbsp;Yeonsoo Joe ,&nbsp;Hun Taeg Chung ,&nbsp;Dong-Myung Shin ,&nbsp;Sung Hoon Back","doi":"10.1016/j.mocell.2025.100210","DOIUrl":"10.1016/j.mocell.2025.100210","url":null,"abstract":"<div><div>eIF2α Phosphorylation helps maintain cellular homeostasis and overcome endoplasmic reticulum (ER) stress through transcriptional and translational reprogramming. This study aims to elucidate the transcriptional regulation of glutathione (GSH) and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) homeostasis through eIF2α phosphorylation and its impact on cell death during ER stress. eIF2α phosphorylation-deficient (<em>A/A</em>) cells exhibited decreased expression of multiple genes involved in GSH synthesis and NADPH production, leading to an exacerbated depletion of both cellular and mitochondrial GSH, as well as mitochondrial NADPH, during ER stress. Impaired GSH homeostasis resulted from deficient expression of ATF4 and/or its dependent factor, Nrf2, which are key transcription factors in the antioxidant response during ER stress. In contrast, the exacerbation of NADPH depletion may primarily be attributed to the dysregulated expression of mitochondrial serine-driven 1-carbon metabolism pathway genes, which are regulated by an unidentified eIF2α phosphorylation-dependent mechanism during ER stress. Moreover, the eIF2α phosphorylation-ATF4 axis was responsible for upregulation of ferroptosis-inhibiting genes and downregulation of ferroptosis-activating genes upon ER stress. Therefore, ER stress strongly induced ferroptosis of <em>A/A</em> cells, which was significantly inhibited by treatments with cell-permeable GSH and the ferroptosis inhibitor ferrostatin-1. ATF4 overexpression suppressed impairment of GSH homeostasis in <em>A/A</em> cells during ER stress by promoting expression of downstream target genes. Consequently, ATF4 overexpression mitigated ferroptosis as well as apoptosis of <em>A/A</em> cells during ER stress. Our findings underscore the importance of eIF2α phosphorylation in maintaining GSH/NADPH homeostasis and inhibiting ferroptosis through ATF4 and unidentified eIF2α phosphorylation-dependent target(s)-mediated transcriptional reprogramming during ER stress.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100210"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143634086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RIPK3 in necroptosis and cancer","authors":"Michael J. Morgan ,&nbsp;You-Sun Kim","doi":"10.1016/j.mocell.2025.100199","DOIUrl":"10.1016/j.mocell.2025.100199","url":null,"abstract":"<div><div>Receptor-interacting protein kinase-3 is essential for the cell death pathway called necroptosis. Necroptosis is activated by the death receptor ligands and pattern recognition receptors of the innate immune system, leading to significant consequences in inflammation and in diseases, particularly cancer. Necroptosis is highly proinflammatory compared with other modes of cell death because cell membrane integrity is lost, resulting in releases of cytokines and damage-associated molecular patterns that potentiate inflammation and activate the immune system. We discuss various ways that necroptosis is triggered along with its potential role in cancer and therapy.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100199"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143516211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM structures of mouse bestrophin 1 channel in closed and partially open conformations","authors":"Kwon-Woo Kim ,&nbsp;Euna Lee ,&nbsp;Ara Ko ,&nbsp;Junmo Hwang ,&nbsp;Kunwoong Park ,&nbsp;Byoung-Cheol Lee ,&nbsp;Ki Woo Kim ,&nbsp;Won-Jong Oh ,&nbsp;Kyuhyung Kim ,&nbsp;Hyun-Ho Lim","doi":"10.1016/j.mocell.2025.100208","DOIUrl":"10.1016/j.mocell.2025.100208","url":null,"abstract":"<div><div>Bestrophin 1 (BEST1) channels are calcium-activated Cl⁻ channels involved in diverse physiological processes, including gliotransmitter release in astrocytes. Although human and chicken BEST1 orthologs have been extensively studied, the structural and functional properties of mouse BEST1 (mBEST1) remain poorly understood. In this study, we characterized the structure-function of mBEST1-BF, a C–terminally tagged variant, using whole-cell patch-clamp recordings, surface biotinylation assays, and single-particle cryo-electron microscopy. Cryo-electron microscopy structural analysis of mBEST1-BF revealed closed and partially open conformations. Comparative analysis with human and chicken BEST1 orthologs highlighted conserved calcium-binding and gating mechanisms, with distinct features in mBEST1, including a wider aperture sufficient to accommodate dehydrated Cl⁻ ions and potential anion-binding sites near Val205 and Gln208 residues. The disordered C-terminal region of mBEST1 remains unresolved, suggesting it may require stabilizing factors for structural determination. Additionally, the autoinhibitory domain, which includes Ser354, likely plays a key role in regulating gating, with Ser354 potentially serving as a phosphorylation site that modulates channel activity. Our findings provide structural and functional insights into mBEST1 and suggest mechanisms underlying its unique gating and ion permeation properties.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100208"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cover and caption","authors":"","doi":"10.1016/S1016-8478(25)00041-X","DOIUrl":"10.1016/S1016-8478(25)00041-X","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100217"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851704","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}

{"title":"Editorial Board Members/Copyright","authors":"","doi":"10.1016/S1016-8478(25)00043-3","DOIUrl":"10.1016/S1016-8478(25)00043-3","url":null,"abstract":"","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100219"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851705","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}

{"title":"Protein-O-fucosylation of coreceptors may be required for Nodal signaling in Xenopus","authors":"Yeon-Jin Kim ,&nbsp;Seung-Joo Nho ,&nbsp;Soo Young Lee ,&nbsp;Chang-Yeol Yeo","doi":"10.1016/j.mocell.2025.100207","DOIUrl":"10.1016/j.mocell.2025.100207","url":null,"abstract":"<div><div>Nodal-related ligands of TGF-β family play pivotal roles for mesoderm induction and body axis formation during vertebrate early embryogenesis. Nodal ligands are distinct from most other TGF-β ligands family as they require EGF-CFC factors as coreceptors for signaling, in addition to their cognate type I and type II TGF-β receptors. In amphibian <em>Xenopus laevis</em> embryos, 5 <em>Nodal-related</em> genes (<em>Xnr1/2/4/5/6</em>) and 2 <em>EGF-CFC</em> genes (<em>XCR1</em>, <em>XCR3</em>) play roles in mesoderm induction and the accumulation of phosphorylated Smad2, while in mammalian embryos, 1 <em>Nodal</em> gene and 1 <em>EGF-CFC</em> gene (<em>Cripto</em>) play roles during mesoderm induction. Mammalian EGF-CFC factors are reported to be <em>O</em>-fucosylated at a conserved threonine residue of the EGF-like motif by protein-<em>O</em>-fucosyltransferase 1 (Pofut1), but this <em>O</em>-fucose modification is shown to be dispensable for Nodal signaling in mammalian embryos. In this study, we investigated the developmental roles of <em>Xenopus laevis Pofut1</em> (<em>XPofut1</em>) and its potential function in Nodal signaling. We found that morpholino antisense-mediated knockdown of <em>XPofut1</em> causes reduction of Smad2 phosphorylation in late blastula and axial truncation in neurula. We also found that the <em>O</em>-fucosyltransferase activity of XPofut1 is important in the marginal zone, but not in the vegetal pole region, of blastula. Interestingly, <em>XPofut1</em> is necessary for Smad2 phosphorylation induced by Xnr1 or Xnr2, but not by Xnr5 or Xnr6. Among the Nodal signaling components, only EGF-CFC factors are known to be modified by Pofut1. Therefore, based on our current observation, we propose that XPofut1 regulates signaling of a subset of nodal ligands in pregastrulation embryos possibly through modulating the function of EGF-CFC factors.</div></div>","PeriodicalId":18795,"journal":{"name":"Molecules and Cells","volume":"48 5","pages":"Article 100207"},"PeriodicalIF":3.7,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143567655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}