Cell Death and Differentiation最新文献

{"title":"Chronic skin and systemic inflammation modulated by S100A8 and S100A9 complexes","authors":"Marta Palomo-Irigoyen, Latifa Bakiri, Tim Hendrikx, Silvia Hayer, Johanna Schaffenrath, Stefanie Widder, Sandra Bachg, Jared Simmons, Richard L. Gallo, Philipp Starkl, Johannes Roth, Erwin F. Wagner","doi":"10.1038/s41418-025-01504-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01504-9","url":null,"abstract":"<p>Increased expression of the homodimeric S100A8 (A8) and S100A9 (A9) alarmins and their Calprotectin (CP) antimicrobial hetero-complex has been reported in Inflammatory Skin Diseases (ISDs) such as Atopic Dermatitis (AD), but the functional consequences of this increase are not known. We evaluated the cell- and tissue-specific functions of A8 and A9 in the local and the extra-cutaneous manifestations of ISD using genetically engineered mouse models. The genes encoding for the A9 or A8 proteins were inactivated in epidermal cells or neutrophils in the <i>JunB</i>^<i>∆ep</i> genetic mouse model for AD. Overall, epidermal inactivation of <i>A9</i> aggravated, while similar <i>A8</i> inactivation ameliorated experimental ISD. Epidermal differentiation and skin inflammation was also ameliorated when <i>A9</i> was inactivated in neutrophils or in all cells. However, complete <i>A9</i> knock-out was associated with worsened systemic effects, such as neutrophilic inflammation and bone loss. In addition, the distal phalanges of the digits displayed increased A8 protein expression, SA overgrowth and bone destruction. Epidermal <i>A8</i> inactivation ameliorated bone loss, but promoted bone destruction in the digits, likely through A8-positive neutrophilic infiltrates. These data show that site- and cell-type-specific A8 and A9 expression modulates chronic skin and systemic inflammation with distinct effects on the skin differentiation and on the musculoskeletal system. These findings pave the way for novel therapies targeting the divergent functions of A8 and A9 to restore epidermal homeostasis and prevent systemic complications.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"8 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822710","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}

{"title":"ZNF593 regulates the cGAS-mediated innate immune response by attenuating cGAS-DNA binding","authors":"Xuemei Bai, Na Dong, Nan Cao, Min Zhou, Jiahua Yuan, Yuling Zhang, Yaxing Liu, JiaJia Zhang, Tian Chen, Feng Liu, Wanwei Sun, Yi Zheng, Wei Zhao, Qiang Shu, Chengjiang Gao, Bingyu Liu","doi":"10.1038/s41418-025-01508-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01508-5","url":null,"abstract":"<p>The enzyme cyclic GMP-AMP synthase (cGAS) is essential for detecting aberrantly located double-stranded DNA (dsDNA) from genomic, mitochondrial, and microbial origins. Through the synthesis of 2′3′-cGAMP, cGAS triggers the activation of the stimulator of interferon genes pathway, which initiates in vivo innate immune responses. Here, we identify zinc finger proteins ZNF593, which translocate from the nucleus to the cytoplasm after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production. ZNF593 directly binds to cGAS and suppresses its activation by inhibiting the cGAS-dsDNA interaction. ZNF593 deficiency increases IRF3 nuclear translocation and promotes DNA virus-triggered IFN production. Furthermore, ZNF593 deficiency promotes antiviral innate responses in vivo, improving survival rates in mice against HSV-1 infection. We further find that ZNF593 plays a protective role in systemic lupus erythematosus (SLE) pathology. Notably, replenishing ZNF593 effectively reduced IFN production in peripheral blood mononuclear cells (PBMCs) of SLE patients or in the TMPD-induced murine SLE model. Our findings suggest that ZNF593 negatively regulates IFN-β signaling by targeting cGAS activation, providing new insights into the regulatory mechanisms for antiviral defenses and autoimmune diseases.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"60 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819555","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}

{"title":"Formyl peptide receptor 1 and its antagonist T0080 in atherosclerosis","authors":"Yu-Jing Li, Xue Zhao, Siting Wu, Nan Yao, Xueyu Zhang, Yanyan Liu, Xiaobing Tian, Yulin Li, Bin Gao, S. Claiborne Johnston, Fu-Dong Shi, Zhiguo Li","doi":"10.1038/s41418-025-01506-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01506-7","url":null,"abstract":"<p>Focal inflammation and arterial damage driven by macrophages are key pathogenic processes in atherosclerosis. However, the mechanisms that regulate these processes remain poorly understood. In this study, we demonstrate that formyl peptide receptor 1 (FPR1) agonist, a mitochondrial N-formyl peptide, is elevated in the blood of patients with atherosclerosis and correlates with carotid stenosis. Macrophages expressing FPR1 were found in atherosclerotic lesions. Conditional deletion of <i>Fpr1</i> in macrophages reduced plaque formation, local inflammation, and aortic atherosclerosis in apolipoprotein E (<i>ApoE</i>)^−/− mice. FPR1 activates protein kinase C (PKC) in macrophages, promoting the production of reactive oxygen species (ROS), tumor necrosis factor alpha (TNF-α) and interleukin-1beta (IL-1β), which accelerates the apoptosis of endothelial cells and smooth muscle cells. To inhibit FPR1 bioactivity, we developed an antagonist, T0080. Therapeutic administration of T0080 attenuates atherosclerotic progression in <i>ApoE</i>^−/− mice. Our findings highlight the pivotal role of FPR1 in macrophage-mediated atherosclerotic plaque formation and support further investigation of T0080-mediated FPR1 inhibition as a potential treatment for atherosclerosis.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"97 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805695","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}

{"title":"Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition","authors":"Tamara Isermann, Kim Lucia Schneider, Florian Wegwitz, Tiago De Oliveira, Lena-Christin Conradi, Valery Volk, Friedrich Feuerhake, Björn Papke, Sebastian Stintzing, Bettina Mundt, Florian Kühnel, Ute M. Moll, Ramona Schulz-Heddergott","doi":"10.1038/s41418-025-01502-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01502-x","url":null,"abstract":"<p>The stress-associated chaperone system is an actionable target in cancer therapies. It is ubiquitously upregulated in cancer tissues and enables tumorigenicity by stabilizing oncoproteins. Most inhibitors target the key component, heat-shock protein 90 (HSP90). Although HSP90 inhibitors are highly tumor-selective, they fail in clinical trials. These failures are partly due to interference with a negative regulatory feedback loop in the heat-shock response (HSR): in response to HSP90 inhibition, there is compensatory synthesis of stress-inducible chaperones, mediated by the transcription factor heat-shock-factor 1 (HSF1). We recently identified that wild-type p53 reduces the HSR by repressing HSF1 via a p21-CDK4/6-MAPK-HSF1 axis. Here, we test whether in HSP90-based therapies, simultaneous p53 activation or direct cell cycle inhibition interrupts the deleterious HSF1-HSR axis and improves the efficiency of HSP90 inhibitors. We found that the clinically relevant p53 activator Idasanutlin suppresses the HSF1-HSR activity in HSP90 inhibitor-based therapies. This combination synergistically reduces cell viability and accelerates cell death in p53-proficient colorectal cancer (CRC) cells, murine tumor-derived organoids, and patient-derived organoids (PDOs). Mechanistically, upon combination therapy, CRC cells upregulate p53-associated pathways, apoptosis, and inflammatory pathways. Likewise, in a CRC mouse model, dual HSF1-HSP90 inhibition represses tumor growth and remodels immune cell composition. Importantly, inhibition of the cyclin-dependent kinases 4/6 (CDK4/6) under HSP90 inhibition phenocopies synergistic repression of the HSR in p53-proficient CRC cells. Moreover, in p53-deficient CRC cells, HSP90 inhibition in combination with CDK4/6 inhibitors similarly suppresses the HSF1-HSR and reduces cancer growth. Likewise, p53-mutated PDOs respond to dual HSF1-HSP90 inhibition, providing a strategy to target CRC independent of the p53 status. In sum, we provide new options to improve HSP90-based therapies to enhance CRC therapies.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"75 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813769","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}

{"title":"The BCL-2 protein family: from discovery to drug development","authors":"Carlo M. Croce, David Vaux, Andreas Strasser, Joseph T. Opferman, Peter E. Czabotar, Stephen W. Fesik","doi":"10.1038/s41418-025-01481-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01481-z","url":null,"abstract":"<p>The landmark discovery of the BCL-2 gene and then its function marked the identification of inhibition of apoptotic cell death as a crucial novel mechanism driving cancer development and launched the quest to discover the molecular control of apoptosis. This work culminated in the generation of specific inhibitors that are now in clinical use, saving and improving tens of thousands of lives annually. Here, some of the original players of this story, describe the sequence of critical discoveries. The t(14;18) chromosomal translocation, frequently observed in follicular lymphoma, allowed the identification and the cloning of a novel oncogene (<i>BCL-2</i>) juxtaposed to the immunoglobulin heavy chain gene locus (<i>IgH</i>). Of note, BCL-2 acted in a distinct manner as compared to then already known oncogenic proteins like ABL and c-MYC. BCL-2 did not promote cell proliferation but inhibited cell death, as originally shown in growth factor dependent haematopoietic progenitor cell lines (e.g., FDC-P1) and in <i>Eμ-Myc/Eμ-Bcl-2</i> double transgenic mice. Following a rapid expansion of the BCL-2 protein family, the Abbott Laboratories solved the first structure of BCL-XL and subsequently the BCL-XL/BAK peptide complex, opening the way to understanding the structures of other BCL-2 family members and, finally, to the generation of inhibitors of the different pro-survival BCL-2 proteins, thanks to the efforts of Servier/Norvartis, Genentech/WEHI, AbbVie, Amgen, Prelude and Gilead. Although the BCL-2 inhibitor Venetoclax is in clinical use and inhibitors of BCL-XL and MCL-1 are undergoing clinical trials, several questions remain on whether therapeutic windows can be achieved and what other agents should be used in combination with BH3 mimetics to achieve optimal therapeutic impact for cancer therapy. Finally, the control of the expression of BH3-only proteins and pro-survival BCL-2 family members needs to be better understood as this may identify novel targets for cancer therapy. This story is still not concluded!</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"183 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813770","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}

{"title":"p53 transcriptionally activates DCP1B to suppress tumor progression and enhance tumor sensitivity to PI3K blockade in non-small cell lung cancer","authors":"Shiqi Chen, Qian Hao, Yu Gan, Jing Tong, Chen Xiong, Quan Liao, Yang Zhang, Ting Ye, Xiang Zhou, Haiquan Chen","doi":"10.1038/s41418-025-01501-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01501-y","url":null,"abstract":"<p>Non-small cell lung cancer (NSCLC), which accounts for approximately 85% of lung cancer patients, is characterized by its aggressive nature and poor prognosis. In this study, we identify decapping mRNA 1B (<i>DCP1B</i>) as a tumor suppressor gene that is transcriptionally regulated by p53. DCP1B is found to inhibit the growth and migration of NSCLC cells. Consistently, the level of DCP1B expression is decreased in NSCLC tissues, and its low expression is associated with NSCLC patients’ unfavorable outcomes. Mechanistic investigations reveal that DCP1B promotes the turnover of mitogen-activated protein kinase 4 (<i>MAPK4</i>) mRNA, and the activation of p53 reduces the expression level of MAPK4 partially through DCP1B. Notably, overexpression of MAPK4 can drive AKT phosphorylation independent of phosphoinositide 3-kinase (PI3K), thus neutralizing the anti-tumor activity of the PI3K inhibitor in NSCLC cells. Moreover, the p53 agonist combined with the PI3K inhibitor can suppress NSCLC proliferation synergistically in vitro and in vivo. Collectively, this study not only uncovers the function and mechanism of the p53-DCP1B-MAPK4 axis in suppressing NSCLC progression but also suggests a promising combination strategy for treating NSCLC.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"14 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805692","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}

{"title":"Re-appraising assays on permeabilized blood cancer cells testing venetoclax or other BH3 mimetic agents selectively targeting pro-survival BCL2 proteins","authors":"Jia-Nan Gong, Tirta M. Djajawi, Donia M. Moujalled, Giovanna Pomilio, Tiffany Khong, Li-Ping Zhang, Pasquale L. Fedele, Michael S. Low, Mary Ann Anderson, Christopher D. Riffkin, Christine A. White, Ping Lan, Guillaume Lessene, Marco J. Herold, Andreas Strasser, Andrew Spencer, George Grigoriadis, Andrew H. Wei, Mark F. van Delft, Andrew W. Roberts, David C. S. Huang","doi":"10.1038/s41418-025-01487-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01487-7","url":null,"abstract":"<p>BH3 mimetic drugs that selectively target the pro-survival BCL2 proteins are highly promising for cancer treatment, most notably for treating blood cancers. Venetoclax, which inhibits BCL2, is now approved for treating chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Preferably, robust and validated assays would identify patients most likely to benefit from therapy with venetoclax itself or with inhibitors of other pro-survival proteins. A sophisticated method that has been developed is the BH3 profiling assay. In this assay, permeabilized, instead of intact, cells are treated for a few hours with inhibitors of the pro-survival BCL2 proteins, and the resultant mitochondrial depolarization measured. Sensitivity to a specific inhibitor (e.g., venetoclax or other BH3 mimetics) is then used to infer the reliance of a tumor (e.g., CLL) on one or more pro-survival BCL2 proteins. However, we found that this methodology cannot reliably identify such dependencies. In part, this is because almost all cells express multiple pro-survival BCL2 proteins that restrain BAX and BAK which must be inhibited before mitochondrial depolarization and apoptosis can proceed. Using genetic and pharmacological tools across multiple cell line models of blood cancer, we demonstrated that selective BCL2 inhibitors have important flow-on effects that includes the redistribution of BH3-only proteins to ancillary pro-survival proteins not directly engaged by the inhibitor. These secondary effects, critical to the biological action of selective inhibitors, were not accurately recapitulated in permeabilized cells, probably due to the limited time frame possible in such assays or the altered biophysical conditions when cells are permeabilized. While we could consistently define the sensitivity of a tumor cell to a particular BH3 mimetic drugs using intact cells, this was not reliable with permeabilized cells. These studies emphasize the need to carefully evaluate assays on permeabilized cells undertaken with inhibitors of the pro-survival BCL2 proteins.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"21 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143813539","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}

{"title":"The metabolic enzyme GYS1 condenses with NONO/p54nrb in the nucleus and spatiotemporally regulates glycogenesis and myogenic differentiation","authors":"Shujun Peng, Canrong Li, Yifan Wang, Yuguo Yi, Xinyu Chen, Yujing Yin, Fan Yang, Fengzhi Chen, Yingyi Ouyang, Haolun Xu, Baicheng Chen, Haowen Shi, Qingrun Li, Yu Zhao, Lin Feng, Zhenji Gan, Xiaoduo Xie","doi":"10.1038/s41418-025-01509-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01509-4","url":null,"abstract":"<p>Accumulating evidence indicates that metabolic enzymes can directly couple metabolic signals to transcriptional adaptation and cell differentiation. Glycogen synthase 1 (GYS1), the key metabolic enzyme for glycogenesis, is a nucleocytoplasmic shuttling protein compartmentalized in the cytosol and nucleus. However, the spatiotemporal regulation and biological function of nuclear GYS1 (nGYS1) microcompartments remain unclear. Here, we show that GYS1 dynamically reorganizes into nuclear condensates under conditions of glycogen depletion or transcription inhibition. nGYS1 complexes with the transcription factor NONO/p54^nrb and undergoes liquid–liquid phase separation to form biomolecular condensates, leading to its nuclear retention and inhibition of glycogen biosynthesis. Compared to their wild-type littermates, Nono-deficient mice exhibit exercise intolerance, higher muscle glycogen content, and smaller myofibers. Additionally, Gys1 or Nono deficiency prevents C2C12 differentiation and cardiotoxin-induced muscle regeneration in mice. Mechanistically, nGYS1 and NONO co-condense with the myogenic transcription factor MyoD and preinitiation complex (PIC) proteins to form transcriptional condensates, driving myogenic gene expression during myoblast differentiation. These results reveal the spatiotemporal regulation and subcellular function of nuclear GYS1 condensates in glycogenesis and myogenesis, providing mechanistic insights into glycogenoses and muscular dystrophy.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"6 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805693","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}

{"title":"Sphingosine kinase 2 deficiency impairs VLDL secretion by inhibiting mTORC2 phosphorylation and activating chaperone-mediated autophagy","authors":"Shuangshuang Zhang, Gaoxiang Li, Lianping He, Fei Wang, Mengru Gao, Tianliang Dai, Yushuang Su, Luyan Li, Ying Cao, Minghua Zheng, Liang Chen, Jun Cao, Hong Zhou","doi":"10.1038/s41418-025-01507-6","DOIUrl":"https://doi.org/10.1038/s41418-025-01507-6","url":null,"abstract":"<p>Hepatic very low-density lipoprotein (VLDL) is essential for maintaining lipid metabolism in the liver. Sphingosine kinases (SphKs) are essential rate-limiting enzymes that catalyze sphingosine phosphorylation to Sphingosine-1-phosphate (S1P). SphKs exist as two isoforms, SphK1 and SphK2, both highly expressed in the liver. SphK1 plays a critical role in regulating hepatic inflammation and drug metabolism. This study aimed to determine whether SphK2 regulates hepatic lipid metabolism, particularly VLDL secretion. Immunohistochemical staining revealed decreased SphK2 protein levels within regions proximal to hepatic lipid accumulation in individuals diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD). <i>Sphk2</i>^{<i>−/−</i>} mice exhibited spontaneous hepatocyte lipid accumulation and reduced VLDL secretion. Proteomic analysis revealed that SphK2 deficiency impaired soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE) complex interactions involved in vesicular transport and organelle membrane fusion. Furthermore, SphK2 deficiency results in accelerated degradation of the SEC22B, STX5A, and GS28 proteins via chaperone-mediated autophagy (CMA), impeding VLDL transport to the Golgi apparatus. MYH1485, a specific activator of mTOR, induces mTORC2 phosphorylation, thereby inhibiting the degradation of SNARE complexes by CMA and counteracting the lipid accumulation induced by SphK2 deficiency. Exogenous S1P supplementation markedly reversed the reduction in mTORC2 phosphorylation and suppressed CMA, thereby improving VLDL secretion. Our study elucidates an inventive regulatory mechanism by which SphK2 modulates CMA by activating mTORC2 phosphorylation, promoting VLDL secretion, and balancing lipid metabolism in the liver. These findings provide insights into SphK2 function and the underlying mechanisms involved in the regulation of VLDL secretion, which may facilitate MASLD treatment.</p><figure><p><b>Proposed model for the role of SphK2 in hepatic VLDL secretion</b>. In hepatocytes, the inhibition of SphK2 activity decreased S1P production, which subsequently downregulates the mTORC2 pathway. This process accelerates the degradation of the SNARE complex components STX5A, GS28, and SEC22B via CMA, which regulates the mutual recognition between VTVs and the Golgi apparatus, ultimately reducing VLDL secretion in hepatocytes.</p></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"20 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143805700","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}

{"title":"Folliculin depletion results in liver cell damage and cholangiocarcinoma through MiT/TFE activation","authors":"Bruno Maria Custode, Francesco Annunziata, Felipe Dos Santos Matos, Valentina Schiano, Veronica Maffia, Milena Lillo, Rita Colonna, Rossella De Cegli, Andrea Ballabio, Nunzia Pastore","doi":"10.1038/s41418-025-01486-8","DOIUrl":"https://doi.org/10.1038/s41418-025-01486-8","url":null,"abstract":"<p>Mutations in the tumor suppressor gene Folliculin (<i>FLCN</i>) are responsible for Birt-Hogg-Dube’ (BHD) syndrome, a rare inherited condition that predisposes affected individuals to skin tumors, pulmonary cysts, and kidney tumors. FLCN regulates key cellular pathways, including TFEB, TFE3, and mTORC1, which are critical for maintaining cell homeostasis. Loss of FLCN leads to both hyperactivation of mTORC1 and constitutive activation of TFEB and TFE3, contributing to tumorigenesis. While previous studies showed that Flcn liver-specific conditional knockout (Flcn^LiKO) mice are protected from developing liver fibrosis and damage upon high-fat diet exposure, the potential role of FLCN loss in liver carcinogenesis remained unexplored. Here, we demonstrate that hepatic loss of FLCN in mice results in cancer associated with inflammation and fibrosis with features of cholangiocarcinoma (CCA). This phenotype emerges in mice over 90-week-old, with a male predominance. Moreover, Flcn^LiKO mice are more prone to develop diethylnitrosamine (DEN)- or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- induced liver tumors with heterogenous histological features. Notably, depletion of TFE3, but not TFEB, in the liver of Flcn^LiKO mice fully rescues the cancer phenotype and normalized mTORC1 signaling, highlighting TFE3 as the primary driver of liver cancer and mTORC1 hyperactivity in the absence of FLCN.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"183 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143784726","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}