Biochimica et biophysica acta. Molecular cell research最新文献

{"title":"Oscillatory shear stress activates integrin β3, blocking autophagic flux in endothelial cells and promoting endothelial cells senescence.","authors":"Shuai Li, Xingyu Jiang, Wenjun Huang, Qingyu Meng, Luya Pu, Banghao Sun, Bin Liu, Fan Li","doi":"10.1016/j.bbamcr.2025.119991","DOIUrl":"https://doi.org/10.1016/j.bbamcr.2025.119991","url":null,"abstract":"<p><p>Atherosclerosis is an age-related cardiovascular disease. The intersections and bends of blood vessels under the direct action of oscillatory shear stress (OSS) are susceptible to atherosclerotic plaque formation, and the expression of age-related factors is significantly increased in plaques. However, the molecular mechanism by which OSS promotes vascular senescence is still unclear. In this study, we found that the expression of age-related factors, such as P16 and P21, was increased in human aortic endothelial cells (HAECs) exposed to OSS. We also found that the expression of autophagy-related gene 5 (ATG5), microtubule-associated protein 1 light chain 3β (MAP1LC3B), and beclin 1 (BECN1) was increased in HAECs exposed to OSS. The expression of sequestosome-1 (SQSTM1/P62) was also increased. Immunofluorescence confirmed that OSS impaired autophagic flux in HAECs by inhibiting the binding of autophagosomes to lysosome, thereby promoting endothelial cell (EC) senescence. The OSS-sensitive gene integrin β3 (ITGB3), which is closely related to EC autophagy and senescence, was screened by proteomics analysis of HAECs in the control and OSS-treated groups. The protein and mRNA expression of ITGB3 was significantly increased in HAECs exposed to OSS. ITGB3 overexpression in HAECs significantly affected the autophagic flux of ECs and promoted EC senescence, resulting in an increase in cells in the G0/G1 phase and cell cycle arrest. ITGB3 knockdown significantly inhibited the block of OSS-induced autophagic flux and senescence in ECs. In addition, in vivo studies showed that treatment with the ITGB3 inhibitor Cyclo(arginine-glycine-aspartate-tyrosine-lysine) [Cyclo(RGDyK)] significantly inhibited high-fat diet-induced plaque formation in the aortae of apolipoprotein E (ApoE)-/- mice. In conclusion, OSS blocks HAECs autophagic flux and promotes senescence via ITGB3 activation, thereby affecting the development of atherosclerosis.</p>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":" ","pages":"119991"},"PeriodicalIF":4.6,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RNA polymerase III transcription machinery and tRNA processing are regulated by the ubiquitin ligase Rsp5","authors":"Aleksandra Łopusińska,&nbsp;Michał Tys,&nbsp;Magdalena Boguta,&nbsp;Małgorzata Cieśla","doi":"10.1016/j.bbamcr.2025.119993","DOIUrl":"10.1016/j.bbamcr.2025.119993","url":null,"abstract":"<div><div>Transfer RNA (tRNA) biogenesis in yeast involves synthesis of the primary transcript by RNA polymerase III (Pol III), followed by processing to remove 5′ and 3′ ends, further maturation, and export to the cytoplasm. In the present study, we found that both tRNA transcription and the initial processing of tRNA precursors are affected by the ubiquitin ligase Rsp5. We observed high levels of unprocessed primary tRNA transcripts in <em>rsp5</em> mutants at elevated temperature, which were reduced upon the overexpression of <em>RPR1</em>, the catalytic subunit of RNase P. This observation suggests a role for Rsp5 in the maturation of 5′ ends of tRNA precursors. Under the same conditions, in vivo labeling showed that the amount of newly synthesized tRNA decreased. Furthermore, we found that Rsp5 directly interacted with the Tfc3 subunit of the TFIIIC transcription factor, which is modified by ubiquitination. The inactivation of Rsp5 catalytic activity influenced the interaction between the general Pol III factors TFIIIB and TFIIIC and decreased the recruitment of TFIIIC to tRNA genes. These findings suggest that Rsp5 ligase is implicated in the control of Pol III transcription in yeast.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119993"},"PeriodicalIF":4.6,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144115480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia-induced phenotypic transformation of scleral fibroblasts promotes activation of the adhesion patch pathway through paracrine effects leading to choroidal damage","authors":"Yuezu Li ,&nbsp;Ou Zhang ,&nbsp;Yanting Pan,&nbsp;Xueling Du,&nbsp;Jun Li","doi":"10.1016/j.bbamcr.2025.119992","DOIUrl":"10.1016/j.bbamcr.2025.119992","url":null,"abstract":"<div><div>Myopia has become an important cause of vision loss, where its prevalence is increasing in the younger population. The pathogenesis of myopia remains poorly understood. In this study, human scleral fibroblasts (HSFs) were induced by hypoxia to verify the effects of hypoxia on the phenotypic transformation and extracellular matrix remodeling of HSFs. Subsequently, exosomes of HSFs under normoxic and hypoxic conditions were extracted and validated to explore the effects of HSFs on human choroidal endothelial cells (HCEC). Transcriptome sequencing analyzed the possible molecular mechanisms by which HSFs affect HCEC. The results showed that hypoxia resulted in reduced proliferative capacity of HSFs, promoted cellular fibrosis as well as aggravated oxidative damage. The HCEC group treated with hypoxia-induced HSFs conditioned medium or exosomes exhibited significantly more cellular damage compared to the normal conditioned group. Transcriptome sequencing showed that differentially expressed genes in hypoxia-induced HSFs-derived exosome-treated HCEC were significantly enriched in the Focal adhesion signaling pathway. This sequencing result was verified by RT-qPCR and Western blot experiments. Our study demonstrated in vitro that hypoxia induces phenotypic transformation of HSFs, and that lead to HCEC damage through a paracrine mechanism, a process that may be mediated by the adhesion patch signaling pathway.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119992"},"PeriodicalIF":4.6,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144092343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPX4 degradation contributes to heat stress-induced liver injury via chaperone-mediated autophagy","authors":"Ting Wang,&nbsp;Xiao Liu,&nbsp;Xinyu Feng,&nbsp;Zhenyu Zhang,&nbsp;Ruiyi Lv,&nbsp;Wenhong Feng,&nbsp;Yukun Zhou,&nbsp;Xueyu Liao,&nbsp;Haoming Tang,&nbsp;Ming Xu","doi":"10.1016/j.bbamcr.2025.119988","DOIUrl":"10.1016/j.bbamcr.2025.119988","url":null,"abstract":"<div><div>Heat stress (HS) is a significant health concern that adversely affects both human and animal health, particularly impacting liver function due to its central metabolic role. This study investigated the mechanisms underlying HS-induced liver injury, focusing on the role of ferroptosis, an iron-dependent form of cell death characterized by lipid peroxidation and cellular iron accumulation. Using mouse and cellular HS models, the results demonstrated that HS induced liver injury through ferroptosis, as evidenced by increased levels of malondialdehyde (MDA), oxidized glutathione (GSSG), and iron, alongside decreased glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. The ferroptosis inhibitor Ferrostatin-1 (Fer-1) effectively mitigated HS-induced liver damage, reducing oxidative stress and restoring GPX4 levels. Furthermore, HS promoted the lysosomal degradation of GPX4 via the chaperone-mediated autophagy (CMA) pathway, which was regulated by heat shock cognate protein 70 (HSC70) and lysosome-associated membrane protein 2A (LAMP2A). Knockdown of LAMP2A in hepatocytes significantly suppressed HS-induced GPX4 degradation, confirming the critical role of CMA in this process. Inhibition of CMA using Apoptozole, an HSC70 inhibitor, or Bafilomycin A1 (Baf-A1), a lysosomal inhibitor, further attenuated HS-induced ferroptosis and liver injury. These findings highlight the critical role of CMA-mediated GPX4 degradation in HS-induced ferroptosis and liver injury, providing potential therapeutic targets for mitigating HS-related liver damage.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119988"},"PeriodicalIF":4.6,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paraoxonase 3 regulates the pore-forming α subunit of the large-conductance K+ channel","authors":"Sarah Christine M. Whelan ,&nbsp;Andrew J. Nickerson ,&nbsp;Nicolas Montalbetti ,&nbsp;Stephanie M. Mutchler ,&nbsp;Marcelo D. Carattino ,&nbsp;Thomas R. Kleyman ,&nbsp;Shujie Shi","doi":"10.1016/j.bbamcr.2025.119990","DOIUrl":"10.1016/j.bbamcr.2025.119990","url":null,"abstract":"<div><div>Paraoxonase 3 (PON3) is expressed in the aldosterone-sensitive distal nephron (ASDN) where the fine tuning of Na⁺ and K⁺ homeostasis in the kidney occurs. Flow-induced K⁺ secretion within intercalated cells (ICs) of the ASDN is mediated by the large-conductance K⁺ (BK) channels. We have previously shown that renal PON3 expression was altered by dietary K⁺ intake and that <em>Pon3</em> knockout (KO) mice had lower plasma [K⁺]. These findings led us to hypothesize that PON3 may have a role in regulating renal K⁺ secretion by altering BK channel functional expression. The present study shows that both PON3 and the pore-forming α subunit of the BK channel (αBK) are expressed in ICs of mouse kidney and that the two proteins co-localize to the same cellular compartments when expressed in HEK293 cells. Using a biochemical approach, we show that PON3 interacts with αBK endogenously in the mouse kidney and when both proteins were co-expressed in HEK293 cells. We also examined the effects of PON3 on αBK expression and channel activity in HEK293 cells. We found that paxilline-sensitive BK currents were significantly reduced by PON3 expression, likely a consequence of lower surface abundance of αBK. Consistent with this finding, we observed a stronger αBK staining signal in ICs of <em>Pon3</em> KO kidneys. Together, our data suggest that PON3 negatively regulates the functional expression of BK channels.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119990"},"PeriodicalIF":4.6,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143947613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The NFE2L2 (NRF2) transcription factor controls genes involved in the oxidative stress response and inflammation in myometrial cells","authors":"Palak Gujral ,&nbsp;Eduardo Orozco-Alonso ,&nbsp;James Saliba ,&nbsp;Xingyue Yan ,&nbsp;Volker Blank","doi":"10.1016/j.bbamcr.2025.119985","DOIUrl":"10.1016/j.bbamcr.2025.119985","url":null,"abstract":"<div><div>The myometrium is the smooth muscle layer of the uterus, which mediates uterine contractions during labor. We treated PHM1–31 myometrial cells with the proinflammatory cytokine interleukin-1 beta (IL1B) and measured a significant increase in reactive oxygen species (ROS). We found that IL1B induces NFE2L2 (NRF2) transcription factor levels. We further showed that siRNA mediated knockdown of NFE2L2 results in a significant increase in ROS. Downregulation of NFE2L2 leads to a decrease of heme oxygenase-1 (HMOX1) and aldo-keto reductase family 1 member B (AKR1B) at the transcript and protein level both in the absence and presence of IL1B. NFE2L2 knockdown also results in reduced <em>ferritin heavy chain 1</em> (<em>FTH1</em>) mRNA expression, but only upon IL1B exposure, while FTH1 protein is downregulated both under basal and IL1B treatment conditions. We confirmed that NFE2L2 directly binds to the regulatory regions of these targets. Previous reports have linked HMOX1 and FTH1 to the oxidative stress response, and AKR1B1 to prostaglandin synthesis. Our data demonstrate that NFE2L2 functions as a key regulator of inflammatory and oxidative stress signaling through the regulation of HMOX1, FTH1, and AKR1B1 expression in myometrial cells. While HMOX1 and FTH1 have established roles in oxidative stress responses, our findings identify AKR1B1 as a novel target of NFE2L2 in myometrial cells, suggesting a role for the transcription factor in prostaglandin metabolism. Thus, NFE2L2 links inflammation and the oxidative stress response to critical pathways that control myometrial cell function and parturition, highlighting their potential as therapeutic targets for treating infection-induced preterm labor.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119985"},"PeriodicalIF":4.6,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143942204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salinomycin inhibits SREBP1 to sensitize ferroptosis and ameliorate sorafenib resistance in clear cell renal cell carcinoma","authors":"Yu Su ,&nbsp;Xuan Liu ,&nbsp;Dekun Wang ,&nbsp;Gang Li ,&nbsp;Xue Mi ,&nbsp;Yuying Zhang ,&nbsp;Shijing Yue ,&nbsp;Zhujun Zhang ,&nbsp;Tianyu Shen ,&nbsp;Xiaoyue Tan","doi":"10.1016/j.bbamcr.2025.119989","DOIUrl":"10.1016/j.bbamcr.2025.119989","url":null,"abstract":"<div><div>Backgrounds</div><div>Resistance to sorafenib, a frontline therapy for advanced ccRCC, is associated with decreased sensitivity to ferroptosis. Our research focuses on elucidating the mechanisms underlying ccRCC's resistance to sorafenib-induced ferroptosis and identifying potential new agents that could overcome this resistance.</div></div><div><h3>Methods</h3><div>The silencing of SREBP1 was employed to evaluate the role of this key transcription factor in lipid synthesis and its contribution to ferroptosis resistance in sorafenib-treated ccRCC cells. The ATF4-mediated induction of SREBP1 following salinomycin treatment was assessed by western blot, RT-PCR, immunohistochemistry, chromatin immunoprecipitation, and dual-luciferase reporter assays. In cultured ccRCC cells, the combined effects of salinomycin and sorafenib on ferroptosis induction were evaluated by assessing cell viability, glutathione levels, malondialdehyde levels, BODIPY fluorescence, and intracellular Fe²⁺ concentration. In an orthotopic ccRCC mouse model, the synergistic effects of salinomycin and sorafenib on both ferroptosis and tumor progression were examined.</div></div><div><h3>Results</h3><div>Overexpression of SREBP1 was observed in ccRCC tumor tissue, and induced by sorafenib treatment. Silencing SREBP1 reduced the resistance of ccRCC cells to ferroptosis induced by sorafenib. Salinomycin decreased ATF4 level, which in turn inhibited <em>SREBP1</em> transcription. Treatment with salinomycin enhanced the sensitivity of ccRCC cells to sorafenib-induced ferroptosis. In the orthotopic xenograft mouse model of ccRCC, the combination of salinomycin and sorafenib showed a synergistic effect in inducing ferroptosis inhibiting tumor growth.</div></div><div><h3>Conclusions</h3><div>Salinomycin treatment mitigates resistance to sorafenib-induced ferroptosis by inhibiting SREBP1. The combination of salinomycin and sorafenib synergistically enhances ferroptosis and suppresses ccRCC growth.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119989"},"PeriodicalIF":4.6,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143960807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NFE2L3 regulates inflammation and oxidative stress-related genes in the colon","authors":"Linda Yaker ,&nbsp;James Saliba ,&nbsp;Liam P.C. Scott ,&nbsp;Anantpreet Kaur Sood ,&nbsp;Palak Gujral ,&nbsp;Eduardo Orozco-Alonso ,&nbsp;Xingyue Yan ,&nbsp;Adam Yeh ,&nbsp;Volker Blank","doi":"10.1016/j.bbamcr.2025.119987","DOIUrl":"10.1016/j.bbamcr.2025.119987","url":null,"abstract":"<div><div>The molecular mechanisms leading to inflammatory bowel disease (IBD) are only partially understood. We investigated the role of the transcription factor NFE2L3 in a mouse model of colitis by inducing inflammation using dextran sodium sulfate (DSS). We confirmed the presence of inflammation by histological analysis and elevated levels of the inflammation marker lipocalin-2 (LCN2) in the stool. We found that <em>Lcn2</em> transcript levels are significantly less elevated in <em>Nfe2l3</em>^−/− mice than wild type mice. We further showed a reduction of <em>Nfe2l3</em> mRNA, in wildtype mice upon DSS treatment. We cross referenced ENCODE ChIP data of NFE2L3 binding partners MAFF and MAFK with known IBD and DSS effectors and identified <em>Stat1</em>, <em>Hmox1</em>, and <em>Slc7a11</em> as potential NFE2L3 targets. These proteins are induced during colitis to suppress the immune response, reduce oxidative stress, and trigger ferroptosis, respectively. We analyzed the candidate targets and observed an increase in their protein expression upon DSS treatment in wild type but not in <em>Nfe2l3</em>^−/− mice. Furthermore, in the absence of DSS, we observed an increase in the basal levels of pSTAT1 and SLC7A11 proteins in <em>Nfe2l3</em>^−/− mice. These data suggest that the NFE2L3 transcription factor primes the microenvironment towards a pro-inflammatory ready state during inflammatory bowel disease (IBD).</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119987"},"PeriodicalIF":4.6,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143976991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting TRPML3 inhibits proliferation and invasion, and enhances doxorubicin sensitivity by disrupting lysosomal acidification and mitochondrial function in triple-negative breast cancer","authors":"Gabriela Maria De Abreu Gomes ,&nbsp;Mengnan Xu ,&nbsp;Alia Kazim Rizvi Syeda ,&nbsp;Renee Raudonis ,&nbsp;Shekoufeh Almasi ,&nbsp;Vishnu Vijay Vijayan ,&nbsp;Shashi Gujar ,&nbsp;Xianping Dong ,&nbsp;Zhenyu Cheng ,&nbsp;Thomas Pulinilkunnil ,&nbsp;Yassine El Hiani","doi":"10.1016/j.bbamcr.2025.119979","DOIUrl":"10.1016/j.bbamcr.2025.119979","url":null,"abstract":"<div><div>TNBC remains the most aggressive and therapy-resistant type of breast cancer, for which efficient targeted therapies have not been developed yet. Here, we identified TRPML3 (ML3) as a potential therapeutic target in TNBC. Our data showed that ML3 is significantly upregulated in TNBC cells compared with nontumorigenic control cells. ML3 knockdown (KD) impairs TNBC cell proliferation by inducing cell cycle arrest and caspase-dependent apoptosis. ML3 KD also inhibits TNBC cell migration and invasion. Mechanistically, ML3 KD reduces lysosomal number and enhances lysosomal acidification, which in turn activates mTORC1, thereby inhibiting autophagy initiation and flux. This disruption negatively impacts mitochondrial function, as evidenced by reduced ATP production, increased ROS and NO production, and mitochondrial fragmentation. Importantly, ML3 KD enhances TNBC cell sensitivity to doxorubicin and paclitaxel. The finding suggests that targeting ML3 disrupts lysosomal and mitochondrial homeostasis and enhance chemosensitivity, presenting ML3 as a potential therapeutic vulnerability in TNBC enhancing chemosensitivity.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119979"},"PeriodicalIF":4.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of NAMPT as a therapeutic strategy to suppress tumor growth in lymphangioleiomyomatosis","authors":"Shahrzad S. Fard ,&nbsp;Nandini Kundu ,&nbsp;Alek S. Torres ,&nbsp;Christina L. Faltas ,&nbsp;Julie S. Di Martino ,&nbsp;Marina K. Holz","doi":"10.1016/j.bbamcr.2025.119986","DOIUrl":"10.1016/j.bbamcr.2025.119986","url":null,"abstract":"<div><div>Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease driven by mutations in the <em>TSC1</em> or <em>TSC2</em> genes, leading to constitutive mTORC1 activation and uncontrolled cell proliferation. Current therapies, like rapamycin effectively stabilize disease progression but mainly exert cytostatic effects and promote autophagy, a survival mechanism in LAM cells. These limitations highlight the need for the development of innovative therapies to achieve more effective and lasting results. To explore alternative therapeutic targets, we investigated the role of nicotinamide phosphoribosyltransferase (NAMPT), a key regulator of NAD⁺ biosynthesis, in LAM and <em>TSC2</em>-deficient cells using a potent inhibitor, FK866. Our study demonstrates that FK866 depletes NAD⁺ levels in these cells, exerting a dual effect by activating AMPK and subsequently inhibiting mTORC1 signaling while suppressing autophagy. Unlike rapamycin, FK866 does not induce compensatory Akt activation, significantly inhibits LAM cell proliferation and induces apoptosis. Additionally, using an in vivo chicken egg chorioallantoic membrane (CAM) model, we showed that FK866 treatment significantly reduces LAM tumor growth compared to controls suggesting that NAMPT inhibition disrupts metabolic and survival pathways critical for <em>TSC2</em>-deficient cell viability and tumor progression. Our results establish NAMPT as a promising therapeutic target for LAM, offering a two-prong strategy to suppress tumor growth and enhance apoptosis, providing an alternative to current mTOR-based therapies.</div></div>","PeriodicalId":8754,"journal":{"name":"Biochimica et biophysica acta. Molecular cell research","volume":"1872 6","pages":"Article 119986"},"PeriodicalIF":4.6,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}