Cellular and Molecular Life Sciences最新文献

{"title":"Inhibition of ferroptosis via SLC25A39-NRF2 axis drives Osimertinib resistance in lung adenocarcinoma.","authors":"Kai Fu, Zhilin Zeng, Wenfeng Wang, Wei Wu, Yijie Gong, Xiangning Fu, Yixin Cai, Changyu Liu","doi":"10.1007/s00018-026-06313-y","DOIUrl":"10.1007/s00018-026-06313-y","url":null,"abstract":"<p><strong>Objective: </strong>Overcoming resistance to Osimertinib remains a major clinical challenge in lung adenocarcinoma (LUAD). The molecular mechanisms driving this resistance are still not fully understood.</p><p><strong>Methods: </strong>Integrated bioinformatics analysis and functional assays were performed to investigate the role of SLC25A39 in LUAD progression and drug resistance. Mechanistic studies were conducted using co-immunoprecipitation and rescue experiments. Osimertinib-resistant cell models and xenograft assays were used to evaluate therapeutic responses.</p><p><strong>Results: </strong>SLC25A39 was significantly upregulated in LUAD and correlated with unfavorable patient outcomes. Functional studies showed that SLC25A39 depletion suppressed malignant phenotypes and enhanced ferroptosis, whereas its overexpression produced the opposite effects. Mechanistically, SLC25A39 was found to interact with NRF2 and was associated with increased NRF2 stability and transcriptional activity, leading to enhanced glutathione synthesis and attenuation of lipid peroxidation. Importantly, silencing SLC25A39 sensitized LUAD cells to Osimertinib. Consistent with this, pharmacological induction of ferroptosis using RSL3 markedly enhanced the antitumor effects of Osimertinib in both parental and resistant models, resulting in reduced tumor growth in vitro and in vivo, particularly in SLC25A39-high contexts.</p><p><strong>Conclusion: </strong>SLC25A39 promotes LUAD progression and Osimertinib resistance by suppressing ferroptosis via NRF2. Targeting ferroptosis may represent a promising strategy to overcome Osimertinib resistance.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PHLDA1 knockdown exacerbates emphysema in COPD by attenuating proliferation of alveolar type II cells via modulating GLI1 nuclear translocation.","authors":"Shuang Bai, Shuaifu Wang, Rui Ye, Di Wang, Mingxin Ma, Li Zhao","doi":"10.1007/s00018-026-06333-8","DOIUrl":"10.1007/s00018-026-06333-8","url":null,"abstract":"<p><p>The emphysematous phenotype is an important phenotype in chronic obstructive pulmonary disease (COPD), with substantial morbidity and mortality. The mechanisms underpinning the role of alveolar type II (AT2) cells in alveolar repair within this phenotype remain poorly understood. This study aimed to elucidate the role of PHLDA1, a potential stemness regulator in AT2 cells, on emphysema development. Utilizing mice model, we performed a targeted knockdown of PHLDA1 in AT2 cells and subsequently exposed these mice to tobacco smoke to assess the resultant severity of emphysema and related alveolar damage. We manipulated PHLDA1 expression in AT2 cells line or primary mouse AT2 cells to examine its influence on AT2 stemness-related processes- differentiation, proliferation, and wound closure ability. The specific pathway of PHLDA1 mediated in AT2 cells, as well as its interaction with the GLI1 protein, was further investigated. Mice with reduced PHLDA1 expression developed the emphysema independent of smoking exposure. PHLDA1 knockdown in AT2 cells attenuated their proliferation via the Hedgehog pathway, impairing wound closure ability in the emphysematous phenotype. We also discovered a binding relationship between PHLDA1 and GLI1, where PHLDA1 modulates the nuclear translocation of GLI1, thus regulating the Hedgehog pathway and influencing the stemness and proliferation of AT2 cells. Our study suggests that PHLDA1 is a critical factor in the proliferation process of AT2 cells via modulation of GLI1 nuclear translocation. This regulation is essential to the pathogenesis of the emphysematous phenotype in COPD, signifying potential therapeutic targets for intervention.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-Cell dissection of fibrodysplasia ossificans progressiva identifies SPP1 as a mediator of macrophage-fibroadipogenic progenitors crosstalk.","authors":"Riccardo Gamberale, Mauro Bergamaschi, Anna Sofia Tascini, Cristina D'Orlando, Michela Signo, Antonello Spinelli, Raffaella Meneveri, Renata Bocciardi, Bénédicte Chazaud, Emanuele Azzoni, Silvia Brunelli","doi":"10.1007/s00018-026-06320-z","DOIUrl":"10.1007/s00018-026-06320-z","url":null,"abstract":"<p><p>Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder caused by gain-of-function mutations in ACVR1/ALK2, leading to progressive heterotopic ossification (HO) through endochondral bone formation. Inflammatory flare-ups often precede new ossification events, but the cellular and molecular mechanisms linking immune responses to progenitor cell fate remain incompletely understood. Here, using a tamoxifen-inducible Acvr1R206H mouse model of FOP and a reproducible muscle injury protocol, we combined single-cell RNA sequencing with in vitro assays to dissect early events during lesion formation. We identified an expansion of macrophages (MPs) and fibro-adipogenic progenitors (FAPs) in FOP mice, with both populations exhibiting inflammatory and osteochondrogenic transcriptional signatures. Cell-cell interaction analysis revealed a self-reinforcing network of cytokine signaling among MPs and a prominent MP-FAP communication axis centred on SPP1. Functional studies confirmed that SPP1 enhanced FAP osteogenic differentiation and that its inhibition partially reversed this phenotype in vitro and attenuated HO in vivo. Our findings highlight the critical role of inflammatory MPs in shaping the fate of resident stromal mesenchymal progenitors (e.g. FAP) and suggest that early immune-stromal interactions set the stage for HO. Targeting this immune-mesenchymal crosstalk may represent a potential complementary strategy for preventing or mitigating disease progression in FOP.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ablation of the renal tubular gluconeogenic enzyme PCK1 drives AKI-to-CKD transition by negatively regulating the TGF-β/Smad3 signaling pathway.","authors":"Jing-Xuan Gan, Meng-Fan Li, Hai-Hua Deng, Qiu-Tong Liu, Zhi-Xiao Chen, Chun-Ling Liang, Li-Xin Wang, Xu-Sheng Liu, Yue-Yu Gu","doi":"10.1007/s00018-026-06310-1","DOIUrl":"10.1007/s00018-026-06310-1","url":null,"abstract":"<p><p>The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by progressive renal fibrosis, yet the key tubular regulatory factors driving this maladaptive repair remain inadequately defined. In this study, we investigated the role of phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme of gluconeogenesis, in the AKI-to-CKD transition. Analysis of human single-cell RNA sequencing (scRNA-seq) datasets revealed a profound downregulation of PCK1 in injured proximal tubule cells, which correlated with the upregulation of pro-fibrotic markers. In rodent models, we demonstrated that the loss of PCK1 precedes significant collagen deposition and acts as a primary driver of fibrogenesis. Mechanistically, PCK1 deficiency enhanced TGF-β1-induced Smad3 phosphorylation and nuclear translocation, whereas PCK1 overexpression suppressed Smad3 activation as well as the expression of fibrosis-related genes and proteins. Our functional assays supported that PCK1 serves as an endogenous negative regulator and antagonist of Smad3, its depletion releases the restraint on Smad3 phosphorylation and nuclear translocation, leading to the loss of tubular epithelial identity. Significantly, the pharmacological or genetic restoration of PCK1 effectively blunted Smad3 activation and attenuated renal fibrosis in vitro. These findings identify PCK1 as a critical metabolic regulator that maintains tubular homeostasis and suggest that PCK1-targeted modulation of Smad3 signaling may be a promising therapeutic strategy for arresting the progression of chronic kidney disease following acute injury.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LncRNA modulates Dpp-mediated wing development to influence flight in Aedes aegypti.","authors":"Jianping Cao, Lin Ling","doi":"10.1007/s00018-026-06325-8","DOIUrl":"10.1007/s00018-026-06325-8","url":null,"abstract":"<p><p>The flight capability of Aedes aegypti underpins global spread of vector-borne diseases (e.g., dengue, Zika, chikungunya), making it a key control target. Decapentaplegic (Dpp), evolutionarily conserved in insect morphogenesis, has unclear spatiotemporal regulatory networks in Ae. aegypti wing bud/haltere development. Here, we identify a wing bud/haltere-specific long non-coding RNA (lncRNA), AAEL025449, forming a competing endogenous RNA (ceRNA) axis to regulate Dpp-mediated development. Spatially, AAEL025449 acts as a microRNA-281 (miR-281) sponge, relieving Dpp transcriptional repression in wing buds. Temporally, it tunes Dpp dynamics during critical apoptosis windows, enabling Dpp to modulate apoptotic timing via the canonical c-Jun N-terminal kinase (JNK) pathway. Disruption of this axis results in shorter wings, indirectly compromising flight capacity and reducing mating success, thereby linking molecular perturbations to fitness-related traits. Additionally, it further clarifies the key temporal-spatial nodes where Dpp regulates wing bud cell apoptosis via JNK, with the spatial node differing from conventional Dpp regulation of wing bud development and manifesting as a gradient diffusion from anterior to posterior wing bud margin during the critical apoptosis period in Ae. aegypti. Our study uncovers a novel spatiotemporal regulatory mechanism for wing bud plasticity, advancing insights into insect wing bud adaptive evolution. This ceRNA axis provides a foundation for selecting targets to suppress mosquito populations and mitigate disease transmission.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148351168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRMT5-Cacna1d axis maintains calcium homeostasis to regulate postnatal motor development in mice.","authors":"Jianbo Cao, Zixuan He, Weitai Chai, Meng Tian, Tianyan Wei, Xiu Liu, Yue Wang, Shuang Liu, Ruitong Liu, Yue Yin, Yajun Wang, Tong Liu, Zheng Liang, Songyan Liu, Shilai Bao, Huali Yu, Xiaoxiao He, Xiaojuan Zhu","doi":"10.1007/s00018-026-06306-x","DOIUrl":"10.1007/s00018-026-06306-x","url":null,"abstract":"<p><p>Epigenetic regulation of neuronal calcium signaling during postnatal cortical development is critical for voluntary movement. Protein arginine methyltransferase 5 (PRMT5) acts as an epigenetic regulator that is involved in movement disorders, yet its underlying mechanism remains poorly understood. Here, we report that conditional knockout of Prmt5 in excitatory neurons (cKO^Nex) during motor cortex development leads to severe hyperactivity and shortened lifespan in mice. Transcriptomics analysis reveals that PRMT5 deficiency upregulated Cacna1d expression without affecting its alternative splicing. We demonstrate that PRMT5 directly binds to the Cacna1d promoter, and represses its expression via catalyzing H4R3me2s histone methylation. Electrophysiological studies showed deletion of Prmt5 increased calcium influx and neuronal excitability, resulting from elevated L-type voltage-gated calcium channel (Cav1.3) activity. The enhanced calcium level further leads to oxidative phosphorylation defects in neurons. Importantly, administration of the L-type channel blocker, nimodipine, rescues hyperactivity and neuronal hyper-excitability in vivo, as well as markedly extends the lifespan of cKO^Nex mice. Our findings establish a novel epigenetic mechanism wherein PRMT5-Cacna1d axis regulates neuronal excitability and motor development. These data provide new insights into the calcium channelopathy of movement disorders.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TROP2 promotes bone metastasis of colorectal cancer through interaction with the fibronectin-integrin axis.","authors":"Le-Xin Xiao, Yan-Lin Huang, Chun-Hong Liao, Hua-Ping Xie, Hao Hu, Dong-Mei Chen, Jia-Liang Wang, Lin Gu, Yu-Rong Gu, Jian Xiao, Yi-Fan Lian, Shan-Shan Li","doi":"10.1007/s00018-026-06315-w","DOIUrl":"10.1007/s00018-026-06315-w","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) is the third most common cancer in the world. Bone metastasis, which occurs in advanced cancer, causes severe damage and accelerates patient death. TROP2, encoded by the TACSTD2 gene, is highly expressed in multiple types of cancer and is associated with tumor proliferation, invasion and metastasis. However, the role of TROP2 in CRC is unclear.</p><p><strong>Methods: </strong>TROP2 expression was detected in tumor tissues of CRC patients with or without bone metastases, as well as CRC cell lines. The functional role of TROP2 on CRC cells was validated by in vitro cell culture models and in vivo mouse experiments. Comparative proteomics was used to discover the interactome of TROP2, and later confirmed by immunoprecipitation and immunofluorescent studies. The therapeutic role of TROP2-targeted agent in CRC was verified by intratibial injection mouse models.</p><p><strong>Results: </strong>TROP2 was highly expressed in the tumor tissues of CRC patients, with largely negative expression in the normal counterparts. CRC patients with bone metastasis had even higher TROP2 expression in the tumors than those with primary carcinoma only. We demonstrated that TROP2 promoted the proliferation and migration of CRC cells by in vitro and in vivo experiments, and the pro-invasive and pro-adhesive effects of TROP2 in CRC cells could be enhanced by co-culturing with bone marrow mesenchymal stem cells (BMSCs). Mechanistically, we validated that TROP2 was able to interact with fibronectin (FN) expressed by BMSCs, which increased the expressions of α5, αV, and β3 integrin subunits and facilitated the expression of integrin-linked kinase (ILK) on CRC cells. This interaction was required for the downstream activation of PI3K-Akt signaling and the CRC cell adhesion to BMSCs. Furthermore, intratibial injection mouse experiments verified that TROP2 promoted the colonization of CRC cells in bone marrow, and the combination of the TROP2-targeted antibody-drug conjugate, Sacituzumab Govitecan, and anti-integrin α5β1 monoclonal antibody, Volociximab, was effective in inhibiting bone colonization of CRC cells.</p><p><strong>Conclusion: </strong>TROP2 promotes CRC bone metastasis by interacting with bone marrow-derived FN-integrin axis. Through its adhesive function, TROP2 may coordinate with the specialized bone niche to facilitate metastatic colonization and establish a permissive environment for stromal-tumor interactions. Targeting this axis offers a promising therapeutic strategy for managing bone metastasis in CRC and potentially other TROP2-overexpressing malignancies.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances and clinical potential of epigenome editing.","authors":"Insung Choi, Sueon Kim, Inwha Baek","doi":"10.1007/s00018-026-06311-0","DOIUrl":"10.1007/s00018-026-06311-0","url":null,"abstract":"<p><p>Epigenome editing has emerged as a powerful platform to modulate gene expression in a precise and reversible manner. Recent advances have significantly improved the efficiency, specificity, and durability of epigenome editing systems, enabling fine-tuned transcriptional control. Building on these developments, epigenome editing platforms are now being explored for therapeutic applications. In this review, we summarize the evolution of clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing technologies, highlighting key improvements in effector modules. We then discuss the disease models in which epigenome editing has been applied, including monogenic disorders, cancer, neurological diseases, and chronic diseases. These examples demonstrate the broad therapeutic promise of targeted epigenetic modulation across diverse pathological contexts. Finally, we tackle key barriers to clinical translation, including cell-type and chromatin context-specific design, in vivo delivery, and multi-gene targeting for complex disease. Collectively, this review underscores the potential of epigenome editing as a versatile platform for precision medicine.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PARK2 Inhibits the progression of colorectal cancer via ubiquitinating MARCKSL1 to inhibit the c-Myc pathway.","authors":"Jian Lin, Xiaobin Cheng","doi":"10.1007/s00018-026-06312-z","DOIUrl":"10.1007/s00018-026-06312-z","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148326993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: SIRT3 activation protects from nabumetone-induced mitochondrial toxicity in adult human cardiomyocytes.","authors":"Yafei Huang, Hong Liu, Chao Tong, Zhimin Wang, Miaomiao Xu, Mengqi Dong, Rongjia Rao, Xianqiang Wang, Wei Feng, Zhan Hu, Fei Xu, Wei Zhao, Li Wang, Shengshou Hu, Bingying Zhou","doi":"10.1007/s00018-026-06288-w","DOIUrl":"10.1007/s00018-026-06288-w","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"83 1","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13309579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337943","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}