Cell Reports MedicinePub Date : 2026-03-17Epub Date: 2026-02-26DOI: 10.1016/j.xcrm.2026.102638
Casey R Ager, Aleksandar Obradovic, Patrick McCann, Matthew Chaimowitz, Alexander L E Wang, Neha Shaikh, Parin Shah, Samuel S Pan, Caroline J Laplaca, Renu K Virk, Jessica C Hill, Collin Jugler, Grace DeFranco, Nilika Bhattacharya, Kade R Copple, Phuong Nguyen, Howard I Scher, Guarionex Joel DeCastro, Christopher B Anderson, James M McKiernan, Catherine S Spina, Mark N Stein, Karie Runcie, Charles G Drake, Andrea Califano, Matthew C Dallos
{"title":"Neoadjuvant Fc-enhanced anti-CTLA-4 targets Tregs to augment androgen deprivation in high-risk prostate cancer: A randomized phase I trial.","authors":"Casey R Ager, Aleksandar Obradovic, Patrick McCann, Matthew Chaimowitz, Alexander L E Wang, Neha Shaikh, Parin Shah, Samuel S Pan, Caroline J Laplaca, Renu K Virk, Jessica C Hill, Collin Jugler, Grace DeFranco, Nilika Bhattacharya, Kade R Copple, Phuong Nguyen, Howard I Scher, Guarionex Joel DeCastro, Christopher B Anderson, James M McKiernan, Catherine S Spina, Mark N Stein, Karie Runcie, Charles G Drake, Andrea Califano, Matthew C Dallos","doi":"10.1016/j.xcrm.2026.102638","DOIUrl":"10.1016/j.xcrm.2026.102638","url":null,"abstract":"<p><p>Despite high rates of post-surgical recurrence in men with high-risk localized prostate cancer (PCa), there is currently no role for neoadjuvant therapy. Tumor infiltrating regulatory T cells (TI-Tregs) limit the antitumor effects of presurgical androgen deprivation therapy (ADT). We present a neoadjuvant clinical trial testing whether an afucosylated anti-CTLA-4 antibody (BMS-986218) with ADT is safe, feasible, and reduces TI-Treg frequencies. This single-center, two-arm, open-label study randomizes 24 men with high-risk localized PCa to ADT with or without BMS-986218 prior to radical prostatectomy. Treatment is well tolerated and feasible. Mechanistic studies reveal reductions in TI-Treg frequencies correlate with CD16a/FCGR3A on tumor macrophages, dendritic cell (DC) modulation, and augmented T cell priming following BMS-986218 treatment. Depth of Treg inhibition and increased DC frequencies are associated with improved clinical outcomes. Overall, this study supports the feasibility and biological activity of neoadjuvant ADT + Fc-enhanced anti-CTLA-4 in high-risk PCa. Trial is registered at clinicaltrials.gov (NCT04301414).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102638"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-03-17Epub Date: 2026-02-27DOI: 10.1016/j.xcrm.2026.102632
Aleksandra Georgievski, Noémie Blanc, Mélanie Bruchard, Cassandre Pignol, Pierre-Simon Bellaye, Carmen Garrido, Ronan Quéré
{"title":"Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy.","authors":"Aleksandra Georgievski, Noémie Blanc, Mélanie Bruchard, Cassandre Pignol, Pierre-Simon Bellaye, Carmen Garrido, Ronan Quéré","doi":"10.1016/j.xcrm.2026.102632","DOIUrl":"10.1016/j.xcrm.2026.102632","url":null,"abstract":"<p><p>We develop valrubicin-loaded immunoliposomes (Val-ILs), a nanoparticle-based therapy designed to target immunosuppressive cells that promote immune evasion in cancer. In vivo screening following intravenous administration in mice identifies nine relevant surface targets, including known immunoregulatory markers (LAG-3 and VEGFR2) and not-well-characterized candidates (CD11b, CD64, TIM1, CD200R3, CD204, CD49b, and SIGLEC-F). Within the tumor microenvironment, Val-ILs treatment broadly reduces the expression of these antigens on immunosuppressive populations, including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and T helper 17 cells, as well as on innate anti-tumor cells such as tumor-associated natural killer cells and tumor-infiltrating dendritic cells. Across four murine cancer models, two responsive (T and B lymphomas) and two resistant (orthotopic breast and lung cancers), Val-ILs decorated with antibodies against the nine targets significantly enhance anti-PD-1 efficacy. This combination boosts the presence of CD4<sup>+</sup> and CD8<sup>+</sup> tumor-infiltrating lymphocytes, reprograms tumor-associated macrophages toward an M1-like phenotype, and improves tumor control and metastasis reduction.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102632"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006431/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-03-17Epub Date: 2026-03-10DOI: 10.1016/j.xcrm.2026.102663
Catherine Kirkpatrick, Charles M Quick, Steven R Post, Yuet-Kin Leung, Ruud P M Dings, Chrystal M Paulos, Lyle Burdine, Yong-Chen William Lu
{"title":"Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure.","authors":"Catherine Kirkpatrick, Charles M Quick, Steven R Post, Yuet-Kin Leung, Ruud P M Dings, Chrystal M Paulos, Lyle Burdine, Yong-Chen William Lu","doi":"10.1016/j.xcrm.2026.102663","DOIUrl":"10.1016/j.xcrm.2026.102663","url":null,"abstract":"<p><p>T cells are pivotal to cancer immunotherapy, yet chemotherapy may erode their fitness. Using a single-cell technique, we show that exposure to two widely used chemotherapeutic agents, 5-FU (5-fluorouracil) and cisplatin, induces non-synonymous mitochondrial DNA (mtDNA) mutations in T cells. Notably, nearly all detected mtDNA mutations are transition mutations. Like the effects observed in genomic DNA mutations, the impacts of mtDNA mutations in T cells appear to be random. Some T cells with mtDNA mutations concentrate in clusters associated with gene markers, while others do not. Additionally, several mtDNA mutations are found in the fraction of treated T cells with low mitochondrial activity, suggesting their potential effect on mitochondrial function. Importantly, mtDNA mutations are detected in tumor-infiltrating T cells from patients with colorectal cancer who received chemotherapy. Our findings uncover an unappreciated consequence of chemotherapy on T cell mitochondria, and these results raise concerns about administering immunotherapy and chemotherapy concurrently.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102663"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147431194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bi Ning Zhang, Benxiang Qi, Shijiu Chen, Jing Su, Guoyun Li, Xinping Wang, Zhongmei Ren, Hengrui Zhang, Jun Cheng, Jingyu Qu, Yang Yang, Qingjun Zhou, Lin Cong, Lixin Xie
{"title":"Targeted AAV6 gene therapy restores corneal endothelial function in three hereditary corneal dystrophies.","authors":"Bi Ning Zhang, Benxiang Qi, Shijiu Chen, Jing Su, Guoyun Li, Xinping Wang, Zhongmei Ren, Hengrui Zhang, Jun Cheng, Jingyu Qu, Yang Yang, Qingjun Zhou, Lin Cong, Lixin Xie","doi":"10.1016/j.xcrm.2026.102649","DOIUrl":"10.1016/j.xcrm.2026.102649","url":null,"abstract":"<p><p>The corneal endothelium maintains corneal transparency and vision. Hereditary corneal dystrophies, including macular corneal dystrophy (MCD), Fuchs endothelial corneal dystrophy (FECD), and congenital hereditary endothelial dystrophy (CHED), cause progressive endothelial dysfunction, for which corneal transplantation is currently the main treatment. We evaluate an adeno-associated virus (AAV)-based gene therapy approach in preclinical models of MCD, FECD, and CHED. A refined intracameral injection method enables uniform endothelial transduction without corneal puncture. A single AAV6 administration supports sustained transgene expression in the corneal endothelium for over 18 months without detectable adverse immune responses. In MCD mice, AAV6-Chst5 reduces corneal opacification and restores keratan sulfate levels. In FECD mice, AAV6-Col8a2 prevents corneal opacity in 87.5% of treated eyes. In the CHED model, AAV6-Slc4a11 resolves corneal edema within 7 days. Single-cell RNA sequencing identifies Wnt5a as a downstream factor associated with MCD pathogenesis. These findings support the therapeutic potential of endothelial-targeted gene delivery for corneal endothelial disorders.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"7 3","pages":"102649"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ying Xu, Xin-Yi Liu, Hang Zhang, Li Chen, Han Wang, Zhi-Ming Shao, Yi Xiao, Yi-Zhou Jiang
{"title":"Comprehensive single-cell metabolic profiling identifies targets to sensitize triple-negative breast cancer to chemo-immunotherapy.","authors":"Ying Xu, Xin-Yi Liu, Hang Zhang, Li Chen, Han Wang, Zhi-Ming Shao, Yi Xiao, Yi-Zhou Jiang","doi":"10.1016/j.xcrm.2026.102659","DOIUrl":"10.1016/j.xcrm.2026.102659","url":null,"abstract":"<p><p>The treatment of triple-negative breast cancer (TNBC) poses significant challenges, necessitating innovative approaches to identify therapeutic targets. This study presents a cohort of patients with early-stage TNBC receiving neoadjuvant chemotherapy or chemo-immunotherapy, leveraging single-cell RNA sequencing and metabolic analysis to elucidate the impact of metabolic reprogramming on treatment response. Our findings reveal metabolic heterogeneity at levels of metabolic genes, pathways, and fluxes. Cell-type-specific metabolic traits show stronger associations with therapeutic response compared with bulk metabolic features and the proportion of major cell types. We identify a dynamic collaboration between tumor cells and myeloid cells driven by differential glucose utilization and lactate production, which facilitates tumor progression. Monocarboxylate transporter 1 (MCT1) inhibitors disrupt their interaction, enhancing the efficacy of anti-PD-1 and antibody-drug conjugate (ADC) treatments in TNBC mouse models. Overall, our study delineates the single-cell metabolic landscape of TNBC and positions MCT1 as a promising target.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"7 3","pages":"102659"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Liang Chen, Nicklas Brustad, Jonathan Thorsen, Tingting Wang, Mina Ali, Julie N Kyvsgaard, Mario Lovric, Parvaneh Ebrahimi, Yang Luo, Casper-Emil T Pedersen, Nicole Prince, Rachel S Kelly, Ann-Marie M Schoos, Nilo Vahman, Morten A Rasmussen, Susanne Brix, Augusto A Litonjua, Scott T Weiss, Craig E Wheelock, Jessica Lasky-Su, Klaus Bønnelykke, Jakob Stokholm, Bo Chawes
{"title":"Maternal 12-HETE is associated with childhood asthma and the responses to prenatal omega-3 supplementation.","authors":"Liang Chen, Nicklas Brustad, Jonathan Thorsen, Tingting Wang, Mina Ali, Julie N Kyvsgaard, Mario Lovric, Parvaneh Ebrahimi, Yang Luo, Casper-Emil T Pedersen, Nicole Prince, Rachel S Kelly, Ann-Marie M Schoos, Nilo Vahman, Morten A Rasmussen, Susanne Brix, Augusto A Litonjua, Scott T Weiss, Craig E Wheelock, Jessica Lasky-Su, Klaus Bønnelykke, Jakob Stokholm, Bo Chawes","doi":"10.1016/j.xcrm.2026.102689","DOIUrl":"10.1016/j.xcrm.2026.102689","url":null,"abstract":"<p><p>A recent mouse study has shown that deficiency in 12-hydroxyeicosatetraenoic acid (12-HETE) affects neonatal alveolar macrophage imprinting and associates with increased respiratory morbidity, but this has not been investigated in humans. Utilizing data from two mother-child cohorts, COPSAC<sub>2010</sub> and VDAART, we demonstrate that undetectable maternal plasma 12-HETE during pregnancy associates with increased risk of childhood asthma and respiratory infections alongside an altered infant airway microbiota structure and airway immune profile. Further, we observed an interaction between maternal 12-HETE levels and maternal N-3 long-chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation in a randomized clinical trial in COPSAC<sub>2010</sub> and maternal dietary n-3 LCPUFA intake in VDAART in relation to offspring respiratory morbidity; higher prenatal n-3 LCPUFA exposure reduced asthma and respiratory infection among mothers with detectable 12-HETE levels. These findings identify maternal 12-HETE as a potential biomarker for risk of offspring respiratory morbidity and suggest that maternal 12-HETE status may determine responsiveness to prenatal n-3 LCPUFA supplementation.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"7 3","pages":"102689"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006429/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Henning Tim Langer, Natalie K Gilmore, Christopher M T Hayden, Julien Roux, Bruno Bariohay, Thaïs Rouquet, Manar Awada, Julie Marcotorchino, Lorrine Bournot, Elizabeth Nunn, Paul M Titchenell, Daniela Liskiewicz, Timo D Müller, Oluwaseun Anyiam, Philip J Atherton, Iskandar Idris, Andreas Hentschel, Andreas Roos, Natalie Haritonow, Kristina Norman, Ursula Müller-Werdan, Keith Baar
{"title":"Weight loss with GLP-1 medicines does not result in a disproportionate loss of muscle mass or function in obese mice and humans.","authors":"Henning Tim Langer, Natalie K Gilmore, Christopher M T Hayden, Julien Roux, Bruno Bariohay, Thaïs Rouquet, Manar Awada, Julie Marcotorchino, Lorrine Bournot, Elizabeth Nunn, Paul M Titchenell, Daniela Liskiewicz, Timo D Müller, Oluwaseun Anyiam, Philip J Atherton, Iskandar Idris, Andreas Hentschel, Andreas Roos, Natalie Haritonow, Kristina Norman, Ursula Müller-Werdan, Keith Baar","doi":"10.1016/j.xcrm.2026.102665","DOIUrl":"10.1016/j.xcrm.2026.102665","url":null,"abstract":"<p><p>The large decrease in body weight with glucagon-like peptide-1 (GLP-1) medicines raises concern about a loss of lean body mass (LBM) and skeletal muscle. In this work, we present four pre-clinical studies and a proof-of-concept clinical trial that address this issue. We report that in obese mice, GLP-1 medicines predominantly reduce body fat alongside a small but significant decrease in LBM. Among lean tissues, loss of liver mass exceeds change in muscle mass. While absolute muscle mass and strength decrease, relative muscle mass and strength improve, resulting in better running performance. Interestingly, while atrophy is similar during immobilization, GLP-1 medicines have a distinct effect on the muscle proteome compared to calorie restriction. Patients with obesity on GLP-1 medicines improve their body composition without negatively affecting strength. Overall, in middle-aged mice and men, GLP-1 medicines slightly decrease absolute muscle values but positively impact body composition and mobility. The clinical trial is registered on clinicaltrials.gov (NCT05606471).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":"7 3","pages":"102665"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neuronal PPP2R5C in plasma is a potential biomarker for early diagnosis of Alzheimer's disease.","authors":"Shilin Luo, Hui Liu, Tingting Xiao, Yunni Li, Xixi Liu, Xuewen Xiao, Xinxin Liao, Yingzi Liu, Yafang Zhou, Jun-Ling Wang, Jifeng Guo, Tian Tu, Xiaoxin Yan, Beisha Tang, Zhentao Zhang, Bin Jiao, Lu Shen","doi":"10.1016/j.xcrm.2026.102631","DOIUrl":"10.1016/j.xcrm.2026.102631","url":null,"abstract":"<p><p>Early intervention is the most effective strategy to impede the progression of Alzheimer's disease (AD), depending on the identification of early diagnostic biomarkers. Here, we isolate neuron-derived exosomes (NDEs) from plasma of familial AD (FAD), presymptomatic FAD (pre-FAD), and healthy controls (cognitively normal [CN]), followed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. A specific peptide from protein phosphatase 2 regulatory subunit B'β (PPP2R5C) shows a progressive decrease from CN to pre-FAD and FAD patients. This decline is further validated in plasma NDEs and brain tissue from amnestic mild cognitive impairment (aMCI) and sporadic AD (SAD) patients. Two independent cohorts confirm the early and differential diagnostic value of plasma PPP2R5C. Immunohistochemistry of Tau Braak-staged brains reveals PPP2R5C reduction preceding Tau hyperphosphorylation. Mechanistically, PPP2R5C interacts with Tau, reducing Tau levels and phosphorylation via unc-51-like kinase 1 (ULK1)-dependent autophagolysosomal activation and PP2A regulation. Our findings suggest that plasma PPP2R5C has the potential to serve as an ideal biomarker for the early diagnosis of AD.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102631"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146257614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-03-17Epub Date: 2026-02-18DOI: 10.1016/j.xcrm.2026.102630
Yong Wang, Yan Xiong, Shuiqiao Liu, Lei Bao, Xing Qiu, Ilia Korboukh, Xiangyang Song, Vanina Toffessi Tcheuyap, Sipeng Wu, Mingyi Chen, James Brugarolas, Jian Jin, Yingfei Wang, Weibo Luo
{"title":"HIF-activated priming of TRAIL-induced cell death determines epigenetic vulnerability in kidney cancer.","authors":"Yong Wang, Yan Xiong, Shuiqiao Liu, Lei Bao, Xing Qiu, Ilia Korboukh, Xiangyang Song, Vanina Toffessi Tcheuyap, Sipeng Wu, Mingyi Chen, James Brugarolas, Jian Jin, Yingfei Wang, Weibo Luo","doi":"10.1016/j.xcrm.2026.102630","DOIUrl":"10.1016/j.xcrm.2026.102630","url":null,"abstract":"<p><p>Activation of hypoxia-inducible factors (HIFs) supports cancer cell survival, yet how HIFs govern cell death remains unclear, despite evidence that HIF-1 acts as a tumor suppressor in cell renal cell carcinoma (ccRCC). Here, we report a cell death-priming role for HIF-1/2 in ccRCC. Through cell viability screens with chemical libraries, we identify SGI1027 and its analog MS1129 as HIF-1/2-dependent cell death inducers that specifically kill VHL-deficient ccRCC cells in vitro and patient-derived xenografts in mice. Mechanistically, SGI1027 and MS1129 induce proteasomal degradation of DNMT1/DNMT3A/DNMT3B proteins, leading to the loss of promoter methylation and subsequent upregulation of TRAIL, DR4, and DR5 in ccRCC cells. HIF-1/2 induces procaspase-10 expression serving a commitment point to activate TRAIL-induced apoptosis in VHL-deficient ccRCC following SGI1027 or MS1129 treatment. Notably, recombinant TRAIL protein synergizes with SGI1027 or MS1129 to kill VHL-deficient ccRCC in mice. Collectively, our study unveils an apoptosis induction strategy that involves hijacking HIFs for ccRCC treatment.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102630"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146225458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cell Reports MedicinePub Date : 2026-03-17Epub Date: 2026-02-24DOI: 10.1016/j.xcrm.2026.102640
Guangjie Sun, Yize Dong, Ying Wang, Yihong Su, Jiajun Chen, Jiali Deng, Lan Luo, Xinyue Cao, Weiping Lu, Kai Chen, Meihua Yu, Yujie Xie, Bingcang Huang, Yu Chen
{"title":"Hierarchically collapsible nanoactuator modulates mitochondrial ferroptosis-bioenergetic homeostasis cascade to decouple ischemic stroke.","authors":"Guangjie Sun, Yize Dong, Ying Wang, Yihong Su, Jiajun Chen, Jiali Deng, Lan Luo, Xinyue Cao, Weiping Lu, Kai Chen, Meihua Yu, Yujie Xie, Bingcang Huang, Yu Chen","doi":"10.1016/j.xcrm.2026.102640","DOIUrl":"10.1016/j.xcrm.2026.102640","url":null,"abstract":"<p><p>Ischemic stroke, a life-altering cerebrovascular emergency triggered by prolonged cerebral hypoperfusion, remains a therapeutic enigma. Current interventions struggle with ischemia-reperfusion injury; restoring blood flow unleashes reactive oxygen species (ROS), driving secondary neuronal damage and functional loss. Ischemia-induced mitochondrial dysfunction heightens oxidative stress and hastens neuronal death. We address oxidative-stress-driven neuronal injury by engineering a hierarchically collapsible nanoactuator suppressing mitochondrial ferroptosis and restoring cellular energy homeostasis. The nanoactuator integrates a diselenide-crosslinked shell conjugated with a mitochondrial-targeting peptide, enabling blood-brain barrier penetration and mitochondrial delivery. Its collapsible core, composed of an ATP-gadolinium coordination polymer encapsulating a ferroptosis inhibitor, enables MRI-guided tracking and ROS-responsive drug release. In damaged mitochondria, the nanoactuator replenishes ATP, restores membrane potential, reduces ROS levels, and alleviates ferroptosis. Intravenous administration in a transient middle cerebral artery occlusion (tMCAO) mouse model demonstrated robust multi-mechanistic neuroprotection. This hierarchical nanoactuator platform offers a strategy for ischemic stroke and related neurodegenerative diseases.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"102640"},"PeriodicalIF":10.6,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13006402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147303000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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