Cell Death Discovery最新文献

{"title":"Antler stem cells effectively alleviate the symptoms of cerebral ischemic injury via immunomodulation of the spleen.","authors":"Si Wu, Yu Gao, Shunshun Zhong, Qianqian Guo, Yan Zhang, Huiying Li, Jiping Li, Huiling Luo, Hongyu Zhang, Qing Leng, Yufang Shi, Zhonghui Liu, Chunyi Li, Guangxian Nan","doi":"10.1038/s41420-026-03218-4","DOIUrl":"10.1038/s41420-026-03218-4","url":null,"abstract":"<p><p>Ischemic stroke is a major cause of disability and mortality worldwide. Increasing evidence indicates that peripheral immune responses contribute to secondary brain injury after stroke. The impact of the splenic response on brain injury has been well documented in animal models. This phenomenon remains poorly defined in the clinical situation. Through a retrospective analysis of 76 patients with acute anterior circulation large-vessel occlusion, we provide novel evidence that post-stroke spleen volume reduction is an outstanding risk factor for cerebral edema expansion, an association partially explained by a concomitant decrease in peripheral lymphocytes. Previous studies have shown that bone marrow-derived mesenchymal stem cells (BMSCs) improve stroke outcomes through immunomodulation peripherally. Nonetheless, efforts to identify more potent MSCs have never ceased. Antler stem cells, known for their potent regenerative and anti-inflammatory properties, represent promising candidates for stroke treatment. Using the transient middle cerebral artery occlusion (tMCAO) model rats, we found that intravenous administration of antler reserve mesenchymal cells (aRMCs, one type of antler stem cells) significantly improved motor function and reduced both cerebral edema and infarct volume, effects that were superior to those observed with BMSC treatment. Notably, these beneficial effects of aRMCs were attenuated in the splenectomized animals. Compared with the model and BMSC groups, the spleens of aRMC-treated rats exhibited increased weight, restored T cell populations, reduced lymphocyte activity, and downregulated expression of T cell migration-related genes. Additionally, these rats displayed decreased T cell infiltration into the cerebral infarct region. Mechanistically, the inhibitory effect of aRMCs on tMCAO-induced splenic T-cell migration is highly likely to be achieved via downregulation of CCR5 expression. These findings demonstrate a causal link between the degree of splenic contraction and the severity of brain edema, suggest spleen-to-brain T-cell migration as a therapeutic target, and position aRMCs as a promising and novel stem cell type for post-stroke neuroprotection with superior efficacy over BMSCs.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13554090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315870","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":"Inhibition of HSPA8 alleviates experimental autoimmune encephalomyelitis via dual modulation of NLRP3 inflammasome activation: suppressing both NF-κB-mediated priming and ASC-dependent assembly.","authors":"Qianqian Bai, Yan Guo, Shunji Pan, Fangfei Liu, Wenchao Tang, Xiaozhi Bai, Shumin Zhang, Xiaoyu Ma, Qizhi Fu, Dongmei Wang, Hua Fan","doi":"10.1038/s41420-026-03215-7","DOIUrl":"10.1038/s41420-026-03215-7","url":null,"abstract":"<p><p>The pathological processes of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are closely associated with excessive activation of inflammasomes. HSPA8 is a constitutively expressed molecular chaperone involved in cellular signaling and immune-inflammatory regulation, but its role in EAE-associated neuroinflammation remains unclear. In this study, we found that HSPA8 was significantly upregulated in the spinal cord tissues of EAE mice and positively correlated with disease severity. Immunofluorescence co-staining showed that HSPA8 upregulation was more prominently associated with Iba1-positive microglia/macrophage-enriched regions than with GFAP- or NeuN-positive regions. Intrathecal knockdown of HSPA8 attenuated EAE progression, reduced inflammatory responses, and alleviated demyelination and axonal injury. In vitro, HSPA8 knockdown reduced NLRP3 inflammasome-mediated IL-1β/IL-18 release, caspase-1 activation, GSDMD-N formation, and pyroptosis in THP-1 cells, bone marrow-derived macrophages, and BV2 microglia, and these effects were partially restored by siRNA-resistant HSPA8 rescue. Mechanistically, HSPA8 knockdown was associated with impaired NF-κB-dependent priming, as reflected by reduced p65 phosphorylation, nuclear translocation, NF-κB transcriptional activity, and pro-IL-1β expression. HSPA8 is also associated with ASC, and HSPA8 knockdown impaired NLRP3-ASC interaction, ASC oligomerization, and ASC speck formation during inflammasome assembly. These findings suggest that HSPA8 is functionally associated with NLRP3 inflammasome activation through both NF-κB‑dependent priming and ASC‑associated assembly, thereby contributing to neuroinflammation in EAE. HSPA8 may represent a potential therapeutic target for MS-related and other inflammasome-driven neuroinflammatory disorders.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307464","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":"The \"Hit-and-Run\" legacy: epigenetic locking and the survival switch in H. pylori-associated gastric cancer.","authors":"Junjie Sun, Pengtao Hu, Benno Traub, Marko Kornmann, Uwe Knippschild, Jian Lu, Chengyu Lv, Georgios Giamas","doi":"10.1038/s41420-026-03210-y","DOIUrl":"10.1038/s41420-026-03210-y","url":null,"abstract":"<p><p>The mortality associated with gastric cancer (GC) is mostly attributed to metastasis that is resistant to therapy, presenting a therapeutic challenge that frequently continues even after effective eradication of Helicobacter pylori (H. pylori). This paper addresses the \"eradication paradox\" by introducing a novel conceptual framework, the \"Survival Switch\" hypothesis: H. pylori infection not only induces a temporary epithelial-mesenchymal transition (EMT) but also stabilizes gastric epithelial cells in a persistent, drug-resistant \"Hybrid Epithelial/Mesenchymal (Hybrid E/M) state.\" We systematically outline this evolutionary trajectory through three distinct phases: (1) The Igniter: The virulence factor Cytotoxin-associated gene A (CagA) compromises junctional integrity and commandeers YAP/ZEB1 signaling to initiate plasticity; (2) The Lock: A \"Hit-and-Run\" mechanism establishes \"epigenetic scarring,\" specifically methyltransferase-like 3 (METTL3)-mediated N⁶-methyladenosine (m⁶A) modifications, that perpetuates the mesenchymal phenotype independently of the bacterial stimulus; and (3) The Niche: An inflammatory ecosystem comprising CAFs and TAMs functions as an extrinsic amplifier, creating a \"fail-safe\" network that reinforces the hybrid state through paracrine feedback loops. We propose a theoretical paradigm shift in clinical practice from broad-spectrum cytotoxicity to a \"Wake-up and Kill\" sequential strategy, employing EMT-reversing drugs to activate the survival switch and re-sensitize tumors before chemotherapy. This review presents a precise strategy for overcoming the epigenetic and stromal barriers of refractory GC by incorporating upcoming technologies like liquid biopsy for dynamic stratification and nanocarrier-based RNA delivery.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307446","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":"Secretory LGALS3BP exacerbates sepsis-associated liver dysfunction by activating inflammasome-mediated pyroptosis.","authors":"Jun-Eul Hwang, Hyun-Jeong Shim, Mi-Ra Park, Young-Kook Kim, Woo-Kyun Bae, Sang-Hee Cho, Ik-Joo Chung, Eun-Gene Sun","doi":"10.1038/s41420-026-03198-5","DOIUrl":"10.1038/s41420-026-03198-5","url":null,"abstract":"<p><p>Sepsis is a life-threatening syndrome characterized by a dysregulated host response to infection, leading to multiorgan dysfunction. Inflammasome activation and pyroptosis are key mechanisms driving sepsis-associated organ dysfunction. However, it remains unclear whether circulating biomarkers actively contribute to disease progression. Although galectin-3-binding protein (LGALS3BP) has been proposed as a diagnostic and prognostic marker of sepsis, its functional role in sepsis-associated organ dysfunction remains undefined. In this study, the dynamics and function of LGALS3BP in sepsis were investigated using cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-induced mouse models. Plasma LGALS3BP levels were markedly elevated during sepsis and were accompanied by increased LGALS3BP expression in multiple organs, particularly in the liver. Hepatocyte-specific LGALS3BP overexpression exacerbated sepsis-associated liver injury, as evidenced by elevated serum alanine aminotransferase and aspartate aminotransferase levels, increased hepatocyte death, and reduced survival. Transcriptomic profiling of septic livers revealed that LGALS3BP overexpression markedly enriched cytokine signaling, inflammatory response gene sets, and the pyroptosis pathway, indicating dysregulated immune responses and an injury-driven transcriptional program during sepsis. RNA sequencing and in vitro experiments using primary hepatocytes treated with recombinant LGALS3BP, which mimics secreted LGALS3BP, demonstrated that recombinant LGALS3BP increased pyroptosis-associated gene signatures but was not sufficient to induce pyroptotic cell death. Instead, recombinant LGALS3BP promoted pyroptotic cell death only in the presence of septic stimuli. Mechanistically, under septic conditions, secretory LGALS3BP activated the TLR2-IRF3-NF-κB signaling axis, leading to NLRP3 inflammasome activation, cleavage of caspase-1 and gasdermin D, and increased IL-1β and IL-18 release, thereby promoting pyroptotic cell death. Importantly, antibody-mediated neutralization of secretory LGALS3BP suppressed TLR2-IRF3-NF-κB signaling and concomitantly attenuated inflammasome activation and pyroptosis in hepatocytes. Collectively, these findings identify LGALS3BP as a key pathogenic driver of sepsis-associated liver dysfunction through pyroptosis-mediated hepatocyte injury. Therapeutic targeting of LGALS3BP may therefore represent a promising strategy to mitigate sepsis-related liver failure beyond its proposed role as a circulating biomarker.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13542268/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307505","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":"AMPK/ SIRT1 signaling pathway activation acts on PGC-1α/ PPARγ to alleviate sepsis-acquired weakness.","authors":"Lu Li, Lingyan Shi, Meirong Liu, Qi Fang","doi":"10.1038/s41420-026-03212-w","DOIUrl":"10.1038/s41420-026-03212-w","url":null,"abstract":"<p><p>Intensive care unit-acquired weakness (ICU-AW) represents a critical complication that severely impairs the prognostic outcomes of patients with sepsis. This study aimed to elucidate whether the activation of the adenosine 5'-monophosphate-activated protein kinase (AMPK)/silent information regulator 1 (SIRT1) signaling pathway ameliorates sepsis-acquired weakness (SAW) via modulating the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)/peroxisome proliferator-activated receptor γ (PPARγ) axis. A PGC-1α knockout mouse model was established using the cecal ligation and puncture (CLP) method to induce sepsis and subsequent SAW. Multiple histological analyses were performed to evaluate tissue pathological lesions, mitochondrial morphological and structural abnormalities, myelin injury, and skeletal muscle alterations. ELISA was utilized to quantify the expression levels of pro-inflammatory factors and neurotransmitters. Western blotting and RT-qPCR were further employed to detect the expression of mitochondrial functional proteins and downstream molecules associated with the AMPK/SIRT1 signaling pathway. Successful construction of the PGC-1α knockout CLP mouse model was confirmed via systematic verification. Functional experiments validated that AMPK/SIRT1 pathway activation exerts protective effects against SAW in CLP mice through targeting the PGC-1α/PPARγ signaling cascade. Mechanistically, AMPK/SIRT1 activation further modulates the PGC-1α/PPARγ pathway, thereby alleviating the progression of SAW. Collectively, targeted regulation of PGC-1α may serve as a promising and actionable therapeutic strategy for the clinical prevention and treatment of ICU-AW in septic patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13542166/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307328","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":"Adipocyte caspase-8 but not RIPK3 promotes adiposity.","authors":"Carmen K Chan, Rukhsana Aslam, Fan Yang, Arshdeep Panesar, Anne Hakem, Razqallah Hakem, Herbert Y Gaisano, Daniel A Winer, Cynthia T Luk","doi":"10.1038/s41420-026-03201-z","DOIUrl":"10.1038/s41420-026-03201-z","url":null,"abstract":"<p><p>Adipocyte death is a key event in the development of white adipose tissue (WAT) inflammation, a major driver of obesity-associated metabolic dysfunction. Receptor-interacting protein kinase 3 (RIPK3) mediates necroptosis, a recently discovered mode of regulated necrosis. Necroptosis has been implicated in several inflammatory pathologies; however, the role of adipocyte necroptosis in obesity remains unclear. In the present study, we sought to investigate the role of adipocyte RIPK3 in obesity and glucose homeostasis. We demonstrated that necroptotic signalling was upregulated in WAT of mice with diet-induced obesity and was associated with body-mass index in human WAT. We also demonstrated that caspase-8, a central regulator of apoptosis, suppresses adipocyte necroptosis both in vitro and in vivo. Adipocyte-specific deletion of caspase-8 in mice reduced adiposity compared to control mice. This difference was not observed with concomitant global deletion of RIPK3. Furthermore, adipocyte-specific deletion of the RIPK3 receptor-interacting protein homotypic interaction motif (RHIM), which is required for necroptotic induction, did not influence weight gain, adiposity, or glucose homeostasis in mice with diet-induced obesity. Caspase-8 knockdown by siRNA or pharmacological inhibition in 3T3-L1 adipocytes suppressed adipogenesis, which may be independent of adipocyte Ripk3. Collectively, our findings suggest that adipocyte RIPK3 RHIM does not play a critical role in obesity and glucose homeostasis. Alternatively, we provide further evidence that caspase-8 plays an essential role in adipocyte differentiation, offering insight into the molecular mechanisms underlying obesity and metabolic dysfunction.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13547226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148307350","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":"Newly identified invasion drivers define the tumor front in oral squamous cell carcinoma.","authors":"Guillermo Flores, Slyn Uaroon, Juan A R Garay, Marion Vanneste, Jesse D Riordan, Adam J Dupuy, Kristina W Thiel, Kaitriana E Colling, Christopher S Stipp, Li-Chun Lin, Bailey Hollis, Mariah R Leidinger, Stephanie J T Chen, Lillian M Graham, Kevin L Knudtson, Michael S Chimenti, Jason A Ratcliff, Zain Mehdi, Madison C McElliott, Eric R Anderson, Michael D Henry, Molly E Heft Neal, J Chad Brenner, Marisa R Buchakjian","doi":"10.1038/s41420-026-03202-y","DOIUrl":"10.1038/s41420-026-03202-y","url":null,"abstract":"<p><p>Cells at the invasive front of oral squamous cell carcinoma (OSCC) occupy a partial epithelial-to-mesenchymal transition (p-EMT) state that drives invasion and therapeutic resistance yet remains poorly understood. To define the regulators of this metastable state, we developed an isogenic OSCC model that captures stable epithelial and p-EMT phenotypes and used it to perform a genome-wide CRISPR invasion screen. This unbiased strategy identified 17 modulators of invasion, most previously unrecognized in cancer and virtually unexplored in OSCC, that converge on cytoskeletal remodeling, adhesion, and epigenetic regulation. Within this network, EDIL3 emerged as a central driver of EMT, invasion, and chemoresistance in head and neck cancer, extending prior reports in other tumor types. Importantly, the invasion signature derived from our screen localized with striking specificity to the tumor invasive front of human OSCC, providing direct clinical validation. Together, these findings reveal a novel, targetable network of transient invasion drivers defining the OSCC tumor front.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293411","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":"PER2 reprograms intracellular cholesterol synthesis to inhibit oral squamous cell carcinoma and the chronotherapeutic efficacy of simvastatin.","authors":"Shilin Yin, Fang Yang, Zhiwei Zhang, Mingyuan Liu, Hong Tang, Kai Yang","doi":"10.1038/s41420-026-03209-5","DOIUrl":"10.1038/s41420-026-03209-5","url":null,"abstract":"<p><p>Dysregulation of cholesterol homeostasis is closely associated with the development of various cancers, but the underlying mechanisms remain unclear. This study found that the circadian clock gene Period 2 (PER2) is downregulated in oral squamous cell carcinoma (OSCC), promoting intracellular cholesterol synthesis and cell proliferation. Conversely, PER2 overexpression inhibits cell proliferation by suppressing intracellular cholesterol synthesis. Mechanistically, PER2 binds to Myosin Heavy Chain 9 (MYH9) and recruits Tripartite Motif Containing-21 (TRIM21) to promote ubiquitin-dependent degradation of MYH9, thereby inhibiting the cholesterol synthesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), reducing intracellular cholesterol synthesis, and suppressing OSCC proliferation. In OSCC xenograft models, overexpression of PER2 or treatment with the HMGCR inhibitor simvastatin significantly inhibited OSCC growth, with the combination showing markedly enhanced anti-OSCC efficacy compared to either approach alone. To explore the circadian regulatory role of PER2, overexpression or silencing experiments in OSCC demonstrated that PER2 modulates the circadian rhythms of HMGCR expression, intracellular cholesterol, and cell proliferation. Further investigations in subcutaneous OSCC mouse models revealed sex-specific circadian rhythms in PER2 and HMGCR expression, intracellular cholesterol, cell proliferation, and tumor growth in OSCC cells. Specifically, the acrophases of these indicators in OSCC of male mice were delayed relative to females, and the mesors of HMGCR expression, intracellular cholesterol, and cell proliferation were significantly higher than in females. The anticancer efficacy of simvastatin against OSCC in mice varied up to 2.5-fold across six different time points within 24 h, with broader time windows for optimal therapeutic efficacy and adverse effects in female mice than in males. This study identified a novel mechanism by which PER2 reprograms intracellular cholesterol, demonstrating that PER2 upregulation combined with simvastatin represents a potential novel strategy to improve the prognosis of OSCC patients, and clarifies that the anti-OSCC effect of simvastatin exhibits time-dependent and sex differences.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13529778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293561","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":"RNA binding motif protein RBM41 promotes colorectal tumorigenesis by impeding the maturation of NDRG1 pre-mRNA.","authors":"Yanxin Liu, Jianfeng Mu, Jiming Yu, Qirong Li, Tiantian Li, Qiang Feng, Tong Sun, Ke Sun, Yang Hao, Jinhai Yu, Dongxu Wang","doi":"10.1038/s41420-026-03197-6","DOIUrl":"10.1038/s41420-026-03197-6","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is a prevalent and highly lethal malignancy. RNA-binding motif (RBM) proteins have been demonstrated in CRC pathogenesis. However, the biological function and regulatory mechanisms of RBM41 in CRC remain poorly understood. Here, we demonstrate that RBM41 is significantly elevated in CRC tissues and is associated with poor prognosis in patients. Overexpression of RBM41 can enhance the malignant proliferation phenotype of CRC cells; in contrast, inhibition of RBM41 significantly decreases CRC cell proliferation and induces autophagic cell death and apoptosis in HT29 and SW480 cells. Mechanistically, RBM41 interferes with the processing of N-myc downregulated gene 1 (NDRG1) pre-mRNA by directly binding to its 3' untranslated region (3' UTR), thereby decreasing the mature transcript and protein levels of tumor suppressor NDRG1. Concurrent knockdown of NDRG1 reversed the oncogenic functions of RBM41 in HT29 cells and in fast-growing xenograft tumors in vivo. Moreover, patient-derived organoid (PDO) models with high RBM41 expression exhibited increased resistance to 5-fluorouracil, oxaliplatin, and irinotecan. In summary, our findings demonstrate that RBM41 promotes CRC progression by post-transcriptionally repressing NDRG1, underscoring its potential as a promising therapeutic target for CRC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13283208/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293512","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":"Thioredoxin system dysregulation and calpain activation drive myocardial disulfidptosis via pathological disulfide bonds remodeling.","authors":"Aling Tang, Bingqing Chen, Weizhen Zhang, Zhimin Gong, Mingming Jin, Xiaoling Xu, Yi Shi, Wei Chen","doi":"10.1038/s41420-026-03200-0","DOIUrl":"10.1038/s41420-026-03200-0","url":null,"abstract":"<p><p>Myocardial infarction (MI) remains a leading cause of death and disability worldwide, yet the molecular mechanisms underlying cardiomyocyte death during ischemic injury are not fully understood. Here, we identify disulfidptosis-a recently described form of regulated cell death-as a novel contributor to myocardial ischemic injury. In ischemia-mimetic models, glucose and oxygen deprivation lead to NADPH depletion and excessive disulfide bond accumulation in cardiomyocytes, accompanied by F-actin cytoskeletal collapse, a defining feature of disulfidptosis. Mechanistically, impairment of the NADPH/thioredoxin (Trx) system amplifies disulfide stress, while calcium overload-induced activation of calpains disrupts cytoskeletal protein conformation, removing steric constraints that normally prevent aberrant disulfide bonding. The synergistic effect of these two processes creates favorable oxidative and spatial structural conditions for the occurrence of disulfidptosis. Inhibition of Trx activity promotes disulfide death; pharmacological inhibition of calpainthe or blockade of calcium overload significantly reduces disulfide accumulation and preserves cytoskeletal integrity, confirming their crucial role in ischemia-induced disulfidptosis. Based on the above findings, this study confirms that disulfidptosis represents a previously unrecognized mechanism of cardiomyocyte death in myocardial ischemia, revealing the mechanistic link between metabolic stress, redox imbalance, and cytoskeletal collapse; and proposing a novel pathological remodeling process of disulfide bonds characterized by \"Cleavage-Fragmentation-Mismatch\". These insights provide new conceptual and therapeutic perspectives for cardioprotection.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13521956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283380","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}