Cell Death & Disease最新文献

{"title":"Disrupting Treg lineage stability elicits RORgT-mediated plasticity and enhances anti-tumor immunity.","authors":"Courtney A Swain, Dominique C Hinshaw, Ian D Miranda, Brandon J Metge, Amr Elhamamsy, Dongquan Chen, Alyssa Lee, Hua Guo, Bhavyasree Papineni, Li'an Williams, Jeffrey C Rathmell, Selvarangan Ponnazhagan, Robert S Welner, Rajeev S Samant, Lalita A Shevde","doi":"10.1038/s41419-026-09025-0","DOIUrl":"10.1038/s41419-026-09025-0","url":null,"abstract":"<p><p>The imbalance of pro-inflammatory and immunosuppressive constituents in the tumor microenvironment (TME) significantly dictates cancer progression, immune invasion, and treatment response. Immunosuppressive regulatory T cells (Tregs) are associated with decreased disease-free survival due to their ability to suppress anti-tumor immunity. Notably, in response to environmental cues, Tregs display functional and phenotypic plasticity with inflammatory helper T cell subsets. Given their predominant role in sustaining immune suppression, it is remarkable that multiple developmental pathways converge to regulate Treg development and function. In this study, we designed, validated, and employed a novel genetically modified mouse model to conditionally ablate the Hedgehog (Hh) gene, Gli2, specifically in Tregs. Ablation of Gli2 activity in Tregs significantly reduced tumor burden, impaired Treg suppressive function, and shifted the transcriptional balance of Foxo3 and Rorγt, transcription factors essential for Tregs and Th17 cells. Spatial mapping highlighted that Gli2 ablation in Tregs enhances the immunogenicity of the tumor and promotes a pro-inflammatory milieu of the TME. This was underscored by a higher tumor immune signature score and enhanced infiltration of cytotoxic CD8⁺ T cells into the tumor. These findings highlight Hh/Gli2 signaling in Tregs as a mechanistic regulator of immunogenicity in the TME and a potential therapeutic target to prime tumors for enhanced responsiveness for adjuvant treatments.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Soluble HER2 promotes chronic antigen-mediated CD8⁺ T-cell dysfunction and limits immunotherapy response in HER2-low triple-negative breast cancer.","authors":"Lanyu Jing, Zhiping Tan, Ziling Wang, Biao Xu, Yunjian Zhang, Nan Shao, Anze Yu, Ying Lin","doi":"10.1038/s41419-026-09094-1","DOIUrl":"10.1038/s41419-026-09094-1","url":null,"abstract":"<p><p>HER2-low triple-negative breast cancer (TNBC) has emerged as a clinically relevant subgroup with distinct therapeutic implications. However, the biological mechanisms underlying its heterogeneous response to immunotherapy remain poorly defined. In this manuscript, we conducted a retrospective translational analysis of patients with HER2-zero and HER2-low TNBC. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry to characterize CD8⁺ T-cell differentiation and functional states. Circulating levels of soluble HER2 extracellular domain (HER2 ECD) were quantified by ELISA, and serum cytokine profiles were assessed using Luminex assays. In vitro assays using tumor-derived conditioned media and purified recombinant HER2 ECD were performed to evaluate the immunomodulatory effects of HER2 antigen exposure. Clinical responses to neoadjuvant chemotherapy with or without PD-1-based immunotherapy were compared between subgroups. In vivo validation was conducted using a syngeneic mouse model. Although the overall proportions of peripheral T cells were comparable between groups, HER2-low TNBC was associated with a shift in CD8⁺ T-cell differentiation toward effector and effector-memory phenotypes, accompanied by increased expression of exhaustion markers. Patients with HER2-low disease exhibited significantly elevated circulating HER2 ECD levels. In vitro, purified recombinant HER2 ECD was sufficient to induce time-dependent activation and subsequent exhaustion-like phenotypes in CD8⁺ T cells, while HER2 blockade in conditioned media partially attenuated these effects. Clinically, HER2-low tumors showed a significantly reduced pathological complete response rate following PD-1-based immunotherapy. Consistently, HER2-targeted therapy enhanced antitumor efficacy and improved CD8⁺ T-cell function when combined with PD-1 blockade in vivo. In summary, HER2-low TNBC is associated with elevated circulating HER2 antigen and a peripheral CD8⁺ T-cell state characterized by progressive differentiation and exhaustion. These findings support a model in which tumor antigen shedding contributes to systemic immune modulation and may limit responsiveness to immunotherapy. Targeting HER2-associated antigen dynamics may represent a potential strategy to improve immunotherapeutic outcomes in HER2-low TNBC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13616914/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148396196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of KIT signaling promotes early tumorigenesis through the AP-1 pathway in APC/TP53 double-knockout human colon organoids.","authors":"Younghee Choi, Eunju Kim, Soo-Yeon Cho, Jihyun Park, Youngwon Cho, Sungho Kim, Sang-Hyun Song, Tae-You Kim","doi":"10.1038/s41419-026-09056-7","DOIUrl":"10.1038/s41419-026-09056-7","url":null,"abstract":"<p><p>Colorectal cancer (CRC) develops through a series of progressive genetic mutations, with alterations in APC and TP53 being the most frequently observed in the early stages. Although the loss of APC is recognized as a significant initiating event, the epigenetic processes through which the simultaneous inactivation of APC and TP53 facilitates the onset of colorectal tumorigenesis remain poorly characterized. To address this gap, we developed a human colon organoid model using CRISPR-Cas9 to achieve a double knockout of APC and TP53. Through extensive multi-omics profiling, we characterized the epigenetic landscape distinctive of early-stage CRC. We identified KIT, a receptor tyrosine kinase, as a critical oncogenic driver that is significantly upregulated in ΔDKO (APC and TP53 double knockout) organoids, thereby activating the MAPK and Wnt signaling pathways to augment proliferation and tumorigenesis. Furthermore, AP-1 transcription factors (FOS/JUN) regulate KIT expression via chromatin remodeling. Functional analyses indicated that KIT is integral to sustaining the elevated proliferation rates observed in ΔDKO organoids. These findings reveal a novel AP-1/KIT signaling axis that is central to the early progression of CRC, thereby presenting a promising avenue for therapeutic intervention.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 alternative NF-κB RelB subunit is a novel critical sensor of lipid metabolism to promote tumor development.","authors":"T Becquard, C Benatar, C Bretot, B Eluard, D Bordereaux, L Thirouard, A Hammoutene, A Montagne, F Dingli, D Loew, C Ransy, M-C Alves-Guerra, C Caradeuc, N Cagnard, M Boissan, N Giraud, F Bouillaud, G Bertho, V Paradis, D Chiron, R Dentin, C Prip-Buus, V Baud","doi":"10.1038/s41419-026-09064-7","DOIUrl":"10.1038/s41419-026-09064-7","url":null,"abstract":"<p><p>Cancer cells reprogram their metabolism to fulfill their high energetic demand. Lipid metabolism is most often reprogrammed for cancer cell survival and tumor development. The role of alternative oncogenic NF-κB/RelB subunit in the reprogramming of lipid metabolism in cancer is unknown. Here we report that RelB plays a central role at the crossroads of lipid storage and liberation of fatty acids from the lipid droplets to feed the fatty acid oxidation (FAO) and mitochondrial energetic metabolism. High RelB expression defines a subset of hepatocellular carcinoma (HCC) patients and cell lines with a peculiar gene expression profile enriched in lipid catabolic-related genes, including lipases. Functional studies revealed that high RelB activation controls the expression of major lipolytic lipases, including adipose triglyceride lipase (ATGL) and monoglyceride lipase (MAGL), and impacts on HCC cell survival, migration, and tumor development in vivo. Altogether, we uncovered that RelB is a central regulator of the lipid metabolism plasticity and an energy homeostasis sensor in cancer cells.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13612402/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived PCSK9-enriched exosomes reprogram adipocytes to drive metabolic dysregulation and immune evasion in triple-negative breast cancer.","authors":"Duanyang Zhai, Yawei Shi, Yuanjian Fan, Shaoquan Zheng, Mengmeng Zhang, Shuling Zhou, Nan Shao, Yunjian Zhang, Jihong Cui, Ying Lin","doi":"10.1038/s41419-026-09027-y","DOIUrl":"10.1038/s41419-026-09027-y","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is characterized by aggressive behaviors, limited treatment options, and poor prognosis. Adipocytes, the predominant cellular component in the tumor microenvironment (TME) of breast cancer, interact bidirectionally with tumor cells, influencing tumor progression and immune evasion. Understanding the interactions between TNBC cells and adipocytes within TME is crucial for identifying new therapeutic targets. We employed murine models and co-culture systems to investigate the effects of adipocyte-TNBC cell interactions on lipid metabolism, signaling pathways, and immune evasion mechanisms. Our findings revealed that TNBC cells utilized PCSK9-enriched exosome transfer to induce the formation of cancer-associated adipocytes (CAAs) from adipocytes. These CAAs, characterized by altered lipid content and a pro-inflammatory secretory profile, contributed to a tumor-promoting environment. Additionally, CAAs enhanced the immune evasion properties of TNBC by modifying the metabolic pathways of tumor cells. In depth, CAAs induced fatty acid oxidation (FAO) in TNBC cells, which facilitated G3BP1-induced stabilization of PCSK9 and promoted OPTN-mediated autophagic degradation of the co-stimulatory molecules CD80 and CD86, which are essential for T cell activation. Our study identifies PCSK9 as a central mediator in the bidirectional interactions between TNBC cells and adipocytes, influencing tumor progression and immune evasion. These insights suggest that targeting the PCSK9 pathway could provide new therapeutic opportunities for TNBC, potentially transforming treatment approaches and improving patient outcomes. Further investigation into the mechanisms by which PCSK9 regulates these processes may yield novel combination strategies to enhance the efficacy of immunotherapy in TNBC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disruption of MCL1/BOK transmembrane interaction as a novel strategy to induce cell death in tumours.","authors":"M Buffa, D Leiva, A Garcia-Jareño, M Garcés-Flores, E Díaz, F Lucantoni, M Telechea, L Chen, E Lucendo, R Shalaby, F Lolicato, W Kulig, A J Garcia-Saez, G Moreno-Bueno, M Sancho, M Orzáez","doi":"10.1038/s41419-026-09074-5","DOIUrl":"10.1038/s41419-026-09074-5","url":null,"abstract":"<p><p>MCL1, an anti-apoptotic BCL-2 family member, is frequently overexpressed in multiple tumour types and correlates with poor prognosis; however, targeting its cytosolic domain to release pro-apoptotic effectors has been limited by cardiotoxicity in clinical trials. In this study, we describe a chemically mediated disruption of the MCL1/BOK transmembrane interaction that induces tumour cell death without affecting viability in 3D cardiomyocyte cultures. Molecular dynamics simulations and LUV-based assays converged to show that the MBoIN179 disrupts transmembrane dimerization, thereby restoring BOK pore formation inhibited by MCL1. In cells, interference with the MCL1/BOK transmembrane interaction promoted relocalization of BOK from the endoplasmic reticulum to mitochondria, where it engaged a BOK-dependent cell death program in both 2D and 3D breast cancer models, leading to reduced tumour growth and metastasis in vivo. Analysis of patient tumour microarrays further showed that BOK is overexpressed in aggressive breast cancer subtypes and correlates with poor prognosis. Together, these findings identify the MCL1/BOK transmembrane interaction as a tumour-selective vulnerability that can be engaged to promote antitumour responses with cardiac safety, highlighting transmembrane interactions as viable molecular targets.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GDPPH1 induces cell cycle arrest by downregulation of CDK4/Cyclin D1 via the m⁶A-METTL14-YTHDF2 axis, attenuating glioblastoma progression.","authors":"Sijia Li, Ruijie Yuan, Jinxuan Su, Ruxi Chen, Xinyi Qu, Lele Zhao, Xiaofeng Zhou, Qiuming Zou, Zhijing Zhang, Siyu Yang, Jianqin Lai, Xiaosong Zhuang, Zisheng Li, Kai Cui, Shengwei Hu, Yongqi Liu, Lili Liu, Zepeng Luo, Zhongping Luo, Wen Li, Yu Yan, Yubo Zhang, Zhiming Zheng, Qi Qi","doi":"10.1038/s41419-026-09036-x","DOIUrl":"10.1038/s41419-026-09036-x","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor in adults, with current therapies failing to achieve significant clinical advancements. GDPPH1, a natural compound derived from Garcinia mangostana L., is known for its antioxidant properties; however, its anticancer effects and underlying mechanisms remain insufficiently understood. In this study, we demonstrate that GDPPH1 significantly inhibits GBM cell proliferation in a concentration-dependent manner by downregulating CDK4 and Cyclin D1 expression, inducing cell cycle arrest at G1/S checkpoint, and promoting apoptosis. Mechanistically, GDPPH1 reduces the m⁶A methylation of CDK4 and CCND1 through METTL14-YTHDF2-mediated transcript decay, resulting in decreased CDK4/CCND1 expression and subsequent decreased RB phosphorylation levels. Further studies revealed that m⁶A-METTL14-YTHDF2 axis is responsible for GDPPH1-induced downregulation of CDK4 and Cyclin D1. Additionally, the in vivo anti-GBM efficacy of GDPPH1 was confirmed using both xenograft and orthotopic intracranial mouse models. Collectively, these findings provide robust evidence supporting GDPPH1 as a promising therapeutic candidate for GBM and offer novel insights into the role of m⁶A RNA methylation in cell cycle regulation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601516/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rethinking LPCAT3 roles in human disease: broadening perspectives beyond ferroptosis.","authors":"Zihan Lin, Qian Jiao, Siqi Liu, Xixun Du, Yu Du, Ying Wang, Mengru Liu","doi":"10.1038/s41419-026-08893-w","DOIUrl":"10.1038/s41419-026-08893-w","url":null,"abstract":"<p><p>Lysophosphatidylcholine acyltransferase 3 (LPCAT3), a membrane-bound O-acyltransferase, is well known for enriching phospholipids (PLs) with polyunsaturated fatty acids (PUFAs) and thereby driving ferroptosis. However, accumulating evidence indicates that LPCAT3 is not merely a ferroptosis effector but a broader integrator of non-ferroptotic functions, such as autophagy, endoplasmic reticulum homeostasis, and inflammatory signaling. Herein, we provide an overview of LPCAT3 functions that explicitly extend beyond ferroptosis. We first provide a comprehensive review of the structural and enzymatic characteristics of LPCAT3, along with its diverse regulatory mechanisms of expression. Subsequently, we summarize how LPCAT3-mediated PL remodeling modulates membrane biophysical properties and further elucidate the downstream effects of this remodeling on the regulation of autophagy, endoplasmic reticulum homeostasis, and inflammatory signaling pathways. Finally, we systematically review the pivotal roles of LPCAT3 in the pathogenesis of multiple human diseases, including neurodegenerative diseases, stroke, atherosclerosis (AS), diabetes mellitus, obesity (OB), non-alcoholic fatty liver disease (NAFLD), and cancer. This review aims to elucidate the functions of LPCAT3 beyond its role in regulating ferroptosis and may provide new insights into its involvement in human diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A ZDHHC3-USP5-PTRF axis links palmitoylation to ferroptosis-associated phenotypes in melanoma.","authors":"Songyun Zhao, Yuankun Liu, Dan Wu, Chenfeng Ma, Peng Luo, Pengpeng Zhang, Yucang He, Xiaoqing Liang, Chao Cheng, Jiaheng Xie, Liqun Li","doi":"10.1038/s41419-026-09053-w","DOIUrl":"10.1038/s41419-026-09053-w","url":null,"abstract":"<p><p>Melanoma is a highly aggressive malignancy with poor prognosis and therapy resistance. Although deubiquitinating enzymes (DUBs) regulate protein stability and cancer progression, their modulation in melanoma remains unclear. Here, we characterized ubiquitin‑specific peptidase 5 (USP5) using proteomic, biochemical, and functional approaches. USP5 was upregulated in melanoma and promoted proliferation, migration, and invasion. Mechanistically, USP5 directly interacted with and deubiquitinated PTRF, preferentially removing K48‑linked polyubiquitin chains to reduce proteasomal degradation. PTRF represents a functionally relevant substrate, though additional targets may exist. USP5 stability itself depended on S‑palmitoylation mediated by the palmitoyltransferase ZDHHC3, which suppressed USP5 ubiquitination and turnover. Silencing ZDHHC3 destabilized USP5, reduced PTRF levels, and impaired tumor growth. Perturbing the ZDHHC3-USP5-PTRF axis modulated ferroptosis‑associated phenotypes in vitro and affected xenograft tumor growth, accompanied by altered oxidative damage markers indicative of redox and lipid peroxidation changes, without directly establishing ferroptosis dependency. Our findings identify ZDHHC3‑mediated palmitoylation as a key determinant of USP5 stability and reveal a palmitoylation-deubiquitination cascade with PTRF as a downstream effector, linking this pathway to ferroptosis‑related cellular phenotypes. Further in vivo studies are needed to clarify mechanistic specificity and ferroptosis dependency.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597508/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial-endoplasmic reticulum interactions in lung diseases.","authors":"Yafang Zhang, Hao Yan, Xianzhi Peng, Lihong Gong, Shenglin Zhang, Dong Liu, Chaoyang Zhang, Cheng Peng, Yunxia Li","doi":"10.1038/s41419-026-09063-8","DOIUrl":"10.1038/s41419-026-09063-8","url":null,"abstract":"<p><p>The pathogenesis of lung diseases is highly complex and multifactorial, posing a persistent challenge to global public health, while effective therapeutic options remain limited. Therefore, systematically elucidating the cellular and molecular mechanisms underlying lung injury is a crucial prerequisite for developing novel therapeutic strategies. Accumulating evidence highlights that the endoplasmic reticulum and mitochondria are key organelles driving the progression of lung injury. Notably, mitochondria-associated membranes (MAMs) form a structural and functional bridge between the endoplasmic reticulum and mitochondria, highlighting the essential role of inter-organellar communication in maintaining lung function homeostasis. This review comprehensively summarizes the autonomous mechanisms of the mitochondria and endoplasmic reticulum in lung injury-related diseases, with a further focus on the complex architecture and regulatory mechanisms of MAMs. It emphasizes the molecular mechanisms by which dysfunctional MAMs contribute to the onset and progression of lung injury, including Ca²⁺ signaling, oxidative stress, lipid synthesis and transport, UPR^ER and UPR^mt, mitochondrial homeostasis, and cell death. Finally, incorporating recent research advances, we discuss the current challenges and future prospects in this field, with particular emphasis on intervention strategies targeting Ca²⁺ transport at MAMs, mitochondrial quality control, endoplasmic reticulum stress, and metabolic coupling, as well as their potential for clinical translation. Overall, a deeper understanding of the functional interaction network among mitochondria, the endoplasmic reticulum, and their associated MAMs is expected to provide a robust theoretical foundation and translational insights for elucidating novel molecular mechanisms underlying lung injury and optimizing therapeutic strategies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597532/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374653","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}