Cell Death Discovery最新文献

{"title":"Unlocking ferroptosis heterogeneity: ATF4 versus SREBF transcriptional programs.","authors":"Mariia V Barannikova, Valeriy K Sulyagin, Dmitry A Korzhenevskii, Varvara D Starodubova, Maria A Sorokina, Alexey M Nesterenko, Guzel R Gazizova, Victoria P Sulyagina, Oleg A Gusev, Elena I Shagimardanova, Vsevolod V Belousov, Olga M Kudryashova, Arina G Shokhina","doi":"10.1038/s41420-026-03238-0","DOIUrl":"10.1038/s41420-026-03238-0","url":null,"abstract":"<p><p>Regulated cell death (RCD) encompasses diverse forms induced by common cellular stressors, including oxidative stress and endoplasmic reticulum stress. Cells may display features from multiple RCD types, implying coexistence of \"pure\" and \"mixed\" forms of cell death. Ferroptosis is an iron-dependent form of RCD characterized by lipid peroxide accumulation and absence of specific biomarkers. Its regulation is heterogeneous and pathway-dependent, reflecting the broader complexity of the RCD spectrum. This study hypothesized two major regulatory pathways governing ferroptosis induction and functioning. The first pathway operates through GPX4, a central enzyme preventing ferroptosis by reducing lipid peroxides. Genetic GPX4 knockout and chemical GPX4 inhibition with ML210 resulted in significant upregulation of mevalonate pathway regulators SREBF1 and SREBF2, indicating compensatory anti-ferroptotic activation through the mevalonate pathway. The second pathway functions through the Xc⁻/GSH system critical for glutathione synthesis. System Xc⁻ inhibition leads to intracellular cysteine depletion with subsequent glutathione depletion, inducing ferroptotic cell death. SREBF transcription factor cascades were downregulated in system Xc⁻/GSH depletion experiments, contrasting with GPX4 inhibition responses. Instead, the system Xc⁻/GSH pathway is primarily governed by ATF4 to maintain cystine uptake and glutathione biosynthesis under stress conditions. These findings confirm ferroptosis as a heterogeneous spectrum of cell death with multiple interacting yet mechanistically distinct pathways. Moreover, these data provide a dynamic multi-omics resource for further ferroptosis research.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601565/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148381706","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":"A WEEV 6K viroporin activates MLKL-dependent necroptosis to drive inflammatory injury.","authors":"Ziyan Zhou, Pengpeng Wu, Zhaobing Gao, Bingqing Xia","doi":"10.1038/s41420-026-03229-1","DOIUrl":"10.1038/s41420-026-03229-1","url":null,"abstract":"<p><p>Neurotropic alphavirus infection is characterized by neuronal injury and sustained neuroinflammation, yet the viral determinants linking membrane perturbation to host inflammatory damage remain poorly defined. Here, we show that the Western equine encephalitis virus (WEEV) 6K protein functions as an ER-localized viroporin, displaying stable single-channel activity with broad cation permeability. Consistent with its ion channel activity, 6K expression perturbs intracellular Ca²⁺ store homeostasis and is associated with cellular injury phenotypes. Mechanistically, 6K predominantly engages MLKL-mediated necroptosis, identifying programmed necrotic signaling as a principal pathway underlying 6K-driven injury under these conditions. Importantly, genetic deletion or pharmacological inhibition of MLKL significantly attenuates 6K-associated cellular damage and inflammatory release, establishing MLKL-dependent execution as a key modifiable node in viroporin-induced host injury. We further identify HYH09-D4 as a protective small molecule that dampens MLKL activation and limits tissue damage associated with 6K expression. Together, these findings define WEEV 6K as a host-facing viroporin that links ionic dysregulation to MLKL-dependent necroptosis and suggest that targeting MLKL may represent a broadly applicable strategy to mitigate host injury driven by 6K-encoding alphaviruses.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374686","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":"Tirapazamine sensitises hypoxic homologous recombination-proficient NSCLC to PARP inhibition.","authors":"Yanyan Jiang, Nuria Vilaplana Lopera, Hala Estephan, Yizhou Wang, Ftoon Aljarbou, Ester M Hammond, Amato J Giaccia, Eui Jung Moon","doi":"10.1038/s41420-026-03233-5","DOIUrl":"10.1038/s41420-026-03233-5","url":null,"abstract":"<p><p>PARP inhibitors (PARPi) are clinically effective in homologous recombination (HR)-deficient tumours, but their application in HR-proficient cancers remains limited. Although hypoxia suppresses HR, this repression alone does not adequately sensitise cancer cells to PARPi due to insufficient endogenous DNA damage. We hypothesised that introducing a hypoxia-selective source of DNA damage could enhance PARPi efficacy. Here, we show that the hypoxia-activated prodrug tirapazamine (TPZ) synergises with the PARPi talazoparib to induce cytotoxicity in HR-proficient non-small cell lung cancer (NSCLC) cells, with preferential activity under hypoxia. Mechanistically, this synergy is driven by increased DNA double-strand breaks (DSBs) and replication stress. These lesions are largely resolved in normoxia but persist in hypoxia. In hypoxic spheroids derived from HR-proficient NSCLC cell lines, the TPZ and talazoparib combination significantly inhibited spheroid growth. In subcutaneous xenografts, the combination similarly suppressed tumour growth in the highly hypoxic A549 and CORL105 models, while showing minimal efficacy in the less hypoxic Calu-3 and H3122 tumours. This study highlights the potential of hypoxia-targeted DNA-damaging agents to expand PARPi utility to HR-proficient cancers and demonstrates that hypoxia enhances the therapeutic effect of this combination.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13598068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374698","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":"Aluminium ammonium sulphate induces epithelial pyroptosis and eosinophilic inflammation under dysbiotic conditions: ameliorative effects of heparin.","authors":"Ayako Wakabayashi, Atsuko Owaki, Ken Iwatsuki, Etsuko Toda, Keisuke Tanaka, Soichiro Kumamoto, Yuichi Koshiishi, Yukino Machida, Shinobu Kunugi, Yasuhiro Nishiyama, Shoji Matsune, Yasuyuki Negishi, Rimpei Morita","doi":"10.1038/s41420-026-03237-1","DOIUrl":"10.1038/s41420-026-03237-1","url":null,"abstract":"<p><p>Aluminium ammonium sulphate (AAS) is a food additive used in some countries, but its effects on intestinal epithelial cells (IECs) remain poorly understood. We investigated whether AAS promotes IEC death and eosinophilic infiltration under dysbiotic conditions and whether heparin suppresses these effects. Mice pretreated with antibiotics or control water were orally administered AAS. IEC death was assessed by RNA sequencing, western blotting, and flow cytometry. Microbiota composition was analysed by 16S rRNA sequencing, and eosinophilic infiltration was evaluated by histology and flow cytometry. Immortalised murine IECs were stimulated with AAS in the presence or absence of bacterial components, and the effects of heparin were examined in vitro and in vivo. Antibiotic-induced dysbiosis altered IEC metabolic programmes and reduced polysaccharide-degrading bacteria. Under these conditions, AAS further reduced Actinobacteria, including Bifidobacterium, increased mitochondrial reactive oxygen species (mtROS), and promoted cleavage of caspase-1, caspase-6, caspase-8, caspase-11, interleukin-33, gasdermin D (GSDMD), and gasdermin E (GSDME) in IECs. These changes were associated with epithelial pyroptosis and eosinophilic infiltration in the small intestine. AAS induced similar cleavage events in IECs primed with lipopolysaccharide and lipoteichoic acid in vitro. Antioxidant studies showed that caspase-1/11-GSDMD activation was ROS-dependent, whereas caspase-6/8-GSDME activation involved ROS-independent mechanisms. Heparin suppressed these cleavage events, reduced IEC death both in vitro and in vivo, and attenuated eosinophilic inflammation. These findings identify a previously unrecognised pro-inflammatory effect of AAS in the dysbiotic gut and suggest low-dose heparin as a potential protective strategy for intestinal epithelial homoeostasis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359629","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 mechanism of 45S5 bioactive glass-mediated, cell-type-specific death of bone tumor cells.","authors":"Joerg Fellenberg, Sarina Losch, Marcela Arango-Ospina, Fabian Westhauser, Burkhard Lehner, Aldo R Boccaccini","doi":"10.1038/s41420-026-03211-x","DOIUrl":"10.1038/s41420-026-03211-x","url":null,"abstract":"<p><p>Despite advances in treatment modalities, current bone tumor therapies still face significant challenges, including severe side effects of conventional approaches, poor survival rates and high rates of tumor recurrence. We previously identified a strong cytotoxic effect of 45S5-bioactive glass (BG) particles on bone tumor cells, indicating possible therapeutic properties of these materials. In order to identify the mechanisms that trigger tumor cell death, we investigated the impact of 45S5-BG on bone tumor cells compared to non-neoplastic cells. Regardless of cell type, BG treatment induced oxidative stress and increased ROS production. Fluorescently labeled SiO₂ particles were rapidly internalized by both cell types. Tumor cell-specific responses included elevation of calcium levels, activation of MAP- and AKT-kinase as well as the release of LDH and ATP from the cells. Apoptosis, pyroptosis and necroptosis could be excluded as possible cell death mechanisms due to the lack of caspase activation and a RIPK3 deficiency of the tumor cells. Rather, we identified an important role of lysosomes and the requirement of intact V-ATPase activity. Together with a strong increase in intracellular Fe²⁺ and MDA levels triggered by BG-treatment, these data strongly suggest that ferroptosis is the main cause of tumor cell-specific death. In combination with the known beneficial effects of BGs on bone regeneration, our data point to a potential therapeutic strategy for promoting bone repair while simultaneously reducing tumor recurrence. Furthermore, understanding the underlying mechanisms and the option to modify the glass composition could help to develop even more potent BG variants.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13324152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366764","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 role and mechanism of tubulin folding cofactor B in glioblastoma migration.","authors":"Bingqiu Zhang, Qiang Wang, Chenglong Ouyang, Mei Yang, Qiuxi Chen, Xiaoqiao Chen, Fei Gao, Hui Liu","doi":"10.1038/s41420-026-03232-6","DOIUrl":"10.1038/s41420-026-03232-6","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most common primary malignant brain tumor in the central nervous system, characterized by high invasiveness, incidence, and mortality. Tubulin folding cofactor B (TBCB) is a microtubule-associated regulator implicated in microtubule plus-end organization and related structural features; however, its role and underlying mechanisms in GBM remain unclear. This study aimed to elucidate the function and mechanisms of TBCB in GBM cell proliferation and migration. Analyses of public databases (GEO, TCGA, CGGA) and clinical GBM specimens revealed that TBCB was significantly upregulated in GBM compared with normal controls, with higher expression correlating with higher WHO grades and poor prognosis. Functionally, TBCB knockdown in U87 and U251 cells significantly inhibited proliferation and migration (assessed by EdU, cell counting, Transwell and wound-healing assays) and impaired cell process formation; consistently, in vivo experiments using orthotopic intracranial xenograft models confirmed that TBCB knockdown suppressed tumor growth and prolonged survival. Mechanistically, reciprocal Co-IP/IF supported association of TBCB with both EB1 and EB3, indicating that TBCB acts as a functional partner of the microtubule plus-end tracking proteins ( + TIPs) EB1 and EB3, co-localizing at cell process tips and being associated with microtubule plus-end organization/comet-like features. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified the MAPK pathway as a key signaling pathway associated with TBCB; Western blotting showed that TBCB knockdown reduced the p-ERK/ERK ratio, and pharmacological modulation with the ERK agonist TPA and the MEK inhibitor U0126 further indicated that ERK-pathway perturbation regulates TBCB in a time-dependent and nonlinear manner in GBM cells. Collectively, these findings indicate that TBCB promotes GBM cell proliferation and migration through EB1/EB3-associated microtubule plus-end organization and is functionally coupled to the ERK-MAPK pathway in a time-dependent and nonlinear manner, suggesting that TBCB is a candidate regulator of GBM progression that warrants further translational validation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359716","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":"Wnt signaling-mediated activation of cancer cell stemness in thoracic SMARCA4-deficient undifferentiated tumor cells.","authors":"Yan Xu, Lumei Wang, Hongjia Zhang, Lin Liang, Hui Han, Tianyu Xiao, Cheng Zhang, Qiye He, Zuoren Yu, Jinli Gao","doi":"10.1038/s41420-026-03224-6","DOIUrl":"10.1038/s41420-026-03224-6","url":null,"abstract":"<p><p>Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) represent a distinct and highly aggressive malignancy characterized by SMARCA4 deficiency, poor prognosis, and resistance to chemotherapy. The lack of clarity regarding the regulatory mechanisms underlying this disease has hindered the development of standardized treatment guidelines. In this study, we analyzed clinical samples and found significantly elevated levels of cancer stem cell markers, including SOX2, CD34, c-Myc, and EpCam, in thoracic SMARCA4-UT, which were further confirmed in SMARCA4-deficient non-small cell lung cancer (NSCLC) cells. Furthermore, SMARCA4 knockdown in NSCLC cells promoted cell proliferation, migration, invasion, and tumorsphere formation in vitro, as well as enhanced tumor growth in a mouse model in vivo. RNA sequencing analysis of SMARCA4-deficient cells revealed the upregulation of a subset of genes, including Wnt10A, and activation of Wnt signaling. This was validated through SMARCA4-ChIP-seq and SMARCA4-ChIP-PCR analyses, Wnt activity reporter assays, and subcellular distribution analysis of β-catenin. Subsequent studies using a small molecule Wnt inhibitor in SMARCA4-deficient cells and thoracic SMARCA4-UT patient-derived organoids demonstrated induction of apoptosis, inhibition of cell stemness, and suppression of tumor cell growth. These results suggest the potential for developing a novel therapeutic strategy targeting cancer stem cells for the treatment of thoracic SMARCA4-UT.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13586300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359758","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":"Spatial transcriptomics in cancer research: insights into tumorigenesis, diagnosis and therapeutics.","authors":"Qiang Wen, Qing Lan, Jianjian Yin, Fei Guo, Xiaosong Wei, Caiyun Wu, Lei Jin, Xu D Zhang, Jinyan Li, Lirong Zhang, Tao Liu","doi":"10.1038/s41420-026-03092-0","DOIUrl":"10.1038/s41420-026-03092-0","url":null,"abstract":"<p><p>Spatial transcriptomics is an innovative technology that enables high-throughput, genome-wide analysis of transcript expression and spatial localization within tissues. By preserving structural organization, it provides critical insights into tumor sub-regions, substructures, and the heterogeneity and plasticity of cancer, stromal, and immune cells, as well as cell-cell interactions. Spatial transcriptomics also offers an unprecedented understanding of the tumor microenvironment, including immune cell infiltration, activation and repression, and immune suppression mediated by stromal cells. Importantly, it deepens our understanding of malignant transformation from precancerous lesions, tumorigenesis, and immune escape. Furthermore, spatial transcriptomics is reshaping cancer subtype diagnosis and risk stratification, uncovering factors associated with drug resistance, predicting therapy responses, and informing the development of personalized cancer treatments and potentially prevention. In summary, spatial transcriptomics serves as a cornerstone of cancer research, transforming the research landscape and unlocking groundbreaking opportunities for precision cancer diagnosis, risk stratification, targeted therapy, and prevention.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13582851/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359673","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":"Die hard: when cells refuse apoptosis-the rise of paraptosis and other death pathways.","authors":"Cecilia Anceschi, Elena Frediani, Jessica Ruzzolini, Francesca Margheri, Anastasia Chillà, Noemi Formica, Elena Andreucci, Fabio Cianchi, Anna Laurenzana, Serena Martinelli","doi":"10.1038/s41420-026-03193-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03193-w","url":null,"abstract":"<p><p>Resistance to apoptosis remains a major barrier in cancer therapy, driving interest in alternative regulated cell death (RCD) programs. Paraptosis, a caspase-independent RCD marked by cytoplasmic vacuolization, ER dilation, and mitochondrial swelling, emerges as a promising vulnerability in apoptosis-refractory tumors. Its therapeutic potential has been limited by incomplete understanding of its dynamic regulation within heterogeneous tumor ecosystems. In this review, we introduce paraptotic plasticity, describing cancer cells' ability to reversibly switch between paraptosis-sensitive and -resistant states in response to metabolic stress, therapeutic pressure, and tumor microenvironmental cues. This plasticity reveals a previously unrecognized mechanism of therapeutic resistance and uncovers exploitable vulnerabilities for precision targeting. We outline key molecular determinants, including ER stress, mitochondrial dysfunction, ion homeostasis, and proteotoxic stress, and highlight the emerging influence of microbiota-derived metabolites in shaping paraptotic outcomes. Finally, we discuss nanotechnology-enabled strategies that leverage these vulnerabilities, offering a translational roadmap to overcome resistance in hard-to-treat cancers.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming in delipidated adipocytes: metabolism, regulation and progress.","authors":"Zhanshuo Chang, Yunjun Liao, Wenqing Jiang","doi":"10.1038/s41420-026-03199-4","DOIUrl":"10.1038/s41420-026-03199-4","url":null,"abstract":"<p><p>Through specific induction protocols in vitro or under physiological or pathological conditions in vivo, mature adipocytes can be converted into mesenchymal stem cells, challenging our traditional understanding of mature adipocyte identity and cell fate determination. Given that dedifferentiated adipocytes are a rich source of stem cells in the human body, they hold great potential for applications in regenerative medicine. This review discusses the process of lipid droplet depletion and the stage-specific metabolic remodeling of intracellular substances-including triglycerides and free fatty acids, energy-related metabolites (ATP, NAD⁺/NADH, acetyl-CoA), as well as the alterations in key proteins, organelle remodeling, and epigenetic modifications. These insights provide a deeper understanding of adipocyte identity and the molecular mechanisms underlying the transition between different adipocyte differentiation stages. The review also highlights advanced techniques in the field, including adipocyte lineage-tracing models and single-cell RNA sequencing, enhancing the accuracy and precision of research while enabling the capture of dynamic changes within cells. These advancements offer a more comprehensive approach to studying dedifferentiated adipocytes.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":10.4,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13572457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148343975","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}