Apoptosis最新文献

{"title":"Targeting the non-coding RNA-PANoptosis axis: a novel frontier in disease diagnosis and therapy","authors":"Shaocong Wang,&nbsp;Chenxi Feng,&nbsp;Xinzhe Chen,&nbsp;Yinghui Li,&nbsp;Kun Wang,&nbsp;Meihua Zhang,&nbsp;Wei Cheng","doi":"10.1007/s10495-026-02413-z","DOIUrl":"10.1007/s10495-026-02413-z","url":null,"abstract":"<div><p>Programmed cell death represents a fundamental process in maintaining organismal homeostasis and responding to pathological challenges. The traditional view considered apoptosis, pyroptosis, and necroptosis as independent death pathways. However, recent research has revealed extensive interactions and synergies among these pathways, leading to the emergence of a novel form of cell death termed “PANoptosis.” Triggered by specific stimuli, PANoptosis involves the assembly of a large multiprotein complex called the PANoptosome. This complex integrates key molecules and morphological features from apoptosis, pyroptosis, and necroptosis, culminating in a highly efficient and coordinated inflammatory cell death program. Concurrently, non-coding RNAs, as crucial regulators of gene expression, participate extensively in the regulation of cellular fate at the post-transcriptional and epigenetic levels. This review systematically summarizes the molecular mechanisms by which non-coding RNAs regulate the core components of PANoptosis and its upstream signaling pathways. It further delves into the pathological role of this regulatory axis in infectious diseases, cancer, neurodegenerative disorders, and autoimmune diseases. Additionally, the article explores the diagnostic potential of non-coding RNA-based approaches and therapeutic strategies targeting the non-coding RNA-PANoptosis axis, while also addressing current challenges related to mechanistic complexity, delivery technologies, and safety assessment. This review aims to establish a systematic framework for the “non-coding RNA-PANoptosis-disease” regulatory axis, providing a theoretical basis for understanding the interactive logic of cell death networks and for developing precise interventions for related diseases.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148688438","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":"ATP6AP2 ameliorates inflammation and pyroptosis in heart failure by promoting lysosome-dependent STING degradation","authors":"Xuan Zhao,&nbsp;Hui Zhang,&nbsp;Xinyue Ding,&nbsp;Huimin Wu,&nbsp;Min Li,&nbsp;Nengpin Yin,&nbsp;Junqing Gao,&nbsp;Youlong Xu,&nbsp;Rui Wang,&nbsp;Zhen Qi,&nbsp;Lina Xing,&nbsp;Zongjun Liu","doi":"10.1007/s10495-026-02415-x","DOIUrl":"10.1007/s10495-026-02415-x","url":null,"abstract":"<div><p>Inflammatory activation is involved in the pathogenesis of heart failure (HF). ATPase H+-Transporting Accessory Protein 2 (ATP6AP2) is an auxiliary subunit of the V-ATPase, and its role in HF is not fully understood. To assess the role and regulatory mechanisms and therapeutic potential of ATP6AP2 in HF, we used a cardiac-specific ATP6AP2 conditional knockout (CKO) mouse model and observed spontaneous cardiac dysfunction, myocardial fibrosis and cardiomyocyte apoptosis in mice. Further studies showed that ATP6AP2 promoted stimulator of interferon genes (STING) degradation through the lysosome-dependent pathway. ATP6AP2 knockdown significantly upregulated STING protein levels, activated the STING-TBK1-IRF3 signaling axis, and promoted pro-inflammatory factor expression and cardiomyocyte apoptosis. In mice with myocardial infarction (MI), myocardial overexpression of ATP6AP2 or treatment with H-151 inhibited the activation of the STING signaling pathway, ameliorated cardiomyocyte apoptosis and inflammatory responses, thereby improving cardiac function. In addition, in macrophages treated with conditioned medium from hypoxia-exposed cardiomyocytes, the levels of pyroptosis-related proteins were markedly increased, whereas ATP6AP2 overexpression or STING inhibition reduced pyroptosis. ATP6AP2 likewise attenuates inflammation and pyroptosis caused by hypoxia in cardiac organoids. In conclusion, activating ATP6AP2 could serve as a promising therapeutic option in HF.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652834","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":"Ruptosis: a novel hormone-triggered cytotoxic cell death program linking endocrine homeostasis to innate immunity","authors":"Feng Tang","doi":"10.1007/s10495-026-02414-y","DOIUrl":"10.1007/s10495-026-02414-y","url":null,"abstract":"<div><p>A landmark 2026 <i>Cell</i> publication by Chai et al. characterized Ruptosis, a previously unclassified form of regulated cell death executed by specialized glandular immune cells termed ruptoblasts in the planarian <i>Schmidtea mediterranea</i>. Triggered exclusively by elevated activin (a dual hormone/inflammatory cytokine), Ruptosis manifests rapid, contact-independent explosive cellular disintegration and releases diffusible toxins to eliminate aberrant somatic cells, stem cells and invading bacteria. Distinct from apoptosis, pyroptosis, necroptosis, ferroptosis and neutrophil NETosis at morphological, biochemical and kinetic levels, this novel lytic pathway substantially expands the canonical regulated cell death (RCD) classification system. This commentary outlines the defining unique features of Ruptosis and discusses its evolutionary implications for cell death and innate immunity research.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148614743","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":"GNAS drives gastric cancer progression via pyrimidine metabolic reprogramming and immune-microenvironment remodeling","authors":"Xinyi Wang,&nbsp;Heng Tian,&nbsp;Jiaju Wang,&nbsp;Yafen Wang,&nbsp;Ran Wei,&nbsp;Yuhan Liu,&nbsp;Yun Hong,&nbsp;Fan Wang,&nbsp;Bangjie Chen","doi":"10.1007/s10495-026-02412-0","DOIUrl":"10.1007/s10495-026-02412-0","url":null,"abstract":"<div><p>Metabolic reprogramming, particularly the altered nucleotide metabolism, is a critical driver of tumor heterogeneity and malignant progression in gastric cancer (GC). However, the core molecular determinants orchestrating this metabolic shift and its subsequent impact on the tumor microenvironment (TME) remain elusive. We integrated single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA-seq data to delineate the metabolic landscape of GC. The metabolic vulnerabilities and functional roles of the identified hub gene were systematically validated using in vitro assays, in vivo xenograft models, and pharmacological metabolic interventions. Pathway-level metabolic flux inference via scRNA-seq revealed a pronounced shift toward nucleotide interconversion and pyrimidine synthesis in malignant epithelial cells. We identified GNAS as a key metabolic hub gene, which is consistently upregulated in highly malignant subsets and strongly predictive of poor patient survival. Pseudotime and spatial transcriptomic analyses demonstrated that GNAS⁺ epithelial cells occupy terminally differentiated malignant states and specifically localize within spatial niches characterized by hyperactive nucleic acid metabolism and an immunosuppressive TME driven by cancer-associated fibroblasts (CAFs). Mechanistically, GNAS depletion profoundly impaired pyrimidine nucleotide (UMP/UDP) biosynthesis, which sequentially attenuated the activity of the ATF3-JUN-ETS1 transcriptional network, leading to suppressed GC cell proliferation, migration, and invasion, alongside induced apoptosis. Notably, exogenous uridine supplementation successfully rescued these malignant phenotypes, whereas pharmacological inhibition of pyrimidine synthesis (DHODH inhibitor) abolished the oncogenic advantage conferred by GNAS overexpression. GNAS is associated with the malignant evolution of GC by driving pyrimidine metabolic reprogramming and spatially coordinating TME remodeling. Targeting the GNAS-mediated metabolic-transcriptional axis exposes a novel therapeutic vulnerability, offering a promising translational strategy for precision oncology in GC.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148598085","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":"Artemisinin liposomes regulates breast cancer metastasis and apoptosis through TIGIT/CD155 signal axis","authors":"Yachan Feng,&nbsp;Zexu Han,&nbsp;Jiangtao Shao,&nbsp;Bilgen Caliskan,&nbsp;Haitao Shi,&nbsp;Libo Du,&nbsp;Xiaolei Zhou,&nbsp;Yike Qi,&nbsp;Jing Zhang,&nbsp;Zining Hao,&nbsp;Xueling Guo,&nbsp;Jin Zhou,&nbsp;Yingze Wang","doi":"10.1007/s10495-026-02373-4","DOIUrl":"10.1007/s10495-026-02373-4","url":null,"abstract":"<div><p>To investigate the mechanism of artemisinin liposomes regulating breast cancer metastasis and apoptosis through TIGIT/CD155 signal axis. Artemisinin liposomes were synthesized by thin film dispersion method and characterized in morphology, zeta potential, hydrodynamic size, entrapment efficiency as well as thermal stability. Furthermore, the cytotoxic effects of artemisinin liposomes on HC11 and 4T1 cell was evaluated by the MTS test. Scratch, transwell and colony formation experiment were conducted to assess the effect of artemisinin liposomes on cell metastasis. Apoptosis, cell cycle arrest were measured using flowcytometry. Meanwhile, bioinformatics analysis was used to investigate the relationship between TIGIT as a drug target for breast cancer and artemisinin liposomes, TIGIT/CD155 signal axis. Additionally, the mouse tumor model(group(saline, artemisinin, liposomes, artemisinin liposomes), dose(100 mg/kg/d)) was employed to detect the tumor-suppressive efficacy. Finally, the expression levels of Src, Akt, Mtor and Stat3 was further explored by Western Blot and RT-PCR to elucidate the regulatory mechanism of artemisinin liposomes on the TIGIT/CD155 signaling axis. The liposomes and artemisinin liposomes had average sizes of approximately 80 nm and 130 nm respectively, with a polydispersity index (PDI) of 0.225, 0.287. Artemisinin was effectively encapsulated within liposomes, as shown by the high encapsulation efficiency of 90.11% ± 0.88, with a cumulative release rate of 32.8% at pH = 5.5. In vitro studies demonstrated that artemisinin liposomes possessed significantly greater cytotoxicity against 4T1 cells, the IC₅₀ values were approximately 480 µM. In contrast to artemisinin alone, artemisinin liposomes can effectively inhibit 4T1 cell metastasis, with an inhibition rate of 93.02% at 20 µM, and also promote cell apoptosis, with an apoptosis rate of 14.17% at 20 µM. Bioinformatic analysis demonstrated that TIGIT/CD155 signal axis was highly expressed in breast cancer and had poor prognosis. In vivo results revealed that artemisinin liposomes alone produced an anti-tumor effect comparable to the combination of TIGIT/CD155 and IL-15. Ultimately, artemisinin liposomes can regulate breast cancer progression by modulating the TIGIT/CD155 signaling axis and critical factors in the SRC pathway, specifically SRC, AKT, STAT3, and mTOR. The clinical treatment of breast cancer does not rely on the use of chemotherapy drugs alone, but selects the effective ingredients of Chinese medicine with higher safety.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590155","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":"IRF1-mediated sensing of oxidized mitochondrial DNA drives macrophage PANoptosis in lung ischemia–reperfusion injury","authors":"Nan Zhang,&nbsp;Zhiyuan Zhang,&nbsp;Jing Yu,&nbsp;Yu Fu,&nbsp;Jiameng Gao,&nbsp;Xuemei Jiang,&nbsp;Yang Jin,&nbsp;Chang Chen,&nbsp;Zongmei Wen","doi":"10.1007/s10495-026-02401-3","DOIUrl":"10.1007/s10495-026-02401-3","url":null,"abstract":"<div><p>Lung ischemia–reperfusion injury (IRI), a significant factor contributing to early mortality following lung transplantation (LTx), is driven by molecular mechanisms that are not yet fully understood. In this study, we elucidate a crucial signaling pathway initiated by extracellular histones (ex-His), which connects mitochondrial damage to inflammatory cell death. Through the use of a murine model of lung IRI and <i>in vitro</i> experiments with alveolar macrophages, we demonstrate that ex-His facilitate Drp1-dependent mitochondrial fission, resulting in the release of oxidized mitochondrial DNA (ox-mtDNA) into the cytosol. Our mechanistic analysis reveals that cytosolic ox-mtDNA is detected by the transcription factor IRF1, which subsequently upregulates NLRC5 at the transcriptional level. Additionally, we identify NLRC5 as a non-canonical scaffold that is essential for the assembly of the PANoptosome, a multi-protein complex that mediates PANoptosis, an inflammatory cell death pathway that aggravates tissue damage. The clinical relevance of this pathway was then examined in lung transplant recipients. An analysis of their peripheral blood mononuclear cells (PBMCs) revealed that patients who developed primary graft dysfunction (PGD) exhibited markedly elevated levels of circulating histones and cytosolic ox-mtDNA. This was associated with hyperactivation of the core signaling axis, characterized by increased Drp1 phosphorylation and elevated expression of IRF1 and NLRC5. Collectively, our study elucidates a comprehensive pathogenic cascade from an extracellular danger signal to a specific cell death program, identifying the ex-His-mitochondria-IRF1-NLRC5 axis as a critical driver of macrophage PANoptosis and a promising therapeutic target for alleviating lung IRI.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148590145","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":"Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges","authors":"Fangquan Chen,&nbsp;Xiutao Cai,&nbsp;Qile Zhou,&nbsp;Zhen Huang,&nbsp;Jie Wang,&nbsp;Rui Kang,&nbsp;Daolin Tang,&nbsp;Jiao Liu","doi":"10.1007/s10495-026-02408-w","DOIUrl":"10.1007/s10495-026-02408-w","url":null,"abstract":"<div><p>Dysregulated pH homeostasis is a defining feature of tumor biology and a potential therapeutic vulnerability. Cancer cells maintain an alkaline intracellular pH, whereas the tumor microenvironment remains acidic and intracellular organelles preserve compartment-specific luminal acidity, together supporting tumor growth, metabolic adaptation, immune evasion, and therapeutic resistance. Recent studies show that modulation of pH regulation across the tumor microenvironment, cytoplasm, and intracellular organelles disrupts ionic balance, impairs organelle function, and triggers regulated cell death, including alkaliptosis and organelle stress–associated lethality. Beyond direct tumor killing, pH modulation also reshapes antitumor immunity by relieving extracellular acidosis, restoring immune-cell function, and inflammatory signaling. In this review, we summarize recent advances in compartmental pH regulation in cancer, with particular emphasis on the distinction between experimentally demonstrated mechanisms and emerging conceptual models. We discuss how alkalization-oriented interventions may suppress tumor growth in selected contexts, but may also produce neutral, adaptive, or even protumorigenic consequences depending on tumor type, buffering capacity, transporter activity, metabolic state, and immune composition. We further evaluate pH-dependent immune regulation, organelle alkalization, alkaliptosis, quantitative pH measurement, and monitoring technologies. Finally, we highlight major translational barriers. A more quantitative, compartment-resolved, and context-aware understanding of pH biology will be required before pH modulation can be reliably translated into clinically useful therapeutic strategies.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576860","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 of HMGB1 in vascular endothelial cells","authors":"Duzhe Jiang,&nbsp;Ye Zhou,&nbsp;Junying Duan,&nbsp;Wei Zhong,&nbsp;Junjie Liu,&nbsp;Rui Chen,&nbsp;Wei Yuan","doi":"10.1007/s10495-026-02406-y","DOIUrl":"10.1007/s10495-026-02406-y","url":null,"abstract":"<div><p>High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern molecule that plays a key role in inflammatory responses and vascular injury. This article elucidates the underlying mechanisms by which HMGB1 regulates the pro-inflammatory phenotypic transformation of vascular endothelial cells (ECs), disrupts vascular barrier homeostasis, bidirectionally regulates angiogenesis, and induces various forms of programmed cell death, such as pyroptosis and ferroptosis, through core receptors, including the receptor for advanced glycation end-products and Toll-like receptors 2 and 4. We also elaborate on how HMGB1 participates in the occurrence and progression of diseases, such as sepsis, pulmonary hypertension, atherosclerosis, ischemia-reperfusion injury, tumors and lung injury, by regulating the biological behaviors of ECs. Although targeting HMGB1 in ECs has significant therapeutic potential, there remains a gap in clinical translation: how to develop novel intervention drugs that can accurately identify the pathogenic conformation of HMGB1 and possess high endothelial targeting capability. This review also summarizes the therapeutic strategies targeting endothelial HMGB1 reported in the literature.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560679","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":"BMSC-derived exosomal METTL3 synergizes with Sevoflurane to inhibit ferroptosis in pulmonary ischemia/reperfusion injury by enhancing USP7 N6-methyladenosine modification","authors":"Liang Zheng,&nbsp;Xiang-yu Xie,&nbsp;Kun Li,&nbsp;Xiao-feng He,&nbsp;Jiang Shen,&nbsp;Cao Gao","doi":"10.1007/s10495-026-02399-8","DOIUrl":"10.1007/s10495-026-02399-8","url":null,"abstract":"<div><p>Inhibition of ferroptosis was shown to alleviate pulmonary ischemia/reperfusion (I/R) injury. This study aimed to investigate the synergistic effects of bone marrow mesenchymal stem cells (BMSC)-derived exosomal METTL3 and Sevoflurane (Sev) in alleviating pulmonary I/R injury through ferroptosis regulation. In our study, pulmonary I/R injury models were established in mice and lung microvascular endothelial cells (LMECs). Commercial kits were used to measure myeloperoxidase (MPO), glutathione (GSH), malondialdehyde (MDA), and iron content. Lipid peroxidation was determined using the BODIPY 581/591 C11 probe by flow cytometry. Total m6A modification was measured by the commercial kit and m6A dot blot, while m6A modification of USP7 mRNA was analyzed by MeRIP and polysome profiling. The interaction between proteins or RNAs was analyzed by Co-IP, FISH combined with immunofluorescence, RNA pull-down, RIP, or dual-luciferase reporter assay. We proved Sev preconditioning mitigated ferroptosis in pulmonary I/R injury by activating the Nrf2 pathway. Co-treatment with BMSC-derived exosomes potentiated the protective effects of Sev by promoting USP7-mediated Nrf2 deubiquitination modification. Mechanistically, BMSC-derived exosomal METTL3 promoted USP7 mRNA translation through YTHDC2-dependent m6A modification. Also, METTL3 knockdown in exosomes suppressed the Nrf2 pathway and exacerbated ferroptosis, while METTL3 overexpression showed opposite effects. YTHDC2 knockdown abolished these protective effects caused by METTL3-overexpressed exosomes. In conclusion, BMSC-derived exosomal METTL3 reinforced the protective effects of Sev by promoting USP7 mRNA translation via YTHDC2-dependent m6A modification. Upregulated USP7 subsequently facilitated Nrf2 deubiquitination, thereby inhibiting ferroptosis and protecting against pulmonary I/R injury.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560701","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":"The autoimmune regulator (AIRE) is a target of the E3-Ubiquitin ligase Seven-in-absentia homolog 1 (SIAH1).","authors":"Adrián Tirado-Herranz,&nbsp;Alba Pastor-Moreno,&nbsp;María Area-Navarro,&nbsp;Jacqueline Noboa-Velástegui,&nbsp;Oscar Conchillo,&nbsp;José Ramón Palacio,&nbsp;Xavier Daura,&nbsp;Iñaki Alvarez","doi":"10.1007/s10495-026-02398-9","DOIUrl":"10.1007/s10495-026-02398-9","url":null,"abstract":"<div><p>The autoimmune regulator (AIRE) is expressed in medullary thymic epithelial cells (mTECs) and is crucial for generating an immunocompetent T cell repertoire during central tolerance. Loss of AIRE function causes autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Intracellular proteins are regulated by ubiquitination pathways. E3 ubiquitin ligases are specific proteins that confer selectivity to polyubiquitination, tagging proteins for proteasomal degradation while also performing other functions. In mTECs, peptides generated via the class I antigen-processing pathway are presented by HLA-I molecules to CD8 thymocytes to eliminate self-reactive T-cell precursors. AIRE induces promiscuous gene expression in mTECs, but little is known about the regulatory mechanisms of AIRE. Previously, we and others demonstrated that AIRE is an apoptosis inductor. Here, we demonstrate that AIRE increases the intracellular levels of SIAH-interacting protein (SIP), an adaptor protein of the SIAH E3 ubiquitin ligase family. We also show that AIRE interacts with SIAH1 in the human thymus. While AIRE contains two putative SIAH-interacting motifs, it interacts with SIAH proteins only through the sequence spanning residues 119–125. AlphaFold modeling indicated that the interaction between AIRE and SIAH1 is highly analogous to that observed between SIP and SIAH1, suggesting that both proteins compete for SIAH1 binding. The CARD domain and the SIAH-interacting motif is required to AIRE-mediated apoptosis. AIRE co-localized with SIAH proteins in the cytoplasm of HEK-293 cells. Finally, SIAH1 ubiquitinated AIRE, targeting it for proteasomal degradation. Collectively, these findings reveal a novel pathway for the degradation and regulation of AIRE.</p></div>","PeriodicalId":8062,"journal":{"name":"Apoptosis","volume":"31 8","pages":""},"PeriodicalIF":9.0,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10495-026-02398-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148433947","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}