MedComm - Future medicine最新文献

{"title":"Immunotherapy in Advanced Gastric Cancer: Advancing Precision Medicine and Emerging Therapeutic Strategies","authors":"Li Zhang,&nbsp;Qihua Zhang,&nbsp;Xueliang Zhang,&nbsp;Aihong Mao,&nbsp;Yuhua Liu,&nbsp;Huiyan Luo","doi":"10.1002/mef2.70051","DOIUrl":"https://doi.org/10.1002/mef2.70051","url":null,"abstract":"<p>Advanced gastric cancer (GC) continues to pose a substantial global health burden, with traditional treatment modalities providing only modest clinical benefit. In recent years, immunotherapy has emerged as a transformative strategy, and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of numerous cancers, including hematologic malignancies, melanoma, and lung cancer. Clinical studies have established that immunotherapy also improves survival in advanced GC, yet critical issues remain regarding the identification of optimal candidates, the clarification of efficacy for monotherapy or combination strategies, and the exploration of potential biomarkers for immunotherapy. This review delineates therapeutic strategies involving ICIs for advanced GC, including single-agent, combination therapy, and dual-ICI approaches. The review also provides a critical appraisal of the utility of biomarkers for predicting therapeutic response, a summary of the current state of CAR-T cell therapy, and an overview of ongoing investigations into cancer vaccines. A strategic framework for the selection of immunotherapy in advanced GC is also proposed. Precision-based strategies have potential in enhancing treatment efficacy and reducing the financial burden of the patient. Despite the paradigm shift brought by immunotherapy in advanced GC, immune-related adverse events (irAEs) remain a significant clinical hurdle. A detailed discussion of these events is beyond the scope of this review due to space constraints.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IgE-Sensitized Mast Cells: A Programmable Platform for Antigen-Triggered Oncolytic Virotherapy","authors":"Lin Chen,&nbsp;Yu-Xuan Jin,&nbsp;Jin-Lyu Sun","doi":"10.1002/mef2.70053","DOIUrl":"10.1002/mef2.70053","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Cell&lt;/i&gt;, Xu et al. developed a “programmable” delivery system using IgE-sensitized mast cells as antigen-triggerable carriers for oncolytic viruses (OVs). This strategy achieves precise, on-demand viral release within the tumor microenvironment (TME) while simultaneously harnessing intrinsic degranulation and chemotactic capacities to transform mast cells from passive vehicles into potent immune “accelerators” that amplify antitumor immunity [&lt;span&gt;1&lt;/span&gt;] (Figure 1).&lt;/p&gt;&lt;p&gt;Oncolytic viruses have emerged as a promising platform that bridges direct tumor lysis and in situ vaccine effects. However, their clinical translation has been persistently constrained by two major bottlenecks. First, following systemic administration, OVs are readily cleared from circulation, exhibit heterogeneous intratumoral distribution, and are substantially neutralized by pre-existing or treatment-induced antiviral antibodies [&lt;span&gt;2, 3&lt;/span&gt;]. Second, even when OVs successfully reach tumors, the immunosuppressive TME often limits dendritic cell (DC) activation and effector T-cell expansion, resulting in an insufficient immune cascade [&lt;span&gt;4, 5&lt;/span&gt;]. Against this backdrop, the selection of mast cells as delivery vehicles by Xu et al. [&lt;span&gt;1&lt;/span&gt;] is far from incidental. Mast cells express high levels of FcεRI on their surface and rapidly undergo degranulation upon IgE crosslinking, releasing cytokines and chemokines that reshape the local immune niche—an intrinsic mechanism ideally suited for spatiotemporally controlled release and immune recruitment amplification.&lt;/p&gt;&lt;p&gt;The study first established and characterized IgE-sensitized mast cells (IgE-MCs). Structurally, scanning electron microscopy revealed corresponding changes in cell morphology and surface features following sensitization and activation. Functionally, antigen stimulation induced robust secretion of TNF-α, IL-6, CCL2, and CCL3, and pharmacological inhibitor pretreatment confirmed the controllability of this activation pathway. Furthermore, through live-cell imaging and confocal z-stack analyses, the authors visualized dynamic interactions between IgE-MCs and tumor cells, as well as granule-associated behaviors. In tumor tissues, alterations in the abundance and enrichment of CD117⁺FcεRI⁺ mast cells were observed. Notably, single-cell transcriptomic profiling and clustering of intratumoral CD45⁺ immune cells demonstrated markedly enhanced immune infiltration following IgE-MC treatment, with gene expression patterns consistent with CD8⁺ T-cell migration. Among these, the CCL3 axis was specifically identified through gene-editing and migration assays as a key driver of activated CD8⁺ T-cell chemotaxis and intratumoral accumulation.&lt;/p&gt;&lt;p&gt;Building upon this foundation, Xu et al. developed the OV@IgE-MC delivery system. Confocal and transmission electron microscopy clearly showed that OVs could be loaded into mast cells and associated with granule structures. ","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70053","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy in Advanced Gastric Cancer: Advancing Precision Medicine and Emerging Therapeutic Strategies","authors":"Li Zhang,&nbsp;Qihua Zhang,&nbsp;Xueliang Zhang,&nbsp;Aihong Mao,&nbsp;Yuhua Liu,&nbsp;Huiyan Luo","doi":"10.1002/mef2.70051","DOIUrl":"https://doi.org/10.1002/mef2.70051","url":null,"abstract":"<p>Advanced gastric cancer (GC) continues to pose a substantial global health burden, with traditional treatment modalities providing only modest clinical benefit. In recent years, immunotherapy has emerged as a transformative strategy, and immune checkpoint inhibitors (ICIs) have revolutionized the treatment of numerous cancers, including hematologic malignancies, melanoma, and lung cancer. Clinical studies have established that immunotherapy also improves survival in advanced GC, yet critical issues remain regarding the identification of optimal candidates, the clarification of efficacy for monotherapy or combination strategies, and the exploration of potential biomarkers for immunotherapy. This review delineates therapeutic strategies involving ICIs for advanced GC, including single-agent, combination therapy, and dual-ICI approaches. The review also provides a critical appraisal of the utility of biomarkers for predicting therapeutic response, a summary of the current state of CAR-T cell therapy, and an overview of ongoing investigations into cancer vaccines. A strategic framework for the selection of immunotherapy in advanced GC is also proposed. Precision-based strategies have potential in enhancing treatment efficacy and reducing the financial burden of the patient. Despite the paradigm shift brought by immunotherapy in advanced GC, immune-related adverse events (irAEs) remain a significant clinical hurdle. A detailed discussion of these events is beyond the scope of this review due to space constraints.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial Proteotoxicity: A New Frontier in Type 2 Diabetes?","authors":"Junlin Wei,&nbsp;Fang Wang","doi":"10.1002/mef2.70054","DOIUrl":"10.1002/mef2.70054","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Nature Metabolism&lt;/i&gt;, Li et al. [&lt;span&gt;1&lt;/span&gt;] identified mitochondrial proteotoxicity due to impaired protein folding as a key driver of β-cell failure in type 2 diabetes (T2D), shifting the focus from canonical endoplasmic reticulum (ER) stress paradigms. The chaperone function of the LONP1–mitochondrial heat shock protein 70 (mtHSP70) axis was found to be essential for maintaining mitochondrial proteostasis, offering a novel therapeutic target for preserving β-cell function in diabetic patients.&lt;/p&gt;&lt;p&gt;The global prevalence of T2D is projected to exceed 1.3 billion by 2050, underscoring the urgent need to identify novel mechanisms of β-cell failure and druggable targets. Large-scale genome-wide association study (GWAS) and multi-omics technologies have advanced our understanding of T2D's genetic heterogeneity. A trans-ancestry meta-analysis of over 2.5 million individuals identified eight mechanistic clusters, each with distinct clinical manifestations and complication risks, highlighting the necessity for targeted therapies to enable precise treatment.&lt;/p&gt;&lt;p&gt;While ER stress has long been implicated in β-cell dysfunction, Li et al. provide compelling evidence that mitochondrial proteotoxicity represents an earlier and more prominent event in human T2D islets. Using unbiased proteomics, they found significant enrichment of insoluble mitochondrial protein aggregates in islets from T2D donors, a signature distinct from ER protein misfolding. The mitochondrial protease LONP1 was identified as a crucial guardian against this proteotoxicity, with its expression notably reduced in T2D β-cells. Using β-cell-specific &lt;i&gt;Lonp1&lt;/i&gt; knockout mice, the authors demonstrated that LONP1 deficiency recapitulates key features of human T2D islets observed in their proteomic analysis, including accumulation of misfolded mitochondrial proteins, bioenergetic deficits, oxidative stress, and β-cell apoptosis. Direct causal evidence in human islets, however, remains to be established. Most importantly, LONP1 protects β-cells via a protease-independent, chaperone-like function by forming a complex with mitochondrial HSP70. The structural basis involves LONP1's chaperone domain interacting with mtHSP70's substrate-binding domain, though the regulation of this complex under diabetic stress requires further investigation. Furthermore, the study linked inadequate adaptive response in T2D to downregulation of ATF5, a known regulator of the mitochondrial unfolded protein response and direct transcriptional activator of &lt;i&gt;LONP1&lt;/i&gt; (Figure 1).&lt;/p&gt;&lt;p&gt;However, to fully appreciate the implications of Li et al.'s findings on LONP1, they must be contextualized within the highly integrated mitochondrial quality control (MQC) network. Mitochondria maintain proteostasis through a coordinated system involving compartment-specific proteases, chaperones, and organellar dynamics. Furthermore, the inner membrane protein TMBIM5 directly binds and inh","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147585248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DYRK Family: A Key Regulator of Metabolic Homeostasis and Its Therapeutic Potential in Kidney Diseases","authors":"Yixuan Zhu,&nbsp;Pengfei Qiao,&nbsp;Yukun Gan,&nbsp;Xiushuo Fu,&nbsp;Xiayue Huang,&nbsp;Sirui Sun,&nbsp;Yafei Gou,&nbsp;Wenjie Xia,&nbsp;Feng Ma,&nbsp;Limin Liu","doi":"10.1002/mef2.70050","DOIUrl":"https://doi.org/10.1002/mef2.70050","url":null,"abstract":"<p>The dual-specificity tyrosine-regulated kinase (DYRK) family, a conserved serine/threonine kinase group, plays a pivotal role in the regulation of metabolic homeostasis by modulating glucose/lipid metabolism, oxidative stress, and calcium-phosphorus balance. Mammalian DYRKs are classified into Class I (DYRK1A and DYRK1B) and Class II (DYRK2, DYRK3, and DYRK4) based on their structural differences, tissue-specific expression, and functional diversity in maintaining systemic metabolic balance. Dysregulation of DYRK-mediated metabolic homeostasis drives the progression of metabolic kidney diseases, key complications of chronic kidney disease. Specifically, DYRK1A aggravates diabetic nephropathy and renal fibrosis; DYRK1B mutations directly trigger mTORC2-mediated lipotoxicity and insulin resistance, promoting glomerulosclerosis; DYRK2 disrupts calcium-phosphorus metabolism and aggravates renal vascular calcification via the Notch/Wnt pathway. DYRK-targeted inhibitors, including harmine, AZ191, and curcumin, have shown therapeutic potential in promoting β-cell regeneration, alleviating metabolic disorders, and suppressing fibrosis. However, insufficient tissue targeting and off-target risks remain critical bottlenecks for clinical translation. Future efforts should integrate gene editing with kidney-specific delivery technologies to enhance therapeutic precision. This review systematically summarizes the structural and functional bases of the DYRK family, its regulatory role in metabolic homeostasis, and its therapeutic prospects in related renal diseases, providing new strategies for precise intervention.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147568054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The DYRK Family: A Key Regulator of Metabolic Homeostasis and Its Therapeutic Potential in Kidney Diseases","authors":"Yixuan Zhu,&nbsp;Pengfei Qiao,&nbsp;Yukun Gan,&nbsp;Xiushuo Fu,&nbsp;Xiayue Huang,&nbsp;Sirui Sun,&nbsp;Yafei Gou,&nbsp;Wenjie Xia,&nbsp;Feng Ma,&nbsp;Limin Liu","doi":"10.1002/mef2.70050","DOIUrl":"https://doi.org/10.1002/mef2.70050","url":null,"abstract":"<p>The dual-specificity tyrosine-regulated kinase (DYRK) family, a conserved serine/threonine kinase group, plays a pivotal role in the regulation of metabolic homeostasis by modulating glucose/lipid metabolism, oxidative stress, and calcium-phosphorus balance. Mammalian DYRKs are classified into Class I (DYRK1A and DYRK1B) and Class II (DYRK2, DYRK3, and DYRK4) based on their structural differences, tissue-specific expression, and functional diversity in maintaining systemic metabolic balance. Dysregulation of DYRK-mediated metabolic homeostasis drives the progression of metabolic kidney diseases, key complications of chronic kidney disease. Specifically, DYRK1A aggravates diabetic nephropathy and renal fibrosis; DYRK1B mutations directly trigger mTORC2-mediated lipotoxicity and insulin resistance, promoting glomerulosclerosis; DYRK2 disrupts calcium-phosphorus metabolism and aggravates renal vascular calcification via the Notch/Wnt pathway. DYRK-targeted inhibitors, including harmine, AZ191, and curcumin, have shown therapeutic potential in promoting β-cell regeneration, alleviating metabolic disorders, and suppressing fibrosis. However, insufficient tissue targeting and off-target risks remain critical bottlenecks for clinical translation. Future efforts should integrate gene editing with kidney-specific delivery technologies to enhance therapeutic precision. This review systematically summarizes the structural and functional bases of the DYRK family, its regulatory role in metabolic homeostasis, and its therapeutic prospects in related renal diseases, providing new strategies for precise intervention.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147567754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs in Methamphetamine: Addiction, Neurotoxicity, and Therapeutic Potential","authors":"Yacoubou Abdoul Razak Mahaman,&nbsp;An-Ping Ye,&nbsp;Ya-Xian Zhang,&nbsp;Ming-Yu Chen,&nbsp;Fang Huang,&nbsp;Rong Liu,&nbsp;Ying-Yan Fang,&nbsp;Xiaochuan Wang","doi":"10.1002/mef2.70049","DOIUrl":"https://doi.org/10.1002/mef2.70049","url":null,"abstract":"<p>Drug addiction is a debilitating condition that causes severe mental and physical impairments. Methamphetamine (METH) is one of the most commonly abused psychostimulants, mainly affecting the brain by releasing dopamine and serotonin. METH addiction has become a serious public health issue, and there is currently no specific treatment available. Although scientists have a good understanding of the mechanisms underlying drug addiction, including METH, our current biological and molecular knowledge of addiction is still incomplete. There is substantial evidence that addiction-related changes are primarily mediated through gene expression regulation. Interestingly, the involvement of microRNAs (miRNAs) in this process could enhance our understanding of the molecular mechanisms underlying METH addiction. Therefore, further understanding the mechanisms behind METH-induced differential changes in miRNAs, along with their pharmacological and genetic manipulation, could lead to promising new treatments for METH addiction. In this study, we first summarized epidemiological data and the addictive and neurotoxic mechanisms of METH, extensively reviewed studies on miRNA expression changes, discussed potential miRNA-targeted therapeutic interventions for METH addiction, and outlined future research directions. We believe this study will provide a clearer understanding of the role of miRNAs in METH addiction and may help scientists develop more effective therapeutic strategies.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147566099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs in Methamphetamine: Addiction, Neurotoxicity, and Therapeutic Potential","authors":"Yacoubou Abdoul Razak Mahaman,&nbsp;An-Ping Ye,&nbsp;Ya-Xian Zhang,&nbsp;Ming-Yu Chen,&nbsp;Fang Huang,&nbsp;Rong Liu,&nbsp;Ying-Yan Fang,&nbsp;Xiaochuan Wang","doi":"10.1002/mef2.70049","DOIUrl":"https://doi.org/10.1002/mef2.70049","url":null,"abstract":"<p>Drug addiction is a debilitating condition that causes severe mental and physical impairments. Methamphetamine (METH) is one of the most commonly abused psychostimulants, mainly affecting the brain by releasing dopamine and serotonin. METH addiction has become a serious public health issue, and there is currently no specific treatment available. Although scientists have a good understanding of the mechanisms underlying drug addiction, including METH, our current biological and molecular knowledge of addiction is still incomplete. There is substantial evidence that addiction-related changes are primarily mediated through gene expression regulation. Interestingly, the involvement of microRNAs (miRNAs) in this process could enhance our understanding of the molecular mechanisms underlying METH addiction. Therefore, further understanding the mechanisms behind METH-induced differential changes in miRNAs, along with their pharmacological and genetic manipulation, could lead to promising new treatments for METH addiction. In this study, we first summarized epidemiological data and the addictive and neurotoxic mechanisms of METH, extensively reviewed studies on miRNA expression changes, discussed potential miRNA-targeted therapeutic interventions for METH addiction, and outlined future research directions. We believe this study will provide a clearer understanding of the role of miRNAs in METH addiction and may help scientists develop more effective therapeutic strategies.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70049","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147566098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitoxyperilysis: A Milestone Discovery in the Field of Cell Death","authors":"Maochen Li,&nbsp;Yuhan Niu,&nbsp;Pengtao Jiao","doi":"10.1002/mef2.70048","DOIUrl":"https://doi.org/10.1002/mef2.70048","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Cell&lt;/i&gt;, Wang and colleagues unveiled a previously unrecognized form of lytic cell death, termed “mitoxyperilysis,” triggered by mitochondria-induced oxidative damage (Figure 1a) [&lt;span&gt;1&lt;/span&gt;]. This work not only provides critical insights into how mitochondrial dysfunction and oxidative stress drive pathogenesis but also presents a potential strategy for treating oxidative stress-associated diseases.&lt;/p&gt;&lt;p&gt;Metabolic homeostasis is crucial for both cells and organisms, and metabolic dysregulation contributes to diverse pathologies, including cancer, non-alcoholic fatty liver disease, and diabetes [&lt;span&gt;2&lt;/span&gt;]. Innate immune activation and metabolic disruption (IIAMD) often occur simultaneously and jointly drive disease progression. For example, malignant cells undergo metabolic reprogramming characterized by lactate accumulation and hypoxia [&lt;span&gt;3&lt;/span&gt;]. The metabolic alterations promote the release of damage-associated molecular patterns (DAMPs), initiate innate immune pathways (e.g., TLR and NLRP3), and finally lead to various forms of cell death (Figure 1b,c) [&lt;span&gt;2&lt;/span&gt;]. Cell death accompanied by impaired membrane integrity and the release of cellular contents further amplifies inflammatory cascades, establishing a feed-forward loop of DAMP release—inflammation—cell death, ultimately resulting in a pathological state [&lt;span&gt;2&lt;/span&gt;]. Although mitochondrial oxidative stress is implicated in various cell death pathways, the mechanisms by which it drives membrane lysis, particularly under IIAMD, remain poorly understood. This necessitates a deeper investigation into how mitochondrial state dictates cell fate and fuels disease progression.&lt;/p&gt;&lt;p&gt;To mimic IIAMD, Wang Y and colleagues treated bone-marrow-derived macrophages (BMDMs) with innate immune stimulants, including PAM3, LPS, R848, and Poly[I:C] under carbon starvation (CS) [&lt;span&gt;1&lt;/span&gt;]. Interestingly, neither innate immune activation nor CS-induced metabolic stress alone induced cell death. However, in the presence of CS, all stimulants except Poly[I:C] triggered robust lytic cell death, characterized by the release of plasma membrane rupture markers LDH and HMGB1, with LPS exhibiting the strongest effect. Consistently, the supplementation of glucose, glutamine, or pyruvate alone suppressed cell death induced by IIAMD. These findings suggest that innate immune triggering and metabolic stress are necessary and sufficient to induce cell death.&lt;/p&gt;&lt;p&gt;The most disruptive aspect of this work is the unveiling of mitoxyperilysis. To investigate whether cell death under IIAMD is induced by canonical pathways, the genetic ablation of key executioners of apoptosis (e.g., Caspase-9), pyroptosis (e.g., NLRP3 and Gasdermin family members such as GSDMD, GSDME, and GSDMC4), and necroptosis (e.g., MLKL) was performed [&lt;span&gt;1&lt;/span&gt;]. However, the genetic ablation did not markedly attenuate IIAMD-induced membrane rupture. Beyond canonical pathways,","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147562895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitoxyperilysis: A Milestone Discovery in the Field of Cell Death","authors":"Maochen Li,&nbsp;Yuhan Niu,&nbsp;Pengtao Jiao","doi":"10.1002/mef2.70048","DOIUrl":"https://doi.org/10.1002/mef2.70048","url":null,"abstract":"&lt;p&gt;In a recent study published in &lt;i&gt;Cell&lt;/i&gt;, Wang and colleagues unveiled a previously unrecognized form of lytic cell death, termed “mitoxyperilysis,” triggered by mitochondria-induced oxidative damage (Figure 1a) [&lt;span&gt;1&lt;/span&gt;]. This work not only provides critical insights into how mitochondrial dysfunction and oxidative stress drive pathogenesis but also presents a potential strategy for treating oxidative stress-associated diseases.&lt;/p&gt;&lt;p&gt;Metabolic homeostasis is crucial for both cells and organisms, and metabolic dysregulation contributes to diverse pathologies, including cancer, non-alcoholic fatty liver disease, and diabetes [&lt;span&gt;2&lt;/span&gt;]. Innate immune activation and metabolic disruption (IIAMD) often occur simultaneously and jointly drive disease progression. For example, malignant cells undergo metabolic reprogramming characterized by lactate accumulation and hypoxia [&lt;span&gt;3&lt;/span&gt;]. The metabolic alterations promote the release of damage-associated molecular patterns (DAMPs), initiate innate immune pathways (e.g., TLR and NLRP3), and finally lead to various forms of cell death (Figure 1b,c) [&lt;span&gt;2&lt;/span&gt;]. Cell death accompanied by impaired membrane integrity and the release of cellular contents further amplifies inflammatory cascades, establishing a feed-forward loop of DAMP release—inflammation—cell death, ultimately resulting in a pathological state [&lt;span&gt;2&lt;/span&gt;]. Although mitochondrial oxidative stress is implicated in various cell death pathways, the mechanisms by which it drives membrane lysis, particularly under IIAMD, remain poorly understood. This necessitates a deeper investigation into how mitochondrial state dictates cell fate and fuels disease progression.&lt;/p&gt;&lt;p&gt;To mimic IIAMD, Wang Y and colleagues treated bone-marrow-derived macrophages (BMDMs) with innate immune stimulants, including PAM3, LPS, R848, and Poly[I:C] under carbon starvation (CS) [&lt;span&gt;1&lt;/span&gt;]. Interestingly, neither innate immune activation nor CS-induced metabolic stress alone induced cell death. However, in the presence of CS, all stimulants except Poly[I:C] triggered robust lytic cell death, characterized by the release of plasma membrane rupture markers LDH and HMGB1, with LPS exhibiting the strongest effect. Consistently, the supplementation of glucose, glutamine, or pyruvate alone suppressed cell death induced by IIAMD. These findings suggest that innate immune triggering and metabolic stress are necessary and sufficient to induce cell death.&lt;/p&gt;&lt;p&gt;The most disruptive aspect of this work is the unveiling of mitoxyperilysis. To investigate whether cell death under IIAMD is induced by canonical pathways, the genetic ablation of key executioners of apoptosis (e.g., Caspase-9), pyroptosis (e.g., NLRP3 and Gasdermin family members such as GSDMD, GSDME, and GSDMC4), and necroptosis (e.g., MLKL) was performed [&lt;span&gt;1&lt;/span&gt;]. However, the genetic ablation did not markedly attenuate IIAMD-induced membrane rupture. Beyond canonical pathways,","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70048","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147562894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}