MedComm - Future medicine最新文献

{"title":"Advancing Surgical Practice With Mixed Reality: Current Innovations and Future Prospects","authors":"Yifan Ke,&nbsp;Kunpeng Hu","doi":"10.1002/mef2.70043","DOIUrl":"https://doi.org/10.1002/mef2.70043","url":null,"abstract":"<p>Mixed reality is an immersive visualization technology based on simultaneous localization and mapping systems and standalone head-mounted displays. It enables seamless integration and dynamic interaction among users, virtual elements, and the physical environment. Although numerous clinical studies and in vitro experiments have confirmed the value of mixed reality in surgical practice, the hierarchy of evidence remains limited. This review draws on published English-language literature to summarize its technical foundations, clinical applications, current innovations, and existing challenges. Specifically, the primary procedures of mixed reality-assisted surgery consist of three-dimensional reconstruction, holographic visualization, and spatial registration. Its clinical applications span preoperative planning, intraoperative navigation, surgical training, and postoperative rehabilitation. However, current limitations include insufficient computational and display capabilities of head-mounted displays, inadequate accuracy in spatial registration, high costs, workflow complexity, and unresolved ethical concerns. Therefore, we recommend increased resource allocation for technological innovations, multicenter randomized controlled clinical trials, and detailed risk-benefit assessments, aiming to establish and validate standardized clinical workflows. As the first comprehensive narrative review to compare the clinical applicability of mixed reality across all surgical specialties, this article outlines future research directions by analyzing representative clinical studies and offers a reliable report on current progress.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145887289","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":"Air Pollution-Induced Epigenetic Regulation in Respiratory Diseases: Mechanisms, Dysregulation, and Therapeutic Opportunities","authors":"Ruitong Zeng,&nbsp;Jiliu Liu,&nbsp;Guoping Li,&nbsp;Junyi Wang,&nbsp;Anying Xiong,&nbsp;Ying Xiong,&nbsp;Xiang He","doi":"10.1002/mef2.70044","DOIUrl":"https://doi.org/10.1002/mef2.70044","url":null,"abstract":"<p>Air pollution poses a significant threat to respiratory health globally, contributing to the development and worsening of diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and lung cancer. A key mechanism behind this involves epigenetic reprogramming, where environmental exposures alter gene activity without changing the underlying DNA sequence itself. This review deciphers the multilayered epigenetic mechanisms linking pollutants (e.g., PM_2.5, cigarette smoke, and ozone) to respiratory pathology, emphasizing reversible modifications that bridge environmental exposure and disease phenotypes. Air pollution-induced epigenetic reprogramming regulates critical biological processes, such as immune imbalance, chronic inflammation, oxidative stress, cellular dysfunction (senescence, apoptosis, and ferroptosis), tissue remodeling (epithelial–mesenchymal transition and fibrosis), and genomic instability. Specifically, aberrant DNA methylation, dysregulated RNA methylation, perturbed noncoding RNA networks, and histone modification abnormalities collectively drive disease pathogenesis. Furthermore, emerging epigenetic therapies targeting these modifications, such as DNA methyltransferase inhibitors (5-AZADC), histone deacetylase inhibitors, and RNA methylation regulators (methyltransferase-like 3 inhibitor STM2457), show promising therapeutic potential. This review highlights the reversibility of epigenetic changes as a strategic basis for intervention, emphasizing the need for future research on mixed exposures, tissue-specific mechanisms, and clinical translation to mitigate the global burden of pollution-related respiratory diseases.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145824856","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":"Artificial Intelligence in Traditional Chinese Medicine: Bridging Ancient Practice and Future Innovation","authors":"Zhehan Jiang,&nbsp;Quanming Peng,&nbsp;Li Li,&nbsp;Shate Xiang","doi":"10.1002/mef2.70042","DOIUrl":"https://doi.org/10.1002/mef2.70042","url":null,"abstract":"<p>Traditional Chinese Medicine (TCM), with its fragmented knowledge system, subjective diagnostics, and limited standardization, faces ongoing challenges in modernization. The rapid development of Large Language Models (LLMs) offers an unprecedented opportunity for the digitalization and standardization of TCM knowledge. By leveraging deep semantic understanding, contextual reasoning, and knowledge-graph–based inference, LLMs can systematize knowledge, integrate multimodal data, and support both standardized and personalized decision-making. Several TCM–LLMs, such as Qibo and MedChatZH, have been developed. Although previous reviews compared individual TCM–LLMs, a comprehensive analysis of common characteristics is lacking. This review addresses this gap by examining the “construction–application–challenges–prospects” paradigm of TCM–LLMs. Construction generally involves collecting authoritative data from diverse sources, standardizing textual content, training and fine-tuning on foundational LLMs, and subsequent evaluation. Key applications include auxiliary diagnosis and treatment, health management, medical education, and drug discovery. Five major challenges are data quality, reasoning performance, multimodal integration, ethical and regulatory compliance, and cultural adaptability. On the basis of this analysis, we propose a classification scheme that categorizes applications into four types and adopt the identified challenges as evaluation dimensions for future TCM–LLMs. This framework aims to clarify conceptual structures, guide methodology, and provide a foundation for innovation and cross-cultural integration in TCM research.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145750836","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":"Optogenetic Regulation of Integrated Stress Responses: Developing Novel Broad-Spectrum Antiviral Strategies","authors":"Shizhan Cui,&nbsp;Zehan Pang,&nbsp;Bixia Hong","doi":"10.1002/mef2.70040","DOIUrl":"https://doi.org/10.1002/mef2.70040","url":null,"abstract":"&lt;p&gt;In a recent publication in &lt;i&gt;Cell&lt;/i&gt;, Wong et al. presented an optogenetic system for screening compounds that specifically modulate the integrated stress response (ISR) [&lt;span&gt;1&lt;/span&gt;]. The authors identified eight non-cytotoxic ISR enhancers as broad-spectrum antiviral agents and revealed their key mechanism: the selective targeting of general control nonderepressible 2 (GCN2) to upregulate activating transcription factor 4 (ATF4) expression, thereby sensitizing cells to stress and apoptosis [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Optogenetics enables precise spatiotemporal control of cellular activity by conferring light sensitivity via heterologous expression of photosensitive proteins. This approach is increasingly being integrated with synthetic biology to facilitate novel paradigms in phenotypic drug discovery [&lt;span&gt;2&lt;/span&gt;]. Meanwhile, the ISR pathway represents a conserved signaling pathway activated by four stress sensor kinases—heme-regulated inhibitor (HRI), protein kinase R (PKR), protein kinase R-like ER kinase (PERK), and GCN2—which respond to diverse stressors such as viral double-stranded RNA [&lt;span&gt;3&lt;/span&gt;]. Upon activation, these kinases phosphorylate the eukaryotic translation initiation factor 2 subunit alpha (eIF2α), leading to the selective translation of ISR-related proteins, such as ATF4, C/EBP homologous protein (CHOP), and growth arrest and DNA damage-inducible protein 34 (GADD34), thereby modulating cell survival and function. Given this regulatory capacity, ISR-enhancing compounds represent a novel strategy for the development of broad-spectrum antiviral therapeutics [&lt;span&gt;3&lt;/span&gt;]. The combination of optogenetics-driven precise manipulation and deeper exploration of the ISR network—particularly its crosstalk with other signaling pathways—may open breakthrough directions for future broad-spectrum antiviral research.&lt;/p&gt;&lt;p&gt;To achieve precise control of the ISR pathway, Taivan et al. developed an optogenetic platform that dynamically stimulates the ISR signaling using a light-activated optogenetic PKR (opto-PKR) [&lt;span&gt;4&lt;/span&gt;]. The dsRBM1 and dsRBM2 regions of PKR were replaced with an optimized mutant of the &lt;i&gt;Arabidopsis&lt;/i&gt; blue light receptor Cry, namely Cry2Olig (E490G). Upon transduction of opto-PKR into cells, exposure to blue light prompted Cry2 aggregation, inducing in PKR oligomerization, kinase activation, and subsequent initiation of ISR. This light-controlled system simulates PKR-mediated ISR activation as observed during viral infection, while avoiding off-target cytotoxicity [&lt;span&gt;4&lt;/span&gt;]. The platform's efficacy was validated through both pharmacological activators and inhibitors of the ISR pathway (Figure 1a) [&lt;span&gt;1&lt;/span&gt;]. Crucially, unlike traditional small-molecule stressors that often cause cross-pathway interference, this approach minimizes such off-target effects and offers immediate deactivation in darkness, enabling transient response unattainable with conventional small-molecule activators.","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695083","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":"Global Burden and Future Projections of Urological Cancers: A Comprehensive Analysis From the Global Burden of Disease Study 2021","authors":"Mengyi Zhu,&nbsp;Haoxuan Wang,&nbsp;Haishan Lin,&nbsp;Guibin Hong,&nbsp;Yun Wang,&nbsp;Fan Jiang,&nbsp;Ye Xie,&nbsp;Runnan Shen,&nbsp;Hongkun Yang,&nbsp;Shaoxu Wu","doi":"10.1002/mef2.70041","DOIUrl":"https://doi.org/10.1002/mef2.70041","url":null,"abstract":"<p>Urological cancers represent a significant and growing global health challenge. This study aims to provide a comprehensive assessment of the global burden, trends, and inequalities of prostate, bladder, and kidney cancers from 1990 to 2021, and to project their future burden to 2050. Utilizing data from the Global Burden of Disease Study 2021, we analyzed incidence, prevalence, mortality, and disability-adjusted life years (DALYs). We employed joinpoint regression to analyze temporal trends, frontier analysis to evaluate healthcare efficiency, and Bayesian age-period-cohort models to project future burden. Risk factor attributions were also quantified. In 2021, prostate cancer demonstrated the highest age-standardized rates across all metrics. From 1990 to 2021, age-standardized mortality and DALY rates declined for all three cancers. The burden was disproportionately higher among males and older populations, with smoking, high fasting plasma glucose, and high body-mass index identified as leading risk factors. Projections to 2050 indicate a continued decline in all age-standardized rates globally. Despite favorable trends in standardized rates, persistent sex disparities, growing absolute case numbers due to population aging, and the influence of modifiable risk factors necessitate targeted public health interventions and strategic healthcare planning.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70041","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619225","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":"Charting the Shared Genetic Architecture Between Breast Cancer and Major Depressive Disorder","authors":"Yilong Lin,&nbsp;Yuning Wang,&nbsp;Ruidan Zhao,&nbsp;Liyi Zhang,&nbsp;Qingmo Yang","doi":"10.1002/mef2.70039","DOIUrl":"https://doi.org/10.1002/mef2.70039","url":null,"abstract":"&lt;p&gt;Individuals suffering from major depressive disorder (MDD) have been reported to be more susceptible to cancer. A recent meta-analysis revealed that individuals with MDD or anxiety had a moderately elevated likelihood of developing cancer (RR = 1.13, 95% CI = 1.06–1.19) and a higher probability of cancer-related death (RR = 1.21, 95% CI = 1.16–1.26) [&lt;span&gt;1&lt;/span&gt;]. The increased susceptibility to cancer among individuals with MDD may arise from multiple mechanisms. On one hand, patients suffering from this disorder are often less likely to participate in early cancer detection and screening programs. On the other hand, dysregulation of neuroendocrine pathways in MDD may further contribute to tumor progression by altering immune function, promoting chronic inflammation, and affecting tumor biology [&lt;span&gt;2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Specially, individuals with MDD also had a higher risk of breast cancer compared to those without MDD [&lt;span&gt;3&lt;/span&gt;], and those patients with both diseases tended to have poorer BC outcomes [&lt;span&gt;2&lt;/span&gt;]. In addition, up to 60% of women experience depression before and throughout their BC diagnosis, affecting women of all races and ages [&lt;span&gt;2&lt;/span&gt;]. However, these observational studies may have been affected by confounding factors and biases.&lt;/p&gt;&lt;p&gt;In this study, we employed a genome-wide cross-trait analysis to chart the shared genetic architecture between BC and MDD, further exploring the genetic and phenotypic relationships. The overview of this study was shown in Figure S1. The genome-wide association studies (GWAS) data of BC and MDD were obtained from The Breast Cancer Association Consortium and Discovery, Biology and Risk of Inherited Variants in Breast Cancer Consortium, and Psychiatric Genomics Consortium. First, we conducted a genetic correlation analysis using linkage disequilibrium score regression (LDSC). Then, we employed two cross-trait meta-analysis methods (the multi-trait analysis of GWAS [MTAG] and the Cross-Phenotype Association analysis [CPASSOC]) to identify common risk SNPs associated with BC and MDD. In addition, pleiotropic analysis under composite null hypothesis (PLACO) was used to identify pleiotropic loci associated with BC and MDD. Based on PLACO analysis, we identified potential pleiotropic loci and genes through Functional Mapping and Annotation of Genetic Associations (FUMA) tool and multimarker analysis of GenoMic annotation (MAGMA) analysis. Finally, we conducted Generalized summary-data-based Mendelian randomization (GSMR) and two-sample Mendelian Randomization (TSMR) to identify the causal associations. MR analysis relies on three core assumptions: (1) the genetic variants used as instrumental variables (IVs) are strongly associated with the exposure; (2) these IVs are independent of confounding factors; and (3) they affect the outcome only through the exposure. The SNPs were selected based on commonly accepted criteria in MR studies: (i) genome-wide significance with a &lt;i&gt;p&lt;/i&gt; ","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145625976","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":"Evaluating the Survival Impact of Neoadjuvant Therapy and Development of Personalized Machine Learning Survival Predictive Model for Breast Cancer Patients Eligible for Breast-Conserving Surgery","authors":"Zhicheng Du,&nbsp;Yongqu Zhang,&nbsp;Weibin Li,&nbsp;Xue Zhao,&nbsp;Xueqi Fan,&nbsp;Jingwen Bai,&nbsp;Guojun Zhang","doi":"10.1002/mef2.70036","DOIUrl":"https://doi.org/10.1002/mef2.70036","url":null,"abstract":"<p>The long-term survival benefit of neoadjuvant therapy (NAT) in breast cancer patients eligible for breast-conserving surgery (BCS) remains uncertain. This retrospective cohort study analyzed 94,677 BCS-eligible patients from the SEER database (2010–2020), including 8565 who received NAT. After propensity score matching (<i>n</i> = 5734 each), NAT significantly improved overall survival (OS) only in patients with triple-negative (HR = 0.79), ER-negative (HR = 0.80), and stage IIA (HR = 0.81) disease. No OS benefit was observed in HER2-positive patients despite high response rates. To guide treatment decisions, two machine learning models using Random Survival Forest were developed to predict 5-year OS, showing good discrimination (C-index: 0.743 for BCS, 0.690 for NAT-BCS). SHAP analysis identified age, stage, and breast subtype as key prognostic factors. Cross-stratification based on predicted OS revealed that 8.9% of BCS patients could benefit from NAT, while 90.8% of NAT-BCS patients might safely omit it. Patients whose treatment matched model recommendations had significantly better survival. These findings suggest that NAT provides limited survival benefit in BCS-eligible patients, with the advantage concentrated in specific subgroups. Predictive modeling offers a clinically useful approach to personalize NAT use, potentially reducing unnecessary treatment while identifying those most likely to benefit.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572234","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":"REV-ERBα–Mediated Hepatic Regulation of Cachexia: A Circadian-Metabolic Axis of Tissue Wasting","authors":"Wenhui Wang,&nbsp;Junke Song,&nbsp;Gaofei Wei","doi":"10.1002/mef2.70038","DOIUrl":"https://doi.org/10.1002/mef2.70038","url":null,"abstract":"<p>In the recent article published in <i>Cell</i> [<span>1</span>], Kaltenecker et al. systematically uncovered the liver as an active pathological driver of cancer cachexia (CCx). Through integrated multi-omics analysis, the study identifies the downregulation of the circadian regulator REV-ERBα (nuclear receptor subfamily 1 group D member 1, NR1D1) as a central mechanism that disrupts hepatic homeostasis and induces abnormal secretion of hepatokines, thereby promoting peripheral tissue wasting. These findings provide a conceptual framework for developing therapeutic strategies targeting the “liver–peripheral tissue” axis in CCx.</p><p>Cancer cachexia is a highly catabolic metabolic syndrome associated with advanced malignancies, characterized by progressive weight loss, skeletal muscle atrophy, and adipose tissue degradation [<span>2, 3</span>]. It is particularly prevalent in pancreatic, gastric, and lung cancers, affecting 50%–80% of patients and accounting for approximately 20% of cancer-related deaths. While previous studies have predominantly focused on local mechanisms of muscle atrophy, such as the ubiquitin-proteasome system (UPS), autophagy, and the NF-κB or FOXO pathways, the systemic metabolic functions of the liver in CCx pathogenesis remain underexplored. Notably, a concurrent study by Garrett et al. published in Cell demonstrated that tumor-driven inflammation can alter the vagal nerve–liver axis, resulting in suppression of hepatic HNF4α and exacerbation of systemic catabolism, further highlighting the critical involvement of the liver in this condition [<span>4</span>].</p><p>Given the pivotal role of the liver in systemic metabolism, the authors hypothesized that tissue wasting in cachexia may originate from hepatic responses to tumor-derived signals, which drive peripheral tissue catabolism through the secretion of specific factors. To investigate this, Kaltenecker et al. performed integrated transcriptomic and epigenomic profiling of hepatocytes from both weight-stable and cachectic cancer mouse models. These analyses uncovered a distinct transcriptional program specific to cachexia, characterized by dysregulated expression of the circadian regulator REV-ERBα. Hepatic restoration of REV-ERBα expression markedly attenuated both muscle and fat wasting. Mechanistically, REV-ERBα modulates tissue degradation by controlling hepatokines that activate catabolic pathways in myotubes and adipocytes. Notably, clinical data further revealed elevated circulating levels of key hepatokines in cachectic patients, independent of classical inflammatory cytokines such as IL-6 or TNF-α, underscoring a novel “hepatokine-peripheral tissue” axis in CCx pathophysiology.</p><p>Delving further into molecular effectors, the authors identified three key liver-secreted proteins-lipopolysaccharide-binding protein (LBP), inter-α-trypsin inhibitor heavy-chain H3 (ITIH3), and insulin-like-growth-factor-binding protein 1 (IGFBP1)–as direct targets of REV-ERB","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469712","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 Sentinel's Betrayal: A STING-Driven Necroptotic Axis in Caspase-8-Deficient Pathology and STING-Associated Vasculopathy With Onset in Infancy (SAVI)","authors":"Xin He,&nbsp;Bin Wang,&nbsp;Long Zhang","doi":"10.1002/mef2.70037","DOIUrl":"https://doi.org/10.1002/mef2.70037","url":null,"abstract":"&lt;p&gt;In a recent publication in Nature, Kelepouras et al. [&lt;span&gt;1&lt;/span&gt;] reveal a new function of STING in regulating programmed cell death. The study identifies that the absence of &lt;i&gt;Caspase-8&lt;/i&gt; leads to abnormal activation of the cGAS–STING signaling pathway, which induces the upregulation of ZBP1 and MLKL and licenses necroptosis independently of TNFR1 and FADD. Crucially, the authors also demonstrate that aberrant activation of STING, whether caused by Caspase-8 loss or by gain-of-function mutation in &lt;i&gt;Sting1&lt;/i&gt;, invariably drives inflammatory necroptosis [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Necroptosis is a programmed cell death pathway executed by RIPK3 and mixed lineage kinase domain-like (MLKL), that has been shown to be involved in various inflammatory diseases and tissue injuries [&lt;span&gt;2&lt;/span&gt;]. Caspase-8 is a key negative regulator of necroptosis Its deficiency permits aberrant activation of the pathway and causes lethal inflammation in development or in a tissue-selective manner. Deletion of TNFR1 can modestly delay dermatitis by inhibiting canonical necrosome assembly. These findings indicate that necroptosis can be activated independently of TNF-induced, FADD-mediated recruitment of RIPK1 and RIPK3 [&lt;span&gt;3&lt;/span&gt;]. However, the upstream signal source and the main regulatory factors remain unclear at this point. STING as a core factor in cellular DNA recognition and the interferon pathway, has traditionally been considered to mainly participate in antiviral and innate immunity, but whether it can be associated with necroptosis has no direct evidence in the past. Deletion of Sting ameliorated the lethal dermatitis caused by loss of Caspase-8 in keratinocytes, providing direct genetic evidence for STING involvement in the observed skin pathology.&lt;/p&gt;&lt;p&gt;Genetic and biochemical evidence indicates that STING agonists enhance TNF-induced cell death in a RIPK3- and MLKL-dependent manner. ZBP1 is essential for the sensitization mediated by STING, and its deletion can completely block STING-induced necroptosis. Genetic and biochemical analysis further shows that STING upregulates ZBP1 and promotes formation of a FADD- and TNFR1-independent ZBP1–RIPK1–RIPK3 complex, thereby triggering necroptosis. Mechanistically, STING upregulates Zbp1 expression via downstream interferon-stimulated gene (ISG) signaling and promotes cytosolic Z-DNA accumulation, which binds to the Zα domains of ZBP1 to initiate activation. ZBP1 then interacts with RIPK1 and RIPK3 through its RHIM domains, forming a FADD- and TNFR1-independent complex that drives necroptosis.&lt;/p&gt;&lt;p&gt;In vivo experiments showed that &lt;i&gt;Casp8&lt;/i&gt;&lt;sup&gt;&lt;i&gt;E-KO&lt;/i&gt;&lt;/sup&gt; mice exhibited severe dermatitis and early death, while simultaneous knockout of STING or TNFR1 could notably delay the progression of inflammation and improve survival, suggesting that STING plays a key role in the pathogenesis of skin inflammation. Histological and molecular analysis further confirmed that STING deficiency specifically","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70037","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145469711","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":"A Machine Learning-Optimized Immunogenic Cell Death Signature Reveals Tumor Immunogenicity and the Immunotherapy Response of Pancancer","authors":"Li Qiu,&nbsp;Danqing Huang,&nbsp;Yuening Zhang,&nbsp;Yingying Zhou,&nbsp;Ming Luo,&nbsp;Chengdong Zhang,&nbsp;Ying Huang,&nbsp;Mingyuan Zou,&nbsp;Wenlong Lu,&nbsp;Hui Liu,&nbsp;Shaowei Liu,&nbsp;Haoyang Huang,&nbsp;Kaiwen Ye,&nbsp;Yuan Hui,&nbsp;Cheng Tang,&nbsp;Zilong Yan,&nbsp;Xi Zhong,&nbsp;Zhiguo Luo,&nbsp;Hongxin Huang,&nbsp;Ming Zhou,&nbsp;Guangshuai Jia,&nbsp;Qibin Leng,&nbsp;Jun Liu","doi":"10.1002/mef2.70035","DOIUrl":"https://doi.org/10.1002/mef2.70035","url":null,"abstract":"<p>Tumor immunogenicity determines their response to immune checkpoint inhibitors (ICIs), but the mechanisms governing pancancer immunogenicity remain incompletely understood. A further critical barrier to developing reliable predictive biomarkers is data set shift, which undermines model generalizability. Here, we address these challenges by developing a novel adversarial validation (AV)-integrated machine learning framework, focusing on immunogenic cell death (ICD)-related gene signatures (ICDRSs). We designed three AV-based strategies to mitigate data set shift and validate the efficacies across multiple machine learning algorithms. Using dual-modal data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), four optimal AV-based classifiers (e.g., GradientBoosting, XGBoost, LGBM, and CatBoost) were screened, which effectively reduced inter-cohort shift, enhancing both accuracy and robustness of downstream analysis. We identified novel risk/protective ICDRSs that strongly predicted patient survival and tumor immunogenicity across cancers. High-risk ICDRSs correlated with immune-exclusive microenvironments marked by impaired antigen presentation and aberrant tumor-associated macrophage development, as revealed by single-cell RNA sequencing. Validation across 13 ICI-treated cohorts revealed the capacity of ICDRSs for anti-PD-1 nonresponse. Mechanistically, risk ICDRSs were linked to CD47-SIRPA-mediated immune evasion and proliferative macrophage subsets with terminal dysfunction. This study advances understanding of tumor immunogenicity, provides novel biomarker development tools, and supports personalized cancer immunotherapy decision-making.</p>","PeriodicalId":74135,"journal":{"name":"MedComm - Future medicine","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/mef2.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145296960","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}