Clinical and Translational Medicine最新文献

{"title":"Integrative single-cell analysis uncovers distinct tumour microenvironment ecotypes and immune evasion across skin cancers","authors":"Lingjuan Huang, Huihui Hou, Xiyuan Zhang, Liang Dong, Wensheng Shi, Mason Liu, Jie Sun, Anil Prakash, Haoqiu Song, Shiyao Pei, Xin Li, Xiang Chen, Shenglin Mei, Mingzhu Yin","doi":"10.1002/ctm2.70611","DOIUrl":"10.1002/ctm2.70611","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Skin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), cutaneous melanoma (CM) and acral melanoma (AM), exhibit profound heterogeneity in clinical behaviour and therapeutic response. However, how tumour-immune ecosystems are remodelled across skin cancer types and disease stages, and how these changes influence immune escape and treatment resistance, remain poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we integrate single-cell transcriptomics data from 102 skin cancer samples (including adjacent normal skin, early-stage and advanced-stage tumours), with bulk RNA-seq prognosis cohorts, immunofluorescence staining and in vitro assays to define clinically relevant immune remodelling patterns.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our analyses identify a malignant <i>NARS2<sup>+</sup>NDUFC2<sup>+</sup></i> melanoma cell subpopulation, characterised by reduced MHC-I expression, enriched in advanced-stage tumours and associated with worse survival and immunotherapy response. CRISPR screening further showed that <i>NARS2</i> and <i>NDUFC2</i> are necessary for the proliferation of melanoma cells, highlighting these genes as potential therapeutic targets. Tumour-associated macrophages (TAMs) originate from both <i>FCN1</i><sup>+</sup> monocytes and <i>FOLR2<sup>+</sup></i> tissue-resident macrophages, displaying two polarisation states with distinct prognostic associations. Specifically, pro-inflammatory <i>CXCL9<sup>+</sup>CXCL10<sup>+</sup></i> TAMs are enriched in SCC, while tissue-remodelling <i>SPP1</i><sup>+</sup> TAMs are predominant in melanoma. Immunofluorescence staining confirmed that <i>SPP1</i><sup>+</sup> macrophage accumulation correlates with advanced stage, metastasis and poor prognosis in the melanoma cohort. Immune ecotype analysis reveals a transition from ‘T-cell-dominant’ ecotypes to ‘desert’ ecotypes as disease advances in BCC, CM and AM. Cell‒cell communication analysis shows that ‘T-cell-dominant’ ecotypes have higher MHC-I signalling pathways in tumour cells, whereas ‘Desert’ ecotypes have higher <i>SPP1<sup>+</sup></i> macrophage signalling, underlining the role of <i>SPP1</i> on immune remodelling. Functional assays confirm that melanoma cells could drive M2 polarisation and SPP1 upregulation in macrophages. Knocking down or overexpressing <i>SPP1</i> correspondingly alters M2 gene expression in macrophages.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study establishes a pan-skin cancer immune remodelling framework, pr","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12869349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146112494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell analysis reveals cytotoxic and memory CD8+ T cells associated with prolonged survival in relapsed/refractory leukaemia patients after haplo+cord haematopoietic stem cell transplantation","authors":"Hua Li,&nbsp;Zheyang Zhang,&nbsp;Ming Zhu,&nbsp;Xiaofan Li,&nbsp;Jinxian Dai,&nbsp;Ping Chen,&nbsp;Fei Chen,&nbsp;Xianling Chen,&nbsp;Yiding Yang,&nbsp;Xiaohong Yuan,&nbsp;Ronghan Tang,&nbsp;Zhijuan Zhu,&nbsp;Hongli Lin,&nbsp;Ting Lin,&nbsp;Mengsha Tong,&nbsp;Tao Chen,&nbsp;Yuanzhong Chen,&nbsp;Jialiang Huang,&nbsp;Nainong Li","doi":"10.1002/ctm2.70529","DOIUrl":"10.1002/ctm2.70529","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Backgroud</h3>\u0000 \u0000 <p>Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for haematological malignancies. Sequential transplantation of haploidentical stem cell and umbilical cord blood (haplo+cord HSCT) among recipients with relapsed/refractory (R/R) leukaemia exhibited superior survival outcomes compared with single cord HSCT. However, the underlying mechanisms remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, we profiled and compared single-cell gene expression and chromatin accessibility in bone marrow from 16 patients receiving haplo+cord or single cord HSCT.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed distinct compositions and functions of global immune landscapes, with haplo+cord HSCT exhibiting effective anti-tumour and anti-viral immunity mediated by type I interferon signalling. Analysis of T cells revealed specific CD8⁺ T cell subtype (CD8-c1), enriched in recipients with haplo+cord HSCT, which was also confirmed by flow cytometry. Functionally, gene signature scoring suggests a dual effector and memory property of CD8-c1 that potentially offers long-term protection. Furthermore, single-cell multi-omics analysis delineated the expression of cytotoxic-related genes up-regulated in CD8-c1 are cooperatively regulated by enhancer networks. Notably, a proportion-based survival analysis indicated that high proportion of CD8-c1 was associated with better survival.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results collectively demonstrate that a population of CD8⁺ T cells with effector and memory properties contributes to improved survival in patients with R/R leukaemia receiving haplo+cord HSCT.</p>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146118151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How generative AI reconfigure clinician–AI and clinician–patient relationships","authors":"Tianyi Shen,&nbsp;Xinru Wang,&nbsp;Yajuan Zhang,&nbsp;Yi Zhang","doi":"10.1002/ctm2.70606","DOIUrl":"10.1002/ctm2.70606","url":null,"abstract":"&lt;p&gt;The rapid uptake of generative AI (GAI) systems in clinical settings—particularly large language models (LLMs) such as DeepSeek—marks a transformative moment for healthcare and necessitates timely regulatory responses to protect safety and equity. In current practice, LLM-based GAI is entering clinical practice through a distinctive ‘dual-interface’ configuration. On one side, models locally deployed or fine-tuned by healthcare institutions are embedded into hospital information systems and patient-facing portals to streamline care processes, support clinical decision-making and facilitate personal health management.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; On the other, general-purpose models developed by companies, such as OpenAI, Google and DeepSeek, are reaching clinicians and patients through a growing ecosystem of chatbot applications.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;These channels make GAI increasingly accessible to both sides of the medical encounter. Clinicians use GAI to retrieve medical knowledge, generate analytic reasoning and obtain suggestions for diagnostic and therapeutic decisions (DTD).&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Simultaneously, patients consult these models about symptoms, use them to interpret complex clinical rationales and review clinicians’ recommendations.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; This dual-interface setting is shifting healthcare away from two separate dyads—‘clinician–patient’ and ‘clinician–AI tool’ (Figure 1A)—toward a configuration where multiple human–AI relations coexist (Figure 1A–D).&lt;/p&gt;&lt;p&gt;This Letter examines two linked axes of change. First, when GAI operates as an interactive cognitive collaborator, it enters the clinician-led chain-of-thought (CoT). In configuration (B), a previously clear ‘clinician–tool’ relation becomes a clinician–AI collaboration requiring a redefinition of roles. Second, when systems capable of generating clinical CoT interact directly with patients and act as decision-making agents, configurations (C)–(D) recast the clinician–patient relationship—its modes of explanation, patient involvement and trust—into a tripartite arrangement that explicitly includes AI.&lt;/p&gt;&lt;p&gt;For decades, medical AI—from rule-based expert systems to deep learning models—was positioned as a ‘tool’. These systems rarely prompted fundamental debate about role sharing,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; because they did not enter the core CoT that structures clinical practice: the process from problem formulation and evidence integration to DTD, which we refer to as the CoT for clinical reasoning and decision-making (clinical CoT).&lt;/p&gt;&lt;p&gt;In the traditional configuration (Figure 1A), the clinical CoT is held exclusively by the clinician. AI systems are invoked only at specific points at the clinician's discretion. Even when they ‘compute faster’, they primarily extend perceptual capacities and function as citable evidence or auxiliary signals rather than genuine ‘speakers’ in clinical deliberation. This configuration persisted because clini","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12865223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioswitches: Towards programmable, on-demand control of therapeutic proteins","authors":"Benedict Wolf,&nbsp;Jan Mathony,&nbsp;Dominik Niopek","doi":"10.1002/ctm2.70612","DOIUrl":"10.1002/ctm2.70612","url":null,"abstract":"&lt;p&gt;Modern biomedicine increasingly relies on proteins as functional agents such as engineered antibodies, cytokines, or CRISPR genome editors. Most of these molecules act continuously as long as they are present in the body. This can pose challenges, particularly when pharmacokinetics is long-lived. Adverse effects such as off-target activity and toxicity may arise in consequence of prolonged drug activity and are difficult to mitigate once a patient has received the therapeutic. This is most extreme in gene-based approaches, where therapeutic proteins are often continuously expressed in engineered cells or in vivo. A prominent example is CAR-T cell therapy, in which patient-derived T cells are modified to express tumour-targeting receptors and can persist for months, or even years, after infusion. Similarly, in vivo gene supplementation therapy commonly relies on long-term viral vector-mediated expression, often intended for a lifetime. These modalities would strongly benefit from the ability to control effector protein activity post-delivery, enabling dose adjustment and rapid risk mitigation if adverse effects should arise.&lt;/p&gt;&lt;p&gt;A compelling solution is to convert proteins into controllable nano-devices, which we here term &lt;b&gt;&lt;i&gt;Bioswitches&lt;/i&gt;&lt;/b&gt;. In our definition, a Bioswitch is an effector protein functionally coupled to a fused sensory domain, enabling reversible ON/OFF control by a defined stimulus such as small molecules, light, or changes in temperature (Figure 1A). This control mechanism relies on allostery, where protein activity is regulated by a sensory module detecting the presence or absence of a stimulus. This induces a local conformational change which is then transmitted, sometimes over long distances, to the protein's functional site, thereby modulating activity (Figure 1A). Owing to its central role in natural proteins, Jacques Monod famously referred to allostery as the “second secret of life”.&lt;/p&gt;&lt;p&gt;To build Bioswitches based on allostery, domain insertion engineering is commonly applied. In short, sensory domains are artificially transplanted into effector proteins via genetic fusion. This approach, however, has been bottlenecked by the challenge of identifying domain insertion sites in effector proteins suitable for sensor fusion, that is sites that preserve function while enabling strong stimulus-dependent regulation through allosteric coupling.&lt;/p&gt;&lt;p&gt;In Wolf et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;, we introduced ProDomino (Protein Domain Insertion Optimizer), a machine-learning pipeline that predicts possible domain insertion sites in custom effector proteins to enable rapid creation of Bioswitches. ProDomino was trained on a large protein sequence dataset that captures natural domain-domain coupling. Specifically, the dataset was built from proteins in which evolution has “nested” one domain within another, a phenomenon that implies structural compatibility and interdomain communication. Operationally, ProDomino takes a cus","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12865224/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell and spatial transcriptomics uncover neoadjuvant chemotherapy-resistant malignant cells with inhibitory signalling on B cells in gastric cancer","authors":"Pei-Yi Han,&nbsp;Xiang-Xi Ye,&nbsp;Xiao Yang,&nbsp;Lin Li,&nbsp;Xuan Zhao,&nbsp;Yan-Fei Shao,&nbsp;Jing Sun,&nbsp;Lu Zang,&nbsp;Ze-Guang Han,&nbsp;Min-Hua Zheng","doi":"10.1002/ctm2.70600","DOIUrl":"10.1002/ctm2.70600","url":null,"abstract":"&lt;p&gt;Dear editor,&lt;/p&gt;&lt;p&gt;Patients with advanced gastric cancer (GC) often receive the neoadjuvant therapy with variable responsiveness. Here, we conducted single-cell RNA sequencing on tumour tissues from GC patients receiving neoadjuvant chemotherapy, integrated with spatial transcriptomics analysis, revealing that resistance to neoadjuvant chemotherapy appears to be driven by SPP1-CD44 axis, which drives immunosuppressive crosstalk between apoptosis-resistant undifferentiated malignant cells and B cells.&lt;/p&gt;&lt;p&gt;GC remains one of the leading causes of cancer-related mortality worldwide.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Neoadjuvant chemotherapy has become a standard treatment modality for these patients with advanced GC but does not always yield satisfactory outcomes.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Activating of anti-apoptotic signalling pathways,&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; the immunosuppressive microenvironment tumour-associated macrophages (TAMs) and regulatory T cells (Tregs) may contribute to the resistance to chemotherapy.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Recent studies have shown that activated B cells can enhance anti-tumour responses by secreting antibodies and cytokines,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; but B cells can also be reprogrammed to promote tumour growth and immune evasion.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; The underlying molecular and cellular characteristics remain unclear.&lt;/p&gt;&lt;p&gt;In this study, we performed multi-omics analysis on tumour tissues from five patients (including 3 responders and 2 non-responders) treated with DOS, SOX and XELOX regimens for 3 or 4 cycles (Table S1), according to the response evaluation criteria in solid tumours (RECIST).&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Whole-exome sequencing revealed that somatic mutations in some genes existed in the residual tumours of all five patients. Interestingly, amongst these genes, ATR, a master regulator of cellular responses to DNA replication stress; ABCB1, an ATP-dependent drug efflux pump for xenobiotic compounds; and NSD1, a histone methyltransferase, have been reported to be involved in anticancer drug resistance. In addition, the mutations of &lt;i&gt;EPB41L3&lt;/i&gt;, &lt;i&gt;TFG&lt;/i&gt;, &lt;i&gt;TAL2&lt;/i&gt;, &lt;i&gt;WWTR1&lt;/i&gt; and &lt;i&gt;ARIH1&lt;/i&gt; were observed in responders, whereas nonsynonymous SNV and frameshift deletion in &lt;i&gt;CCNB1IP&lt;/i&gt; existed in the non-responders (Figure 1A,B). COSMIC signature analysis showed that SBS24 and SBS36, which are respectively associated with aflatoxin exposure and defective base excision repair, appeared to have more contribution in responders (Figure 1C). Transcriptomic analysis showed 161 upregulated and 439 downregulated genes in non-responders (Figure 1D). Interestingly, gene ontology (GO) enrichment analysis revealed suppressed immune response and antibody production in non-responders (Figure 1E).&lt;/p&gt;&lt;p&gt;Furthermore, single-cell RNA sequencing of 36,910 cells identified 8 major cell types (Figure 1F–H). Amongst these, epithelial cells, fibroblasts and smooth muscle cells were enriched in non-responders, ","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12865221/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T-cell exhaustion from a multiomics perspective: Differentiation mechanisms and regulatory networks in the journey from progenitor-Exhausted T cells to terminally exhausted T cells","authors":"Tong Zhu,&nbsp;Xiaoyu Teng,&nbsp;Qinlian Jiao,&nbsp;Yidan Ren,&nbsp;Yunshan Wang,&nbsp;Maoxiao Feng","doi":"10.1002/ctm2.70609","DOIUrl":"10.1002/ctm2.70609","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>A central hurdle limiting the success of T-cell-based immunotherapies is the progressive dysfunction of T cells, known as exhaustion. Overcoming this exhausted state is therefore a pivotal objective in translational oncology and immunology. The advent of single-cell multiomics has fundamentally revised the once-prevailing view of exhaustion as a uniform endpoint. Instead, it is now recognised as a dynamic differentiation process comprising a spectrum of distinct cellular states. This spectrum is organised along a hierarchical axis, originating from progenitor-exhausted (Tpex) cells that retain proliferative potential and advancing towards terminally exhausted (Tex) populations with severely impaired effector functions. We undertake a comprehensive synthesis of multiomics data—spanning transcriptomic, epigenomic, metabolomic, proteomic and posttranslational modification (PTM)-proteomic layers—to decipher the interconnected regulatory programmes that dictate commitment along this exhaustion axis. From this integrated analysis, we derive a unified mechanistic framework that delineates the molecular drivers of Tpex cell fate determination and terminal exhaustion. Beyond its explanatory power for basic biology, this framework serves as a direct roadmap for therapeutic innovation, highlighting novel nodes for intervention aimed at reinvigorating the exhausted T-cell compartment. The practical application of these insights holds significant promise for enhancing the efficacy of established current immunotherapeutic platforms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key points</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>This review is the first to integrate multi-omics evidence for constructing a dynamic regulatory map of T-cell exhaustion.</li>\u0000 \u0000 <li>It highlights the critical cross-omics synergistic mechanisms, such as metabolic reprogramming influencing epigenetic remodeling to drive cell fate.</li>\u0000 \u0000 <li>The multi-omics perspective presented directly informs novel therapeutic strategies.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12865229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146104417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glycolysis enzymes and cellular lactylation in tumour.","authors":"Chenyuan Dai, Lihua Wang","doi":"10.1002/ctm2.70549","DOIUrl":"https://doi.org/10.1002/ctm2.70549","url":null,"abstract":"<p><p>Cellular lactylation, a recently identified post-translational modification, has emerged as a crucial regulator in various biological processes, particularly in cancer. The discovery of lactylation provides a new perspective for understanding the functional significance of the Warburg effect in tumour cells. Enzymes involved in the glycolytic pathway modulate lactylation, influencing tumour genesis and progression. This review explores the intricate relationship between glycolysis, lactylation and tumour biology, with a focus on how enzymes participating in glycolysis impact lactylation in cancer cells. We discuss how glycolytic enzymes regulate lactylation and highlight their broader implications in tumour biology. The role of lactylation in shaping the tumour microenvironment underscores its increasing significance as a biomarker for cancer prognosis and a target for therapeutic intervention. Therefore, we also summarised the potential of targeting lactylation as a cancer therapy strategy. KEY POINTS: Glycolytic enzymes regulate lactylation in cancer cells. Lactylation drives tumour growth, metastasis, immune evasion and contributes to microenvironment remodelling Targeting lactylation holds promise for cancer therapy.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":"e70549"},"PeriodicalIF":6.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Milk fat globule-EGF factor 8/ATP-binding cassette subfamily E member 1 axis maintains mitophagy flux homeostasis to suppress ferroptosis in acute pancreatitis.","authors":"Yifan Ren, Yuxuan Lu, Qing Cui, Hao Shang, Meng Fan, Yun Sun, Xiali Shi, Rongqian Wu, Hongwei Lu","doi":"10.1002/ctm2.70619","DOIUrl":"https://doi.org/10.1002/ctm2.70619","url":null,"abstract":"<p><strong>Background: </strong>Acute pancreatitis (AP) is a severe inflammatory disorder in which mitochondrial dysfunction and ferroptosis critically drive acinar cell injury. Our previous work suggested a protective role for exogenous milk fat globule-epidermal growth factor 8 (MFG-E8) in AP. This study aimed to elucidate the molecular mechanism by which endogenous MFG-E8 mitigates mitochondrial damage and ferroptosis during AP.</p><p><strong>Methods: </strong>Two mouse models of AP were used for in vivo studies, while cerulein + lipopolysaccharide-induced mitophagy and ferroptosis in AR42J cells (cells of the rat exocrine pancreas) for in vitro studies. Mfge8 gene-defective mice and lentivirus were utilised to downregulate MFG-E8 expression in mice and overexpress MFG-E8 in cells, respectively. Dual gene modification was employed to overexpress MFG-E8 and simultaneously knockdown adenosine triphosphate (ATP)-binding cassette subfamily E member 1 (ABCE1) in vitro. One mitophagy agonist and two ferroptosis inhibitors were used in both in vitro and in vivo experiments.</p><p><strong>Results: </strong>Endogenous MFG-E8 expression was downregulated in experimental AP. Genetic deletion of Mfge8 aggravated mitochondrial ultrastructural damage, impaired mitophagy flux and intensified ferroptosis, as evidenced by increased lipid peroxidation, Fe²⁺ accumulation and depletion of glutathione peroxidase. Lentiviral overexpression of MFG-E8 in AR42J acinar cells restored mitophagy activity, preserved mitochondrial membrane potential and reduced oxidative stress. Mechanistically, co-immunoprecipitation confirmed that MFG-E8 directly interacts with ABCE1, a key mitophagy regulator. ABCE1 knockdown abolished the protective effects of MFG-E8 on mitochondrial function and ferroptosis suppression, indicating that the MFG-E8/ABCE1 axis is essential for maintaining mitophagy homeostasis. Pharmacological restoration of mitophagy or inhibition of ferroptosis rescued acinar cell injury caused by MFG-E8/ABCE1 dysregulation. In vivo, ferroptosis inhibition significantly improved pancreatic pathology and survival in Mfge8-deficient AP mice.</p><p><strong>Conclusion: </strong>Endogenous MFG-E8 protects against AP by binding ABCE1 to sustain mitophagy flux and inhibit ferroptosis. Targeting this axis offers a promising therapeutic strategy for mitigating pancreatic injury.</p><p><strong>Key points: </strong>Endogenous MFG-E8 is downregulated in acute pancreatitis (AP), disrupting MFG-E8/ABCE1 complex formation. MFG-E8/ABCE1 axis sustains Parkin-PINK1-mediated mitophagy to clear damaged mitochondria in pancreatic acinar cells. This axis suppresses ferroptosis by reducing Fe²⁺ accumulation and lipid peroxidation, alleviating AP-related pancreatic injury.</p>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":"e70619"},"PeriodicalIF":6.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLINICAL AND TRANSLATIONAL MEDICINE","authors":"","doi":"10.1002/ctm2.70613","DOIUrl":"10.1002/ctm2.70613","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70613","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146162408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HepAssis2^® bioartificial liver system in treating acute-on-chronic liver failure patients: Findings from a phase 1 randomised, open-label clinical trial.","authors":"Zibiao Zhong, Wenjin Liang, Yong'an Dai, Chengbiao Xue, Dawei Zhou, Zhigao Xu, Ling Li, Li Pan, Chongxiang He, Xin Zhou, Wei Zhou, Lihua Zhou, Zhongzhong Liu, Zhiping Xia, Xiaoli Fan, Guizhu Peng, Yanfeng Wang, Ping Zhou, Shaojun Ye, Qifa Ye","doi":"10.1002/ctm2.70620","DOIUrl":"https://doi.org/10.1002/ctm2.70620","url":null,"abstract":"","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"16 2","pages":"e70620"},"PeriodicalIF":6.8,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146212298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}