Frontiers in Cell and Developmental Biology最新文献

{"title":"ANGPTL2 and CP define complementary circadian-associated signals in atrial fibrillation: integrative transcriptomics and external validation.","authors":"Jiahui Wang, Jintao Qian, Junhao Zhang, Guoyu Cao, Boyang Chen, Jian Shi, Qing Zhou","doi":"10.3389/fcell.2026.1949794","DOIUrl":"https://doi.org/10.3389/fcell.2026.1949794","url":null,"abstract":"<p><strong>Introduction: </strong>Atrial fibrillation (AF) develops through the interplay of electrical, structural, inflammatory, and metabolic remodeling. However, the circadian-associated molecular characteristics of the diseased human atrium remain incompletely understood.</p><p><strong>Methods: </strong>We integrated differential expression analysis, circadian gene intersection, weighted gene co-expression network analysis, and complementary feature selection algorithms in a discovery cohort. The prioritized candidate genes were subsequently validated using an independent atrial dataset, human atrial rhythmicity data, single-nucleus transcriptomics, and experimental evidence derived from human and mouse atrial tissues. We additionally performed cross-cohort drug repurposing screening and exploratory molecular docking.</p><p><strong>Results: </strong>ANGPTL2 and CP were identified as prioritized candidate genes associated with circadian rhythms. Both genes were consistently upregulated in fibrillating atria but exhibited distinct expression profiles: ANGPTL2 demonstrated stronger discriminatory power at the tissue level, whereas CP showed a larger but more heterogeneous expression alteration. Both genes displayed rhythmic expression patterns in human atrial appendage tissue and were predominantly enriched in vascular and stromal cell populations, establishing a link between temporal atrial biology and inflammatory-metabolic remodeling as well as copper-redox remodeling. The upregulation of their transcripts and proteins was further validated across independent human samples and an arrhythmia-prone mouse model. No compound met the prespecified multi-source criteria for cross-cohort drug repurposing. An independent exploratory analysis of clinically used antiarrhythmic drugs identified favorable molecular docking profiles for both target proteins.</p><p><strong>Discussion: </strong>ANGPTL2 and CP are externally validated circadian rhythm-associated candidate genes for atrial fibrillation (AF), and may yield experimentally testable candidate gene-drug pairs. However, these findings do not establish causal regulation by the circadian clock, direct molecular binding, or clinical therapeutic efficacy.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1949794"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635327/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149105911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular analysis of Aldh1a2 conditional inactivation in developing limbs reveals mechanisms of retinoic-acid mediated interdigital apoptosis.","authors":"Rodrigue Peraldi, Yacine Kherdjemil, Gabriel Villiard, Nayuta Yakushiji-Kaminatsui, Marie Kmita","doi":"10.3389/fcell.2026.1913173","DOIUrl":"https://doi.org/10.3389/fcell.2026.1913173","url":null,"abstract":"<p><strong>Introduction: </strong>Retinoic acid (RA) plays a plethora of functions during embryonic development as well as post-natal life. In particular, RA function during limb development is associated with interdigital cell death. However, the molecular mechanism(s) through which RA signaling contributes to interdigital cell death remains poorly understood.</p><p><strong>Methods: </strong>To gain insights into the mechanism(s) involved, we used a conditional approach to inactivate the RA catalyzing enzyme Aldh1a2 thereby abrogating RA signaling in the distal limb.</p><p><strong>Results and discussion: </strong>Our data first show that <i>Aldh1a2</i> mutant limb buds are characterized by a lack of apoptosis in the interdigital region, which results in a very severe syndactyly phenotype at birth. Molecular analysis of <i>Aldh1a2</i> mutant distal limb buds reveals that RA regulates the expression of several key genes in the interdigital tissue related to apoptosis in the limb and to the extracellular matrix degradation. The decreased expression of these genes in <i>Aldh1a2</i> mutant limb buds correlates with a decreased activity of their putative regulatory elements bound by the retinoic acid receptors supporting that these genes are possibly direct RA targets. We also identified mild skeletal defects in <i>Aldh1a2</i> conditional mutant, as newborns have smaller digits. This latter phenotype is associated with the decreased expression of genes important for chondrocytes differentiation and proliferation, notably <i>Ihh</i>, <i>Foxc2</i> and <i>Igf1</i>. Finally, we show that the distal expression of <i>Aldh1a2</i> likely relies on the function of <i>Hoxa13</i> and <i>Hoxd13</i> establishing a potential cascade of molecular events responsible for the interdigit tissue regression.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1913173"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The silent dialogue between cells: regulatory roles of non-coding RNAs in cardiovascular disease.","authors":"Zhongwen Zhang, Yufei Yang, Mengzhen Liu, Hang Zhang, Zhaoyu Li, Jingjing Zhang, Haolong Zhang","doi":"10.3389/fcell.2026.1921212","DOIUrl":"https://doi.org/10.3389/fcell.2026.1921212","url":null,"abstract":"<p><p>Non-coding RNAs (ncRNAs) are involved in the occurrence, progression, and repair of cardiovascular disease By post-transcriptional regulation, epigenetic modification, cell-fate determination, and metabolic homeostasis-related pathways, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) regulate the development of atherosclerosis heart failure and hypertension The stability in circulation and cell type-specific expression of these molecules have important implications for early disease detection, risk stratification, and prognostic prediction. The development of more sensitive detection techniques facilitates accurate quantification of ncRNAs in different sources including exosomes, plasma or tissues and promotes translational research. Interventions directed toward the regulation of ncRNAs, such as miRNA inhibition or replacement and modulation of lncRNAs and circRNAs are being developed. Despite existing challenges related to ncRNA delivery, specificity, and methodological standardization, ncRNAs represent promising molecular signatures for personalized medicine. Integrated use of multi-omics, clinical phenotypes and computational algorithms is anticipated to optimize an ncRNA-guided precision management pipeline from diagnosis to prediction and treatment.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1921212"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated single-cell and multi-cohort analyses reveal CTCF as a key regulator of chemo-immunotherapy resistance in lung adenocarcinoma.","authors":"Hui Chen, Taiyang Zhang, Yiwei Zhang, Mohan Li, Haoran Yang, Yue Zhang, Feng Xu","doi":"10.3389/fcell.2026.1922944","DOIUrl":"https://doi.org/10.3389/fcell.2026.1922944","url":null,"abstract":"<p><strong>Background: </strong>Chemo-immunotherapy has improved clinical outcomes in non-small cell lung cancer (NSCLC), but resistance remains a major challenge. The tumor cell states and molecular mechanisms underlying treatment resistance are not fully understood.</p><p><strong>Methods: </strong>Single-cell RNA sequencing data from NSCLC patients receiving chemo-immunotherapy were integrated with public transcriptomic cohorts and functional experiments. Resistance-associated tumor cell populations were identified, and key regulatory factors were investigated through bioinformatic analyses and experimental validation.</p><p><strong>Results: </strong>Single-cell analysis identified a malignant epithelial cell subpopulation enriched in patients with stable disease, suggesting a resistance-associated tumor cell state. Genes derived from this population were associated with unfavorable prognosis and were used to construct a prognostic model with consistent performance across multiple independent cohorts. Among the candidate genes, CTCF was identified as a key regulator associated with poor survival and reduced immune infiltration. In an orthotopic lung tumor model, Ctcf knockdown enhanced the antitumor efficacy of pemetrexed combined with anti-PD-1 treatment and promoted CD8⁺ T-cell activity. Mechanistically, CTCF directly upregulated RRM2 and CD276, which mediated chemotherapy resistance and immune suppression, respectively.</p><p><strong>Conclusion: </strong>Our findings identify CTCF as a critical regulator of chemo-immunotherapy resistance in NSCLC. The CTCF-RRM2/CD276 axis links tumor-intrinsic drug resistance with immune evasion and may represent a potential therapeutic target.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1922944"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635359/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell death pathways in the pathogenesis of depression: mechanisms and therapeutic implications.","authors":"Yuting Xiong, Yuxin Zhang, Hongxin Zhou, Gui Xiao","doi":"10.3389/fcell.2026.1966325","DOIUrl":"https://doi.org/10.3389/fcell.2026.1966325","url":null,"abstract":"<p><p>Depression is a highly prevalent and disabling psychiatric disorder with a complex and incompletely understood pathophysiology. Increasing evidence implicates regulated cell death (RCD), including apoptosis, necroptosis, pyroptosis, and ferroptosis, in neuronal vulnerability, synaptic impairment, and circuit dysfunction associated with depression. This review provides a comprehensive overview of the current understanding of distinct cell death modalities in animal models of depression and human brain tissues, with particular emphasis on their molecular mechanisms and pathological consequences. We further discuss the intricate interactions between cell death pathways and key pathological processes implicated in depression, including neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired neurotrophic support. In addition, we summarize emerging therapeutic strategies targeting cell death-associated signaling pathways, including pharmacological inhibition of specific cell death programs and modulation of shared upstream regulators. By integrating recent advances in molecular neuroscience and psychiatric research, this review provides a conceptual framework for elucidating the cellular mechanisms underlying depression and to highlight potential targets for the development of novel antidepressant therapies.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1966325"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathogenic mechanisms of adult degenerative scoliosis.","authors":"Hongqi Deng, Pengfei Ji, Xiaoling Wang, Yandi Cheng, Peng Wang, Wenjie Liu","doi":"10.3389/fcell.2026.1949453","DOIUrl":"https://doi.org/10.3389/fcell.2026.1949453","url":null,"abstract":"<p><p>Adult degenerative scoliosis (ADS) is not merely a unidimensional sagittal decompensation, but rather a three-dimensional pathological process driven by asymmetric degeneration of intervertebral discs, endplates, facet joints, and paraspinal muscles, wherein coronal scoliosis, sagittal imbalance, and vertebral axial rotation mutually couple and amplify one another. Endplate tilting and nucleus pulposus displacement convert segmental mechanics to an asymmetric pattern, representing the initiating event; all three axes are reciprocally driven through facet joints and ligamentous tension, forming a self-amplifying progression loop; paraspinal muscles on the convex and concave sides exhibit opposing degenerative patterns that exacerbate instability; facet joint sagittalization transitions scoliosis from a compensable to a structurally fixed state; bone density loss and genetic susceptibility modulate individual progression rates. This review systematically synthesizes the above mechanisms and proposes a Three-Axis Reciprocal Coupling Pathogenic Model as a conceptual, hypothesis-generating framework, and discusses potential mechanism-informed intervention directions together with the limitations of the current evidence base. ADS is best understood as a systemic musculoskeletal syndrome involving multiple tissue systems, and this conceptualization may carry implications for early identification and precision intervention pending further validation.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1949453"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13634614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated sperm DNA fragmentation is associated with embryonic developmental attrition after fertilization in conventional IVF cycles.","authors":"Lijun Peng, Mengyi Zhu, Tengfei Wang, Sheng Yang, Yun Le","doi":"10.3389/fcell.2026.1925444","DOIUrl":"https://doi.org/10.3389/fcell.2026.1925444","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The influence of sperm DNA fragmentation on conventional &lt;i&gt;in vitro&lt;/i&gt; fertilization (IVF) outcomes remains controversial, particularly regarding whether its embryological relevance is expressed during fertilization or subsequent embryo development. This study aimed to evaluate the association between sperm DNA fragmentation index (DFI) and stage-specific embryological transition outcomes in a retrospective cohort of first eligible conventional IVF cycles.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This retrospective cohort study included 1,423 first eligible conventional IVF cycles selected from fresh oocyte-retrieval treatment cycles recorded between August 2021 and December 2025. Cycles involving intracytoplasmic sperm injection, rescue intracytoplasmic sperm injection, or mixed fertilization procedures were excluded. Sperm DFI was categorized using a primary threshold of 20%, with cycles classified as lower DFI (≤20%) or elevated DFI (&gt;20%). Embryological development was assessed using stage-specific transition outcomes, including oocyte-to- two-pronuclear (2 P N) formation, 2 P N-to-day-3 good-quality embryo formation, blastocyst formation among embryos cultured for blastocyst development, and blastocyst-to-good-quality blastocyst formation. Binomial regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Multivariable models were adjusted for female age, male age, female body mass index, and basal follicle-stimulating hormone. Additional analyses examined clinically interpretable DFI categories and alternative DFI thresholds.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Among the 1,423 cycles, 1,218 were classified as lower DFI and 205 as elevated DFI. Elevated DFI was not associated with the oocyte-to-2PN transition after adjustment (63.7% vs. 62.3%; adjusted OR, 0.96; 95% CI, 0.84-1.10; P = 0.523). In contrast, elevated DFI was associated with a lower probability of 2 P N-to-day-3 good-quality embryo formation (34.5% vs. 29.4%; adjusted OR, 0.71; 95% CI, 0.57-0.87; P = 0.001). Elevated DFI was also associated with reduced blastocyst formation among embryos cultured for blastocyst development (57.3% vs. 50.4%; adjusted OR, 0.80; 95% CI, 0.66-0.96; P = 0.018). Good-quality blastocyst formation among formed blastocysts was 34.4% in the lower-DFI group and 30.8% in the elevated-DFI group (adjusted OR, 0.87; 95% CI, 0.68-1.11; P = 0.267). Analyses using clinically interpretable DFI categories and alternative thresholds showed that the association was most consistently observed for post-fertilization developmental outcomes rather than normal fertilization.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;In this retrospective cohort of first eligible conventional IVF cycles, elevated sperm DFI was not independently associated with normal fertilization but was associated with modestly reduced post-fertilization embryological development, particularly 2 P N-to-day-3 good-quality embryo formation and blastocyst fo","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1925444"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The roles of centrosome amplification in diabetes-associated diseases.","authors":"Shao Chin Lee, Peng Xu, Qi Gui Wu","doi":"10.3389/fcell.2026.1877870","DOIUrl":"https://doi.org/10.3389/fcell.2026.1877870","url":null,"abstract":"<p><p>The structure and function of the centrosome and the adverse consequences of centrosome aberration are increasingly understood. Centrosome amplification (CA), probably the most studied form of centrosome abnormalities, occurs when a cell harbors more than two centrosomes. Diabetes is associated with the development of numerous diseases, the pathogenesis mechanisms of many of which, if not all, are not well understood. We have reported that diabetes triggers CA, which has pathological roles. In this context, we review the evidence that CA in diabetes promotes the development of diseases (e.g., cancer or vascular complications) via multiple mechanisms (e.g., genomic instability, inflammation, and aberrant ciliogenesis). CA is likely a mechanism underlying many, if not all, disease complications in diabetes.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1877870"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular senescence of renal tubular epithelial cells in diabetic kidney disease: emerging mechanisms and targeted interventions.","authors":"Junwei Shi, Jianing Sun, Junwei Gao, Jun Luo, Yinzhong Dai, Shimei Hua, Chenguang Wu, Lifan Wang, Peng Liu","doi":"10.3389/fcell.2026.1973741","DOIUrl":"https://doi.org/10.3389/fcell.2026.1973741","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease (ESKD), and while current standard treatment strategies can slow disease progression, they are still unable to reverse progressive structural damage to the kidneys. Emerging evidence indicates that the senescence of renal tubular epithelial cells (RTECs) is not only a central feature of early-stage DKD but also a key pathological mechanism driving renal interstitial fibrosis and progressive kidney function decline. This review systematically elucidates the emerging molecular networks governing RTEC senescence within the DKD microenvironment. Specifically, it thoroughly explores the roles of glucolipotoxicity induced by metabolic dysregulation, persistent reactive oxygen species (ROS) stress, DNA damage, senescence-associated secretory phenotype (SASP)-mediated paracrine toxicity, abnormal epigenetic modifications, and failure of endogenous protective mechanisms such as mitophagy. Furthermore, this review provides a brief overview of current potential therapeutic strategies for delaying or eliminating senescent cells, covering research progress and clinical limitations related to sodium-glucose cotransporter 2 (SGLT2) inhibitors, metformin, mesenchymal stem cell (MSC) therapy, and potential natural products.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1973741"},"PeriodicalIF":5.3,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-based early prediction of severe pneumonia risk in hospitalized leukemia patients: a dual-center retrospective cohort study.","authors":"Jian Huang, Qinliang Wu, Yixin Zhang, Kai Wang, Yuanyuan Wang, Chaogui Tang, Chang Li, Ning Lin","doi":"10.3389/fcell.2026.1943797","DOIUrl":"https://doi.org/10.3389/fcell.2026.1943797","url":null,"abstract":"<p><strong>Background: </strong>Severe pneumonia is a major infectious complication in patients with leukemia and may rapidly progress to respiratory failure or septic shock. Disease- and treatment-related immunosuppression increases susceptibility, yet population-specific early risk-stratification tools are limited.</p><p><strong>Objectives: </strong>To develop and externally validate a machine learning model for predicting severe pneumonia in hospitalized patients with leukemia.</p><p><strong>Methods: </strong>Data from 2,978 leukemia patients at two Chinese hospitals were retrospectively analyzed. The derivation cohort was divided into training and internal test sets; SMOTE was applied only to the training set. LASSO and SVM-RFE were used for predictive feature selection, eight machine learning algorithms were compared, and RCS was used for exploratory association analysis. The final model was presented as a nomogram.</p><p><strong>Results: </strong>Seven predictors were retained: age, history of myelosuppression, acute lymphoblastic leukemia (ALL) subtype, cardiac insufficiency, atrial fibrillation, red blood cell distribution width-standard deviation (RDW-SD), and prothrombin time activity. Logistic regression showed the best generalizability, with an area under the curve (AUC) of 0.801 in external validation. Sensitivity analyses showed similar discrimination with multiple imputation and complete-case analysis.</p><p><strong>Conclusion: </strong>We developed and externally validated an interpretable model for severe pneumonia in hospitalized patients with leukemia. Because direct programmed-cell-death biomarkers were not measured and SMOTE substantially altered training prevalence, mechanistic interpretation and absolute-risk calibration require caution. Prospective recalibration and clinical-impact evaluation are needed before routine use.</p>","PeriodicalId":12448,"journal":{"name":"Frontiers in Cell and Developmental Biology","volume":"14 ","pages":"1943797"},"PeriodicalIF":5.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631014/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149106776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}