Cancer cell plasticity enables tumor cells to dynamically transition between diverse phenotypic states, including epithelial–mesenchymal plasticity stemness, dormancy, lineage switching, immune evasion, and therapy-resistant phenotypes. Although metabolic reprogramming and epigenetic regulation have each been recognized as hallmarks of cancer, the mechanistic framework linking metabolic adaptation to dynamic cell-state transitions remains incompletely understood. In this Review, we propose that methylation serves as a major mechanistic interface through which metabolic rewiring can influence adaptive cancer cell plasticity. We discuss how one-carbon metabolism regulates the availability of the universal methyl donor S-adenosylmethionine (SAM), thereby influencing DNA methylation, histone methylation, and multiple forms of RNA methylation, with N6-methyladenosine (m6A) representing the principal RNA modification discussed in this review. Rather than responding uniformly to metabolic change, these methylation systems represent distinct but metabolically connected regulatory layers that share dependence on one-carbon metabolism while differing in their biochemical sensitivities and regulatory outputs. Net methylation states, however, are also shaped by metabolically constrained demethylation, including α-ketoglutarate-, oxygen-, Fe2+-, and flavin adenine dinucleotide (FAD)-dependent eraser pathways. Together, these metabolically responsive writing and erasing processes influence transcriptional stability, chromatin accessibility, and post-transcriptional regulation during reversible cell-state transitions. We further examine how environmental and therapeutic stresses, including hypoxia, nutrient limitation, immune surveillance, and anticancer therapy, reshape methylation programs through metabolic adaptation, and how such remodeling may support phenotypic flexibility and survival under selective pressure. Building upon these advances, we propose the concept of the adaptive methylation landscape, a perturbation-responsive, state-associated, and potentially reversible distribution of methylation states that contributes to shaping the spectrum of cellular states accessible during tumor evolution. Finally, we discuss emerging therapeutic strategies targeting the metabolic-methylation axis and highlight how single-cell multi-omics, spatial epigenomics, functional epigenome editing, and AI may enable dynamic mapping of adaptive methylation landscapes. We propose that cancer cell plasticity is not merely a genetic phenomenon but can also be shaped by metabolically responsive methylation programs, providing a testable conceptual framework for future precision epigenetic therapies.
Plasma cell-free DNA (cfDNA) is a heterogeneous and rapidly changing biological pool derived from malignant cells, normal tissues, and hematopoietic cells. The abundance and molecular composition of circulating tumor DNA (ctDNA) are determined not only by tumor burden but also by tissue architecture, vascular access, cell-death programs, chromatin organization, nuclease processing, systemic clearance, treatment exposure, and clonal evolution. These biological determinants shape the mutation, methylation, fragmentation, nucleosomal, and temporal features exploited by contemporary liquid-biopsy assays. Accurate clinical interpretation therefore requires both sensitive detection and reliable source attribution, particularly the distinction of tumor-derived variants from constitutional germline alterations and clonal hematopoiesis. In this review, we integrate the biological origins and processing of plasma cfDNA with analytical strategies for low-tumor-fraction detection and critically evaluate the evidence supporting postoperative molecular residual disease (MRD), recurrence surveillance, treatment-response assessment, resistance monitoring, and ctDNA-guided therapy across solid tumors. Particular emphasis is placed on distinguishing prognostic validity, treatment-predictive value, and demonstrated clinical utility. Current evidence is strongest in colorectal cancer and, more recently, ctDNA-selected urothelial cancer, whereas routine ctDNA-directed intervention in resected non-small cell lung cancer and breast cancer remains insufficiently validated. By linking cfDNA biology to an explicit hierarchy of clinical evidence, this review defines both the established applications and the major limitations that must be addressed before broader implementation of ctDNA-guided precision oncology.
Necrotizing enterocolitis (NEC) is a rapidly progressive intestinal emergency of preterm infants in which epithelial injury, dysregulated innate immunity, microvascular failure and microbial translocation reinforce one another. Ferroptosis and pyroptosis have emerged as complementary components of this process. Ferroptosis is driven by iron-dependent phospholipid peroxidation and failure of the SLC7A11–glutathione–GPX4 defense system, whereas pyroptosis is executed by inflammasome-activated gasdermins with release of interleukin-1β, interleukin-18 and damage-associated molecular patterns. Recent NEC studies implicate epithelial ferroptosis, inflammasome–GSDMD activation, mitochondrial dysfunction, and immune-cell death programs across epithelial, myeloid, lymphoid, and platelet compartments. Current data support convergence through redox stress, mitochondrial injury, damage-associated molecular patterns (DAMPs), and barrier failure; however, coexistence of ferroptotic and pyroptotic signals should not be interpreted as proven reciprocal crosstalk. Direct causal coupling between these pathways in human NEC remains unconfirmed. This Mini Review integrates epithelial, immune and vascular evidence; evaluates candidate biomarkers including HMGB1, intestinal fatty acid-binding protein, S100A12, DEFA6 and lipopolysaccharide-binding protein; and proposes a precision-targeting framework. Human milk–based supportive strategies are clinically relevant, whereas FXR/ACSL4 modulation, ferroptosis inhibitors, NLRP3/GSDMD blockade, and mitophagy-directed interventions remain predominantly experimental in NEC. Progress will require cell-resolved human validation, longitudinal biomarker panels and developmentally appropriate combination strategies that interrupt the death–inflammation cycle without impairing host defense or intestinal maturation.
BackgroundLARP7 encodes a critical scaffold protein of the 7SK small nuclear ribonucleoprotein (7SK snRNP) complex that regulates RNA polymerase II transcriptional elongation. Biallelic loss-of-function variants in LARP7 cause Alazami syndrome, a rare neurodevelopmental disorder characterized by intellectual disability, growth restriction, and distinctive craniofacial features. However, the transcriptomic consequences of LARP7 deficiency in human cells remain poorly understood, and the phenotypic spectrum of the disorder is incompletely defined.MethodsWe investigated a 6-year-old boy with clinically diagnosed Alazami syndrome who carried a novel homozygous LARP7 frameshift variant. Clinical evaluation and exome sequencing of blood-derived genomic DNA were performed, while quantitative PCR, Western blotting, and transcriptomic analysis were conducted using patient-derived dermal fibroblasts. Transcriptomic consequences of LARP7 deficiency were assessed by RNA sequencing, followed by single-subject differential expression, pathway enrichment, and network analyses.ResultsThe patient presented with classical features of Alazami syndrome and tetralogy of Fallot, a cardiac manifestation not previously reported in the disorder. The novel homozygous LARP7 frameshift variant resulted in marked depletion of LARP7 transcripts and complete loss of full-length protein. Transcriptome-wide analysis identified 1,224 dysregulated genes involved in extracellular matrix organization, developmental remodeling, cell-cycle regulation, and immune signaling. Pathway and network analyses highlighted dysregulation of STAT3-associated signaling together with SMAD3-linked extracellular matrix and developmental programs, identifying candidate developmental and tissue-remodeling pathways that warrant further investigation in disease-relevant models.ConclusionThis study provides the first comprehensive transcriptomic characterization of genetically confirmed LARP7 deficiency in primary human cells and potentially expands the phenotypic spectrum of Alazami syndrome. The findings reveal widespread dysregulation of developmental and extracellular matrix pathways, offering new insight into the molecular basis of the multisystem manifestations of Alazami syndrome and providing a framework for future functional and genotype–phenotype studies.
BackgroundChronic inflammation and metabolic dysregulation are increasingly recognized as interconnected drivers of tumorigenesis and immune evasion, yet their combined prognostic and mechanistic relevance in lung adenocarcinoma (LUAD) remains poorly defined.MethodsA curated 117-gene set representing systemic inflammation-metabolism dysregulation was obtained from MSigDB. Core prognostic genes were identified through differential expression analysis and univariate Cox regression. Using TCGA-LUAD as the training cohort and six independent GEO cohorts for external validation, 101 machine learning algorithm combinations were systematically evaluated to construct a robust prognostic model. Model performance was assessed by C-index, time-dependent ROC, and PCA. Immune characteristics were analyzed using TCIA, ESTIMATE, and TIMER-based deconvolution. ATP2A2, identified as the gene most strongly correlated with risk score, underwent multi-cohort transcriptomic and immunohistochemical validation, in vitro functional characterization, and mechanistic investigation via IOBR-integrated immune profiling. Single-cell RNA sequencing and multiplex immunofluorescence provided cellular-resolution verification of microenvironmental associations.ResultsThe RSF + SuperPC model achieved optimal performance and effectively stratified patients into high- and low-risk groups with significantly divergent survival across all seven cohorts. High-risk tumors showed reduced immune/stromal infiltration and elevated tumor purity. ATP2A2 was consistently overexpressed in tumor tissue, correlated with poor differentiation, advanced stage, and shorter survival, and predicted immunotherapy resistance. Mechanistically, high ATP2A2 expression was associated with suppressed immune cell infiltration, attenuated chemokine signaling, impaired cancer-immunity cycle activity, and an “immune-desert” phenotype confirmed by single-cell and spatial analyses.ConclusionThis study establishes a validated inflammation-metabolism-based prognostic signature in LUAD and identifies ATP2A2 as a key driver linking tumor aggressiveness to immunosuppressive microenvironment remodeling, positioning it as a promising prognostic biomarker and potential therapeutic target for overcoming immunotherapy resistance.
