[This corrects the article DOI: 10.3389/fnut.2026.1782217.].

Metastasis and immunosuppression remain major barriers to effective treatment of lung adenocarcinoma (LUAD), yet the metabolic mechanisms governing the pro-tumor functions of tumor-associated macrophages are incompletely understood. In this study, we identified Uridine Phosphorylase 1 (UPP1) as a macrophage-enriched metabolic regulator associated with LUAD progression. By integrating single-cell RNA sequencing with clinical cohort analyses, we found that UPP1 was preferentially expressed in tumor-associated macrophages and was associated with adverse clinical outcomes. Functional and mechanistic studies demonstrated that dysregulated UPP1 disrupted nucleotide homeostasis, leading to mitochondrial reactive oxygen species accumulation and mitochondrial DNA leakage. These mitochondrial stress signals activated the cGAS-STING pathway, which preferentially engaged NLRP3 inflammasome signaling rather than canonical antiviral responses. Consequently, macrophages underwent pyroptosis and released elevated levels of interleukin-1β (IL-1β). Through paracrine signaling, macrophage-derived IL-1β promoted epithelial-mesenchymal transition in LUAD cells and enhanced their invasive capacity in vitro. Consistent with these findings, co-injection of UPP1-overexpressing macrophages significantly increased spontaneous lung metastasis in vivo. Clinically, elevated UPP1 expression served as an independent predictor of poor survival. Furthermore, pharmacological blockade of this signaling cascade or neutralization of IL-1β attenuated macrophage-induced malignant phenotypes in tumor cells, highlighting the therapeutic relevance of this pathway. Collectively, our findings identify a macrophage-specific immunometabolic circuit in which UPP1-driven mitochondrial stress activates the mtROS-cGAS-NLRP3 axis, promoting IL-1β-dependent macrophage-tumor crosstalk and metastatic progression. These results suggest that UPP1 may serve as both a prognostic biomarker and a potential therapeutic target in LUAD.

Resistance to lenvatinib remains a major barrier in the treatment of advanced hepatocellular carcinoma (HCC), underscoring the urgent need to elucidate the underlying mechanisms and identify actionable therapeutic targets. In this study, we identified a neurosecretory factor derived from HCC cells, Nerve Growth Factor (NGF), as a critical mediator of lenvatinib resistance. Utilizing an innovative in vivo-in vitro cross-circulated strategy, we established a phenotypically stable lenvatinib-resistant HCC cell line (LenR-cells). Through proteomic screening of conditioned media and subsequent functional validation, we demonstrated that NGF secretion progressively increases with the acquisition of resistance. Mechanistically, we uncovered that the SRPK1-SRSF1 axis drives enhanced NGF production by regulating alternative splicing of its precursor transcript, specifically promoting the expression of a shorter, translationally efficient isoform (proNGF-B). Elevated NGF subsequently activates the non-canonical MAPK pathway (MEK5-ERK5) via its high-affinity receptor TrkA, thereby sustaining tumor cell viability and proliferation under sustained tyrosine kinase inhibitor pressure. Critically, pharmacological co-targeting of TrkA with the clinically approved inhibitor larotrectinib restored lenvatinib sensitivity in both patient-derived organoids and xenograft models, producing marked synergistic anti-tumor effects without evidence of exacerbated toxicity. Clinical analyses of two independent patient cohorts further confirmed that elevated NGF expression is significantly associated with poor response to lenvatinib, shorter recurrence-free survival, and worse overall survival. Our findings unveil a critical and previously underappreciated role for tumor-derived NGF in orchestrating adaptive signaling through a precise post-transcriptional regulatory circuit and propose a readily translatable, biomarker-guided combination strategy to overcome lenvatinib resistance in HCC.

To identify microRNAs (miRNAs) responsive to powdery mildew (PM) infection and elucidate their regulatory roles in melon PM resistance, thereby laying a foundation for deciphering the underlying molecular mechanisms, we combined high-throughput sequencing with bioinformatics analysis to screen PM-responsive miRNAs and their target genes using PM-resistant and PM-susceptible melon genotypes. In total, 113 non-redundant miRNAs were identified in both genotypes, including 70 known and 43 novel miRNAs. Subsequent differential expression analysis revealed distinct miRNA responses to PM infection between resistant and susceptible genotypes. Upon PM inoculation, 13 miRNAs showed significant differential expression in both susceptible and resistant genotypes. In addition, four miRNAs, including miR164c, miR396a, miR398a and miRn39, displayed differential expression specifically in the susceptible genotype. Conversely, five miRNAs (miR167c, miR398b, miR399g, miR530a and miRn8) showed differential expression exclusively in the resistant genotype upon PM infection. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses demonstrated that these miRNAs mediate melon’s susceptibility or resistance to PM by modulating plant immune homeostasis, antioxidant metabolism, and pathogen-triggered cell death. Quantitative real-time PCR (qRT-PCR) validation confirmed a negative regulatory relationship between the expression of PM-responsive miRNAs and their predicted target genes. Collectively, our findings provide novel insights and candidate targets for further investigations into miRNA functions and regulatory mechanisms underlying melon PM resistance.

Leaf color mutants are key resources for uncovering the molecular mechanisms of chloroplast development and photosynthesis. Here, we identified a novel yellow-green melon mutant, ‘ygp2’, which displays yellow-green leaves and dwarfism throughout development. Genetic analysis indicated that the trait is controlled by a single recessive nuclear gene. Map-based cloning delimited the candidate region to an 805 kb interval on chromosome 11, within which only one missense mutation was identified in MELO13C_11G242690, encoding a triosephosphate isomerase (CmpdTPI). Phylogenetic analysis suggested its plastid localization, which was confirmed by transient expression of CmpdTPI-GFP in tobacco. The ‘ygp2’ mutant exhibited significantly reduced TPI enzyme activity and net photosynthetic rate. Transcriptome analysis revealed downregulation of genes related to light-harvesting complexes, cell division, and the cell cycle. These results demonstrate that the point mutation in CmpdTPI impairs chloroplast function and photosynthesis, leading to the yellow-green phenotype in melon. This study provides insight into the role of plastidial TPI in chlorophyll metabolism and chloroplast development.

Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by early metastasis and metabolic reprogramming, yet the epigenetic drivers linking these features remain poorly defined. This study investigates the role of CDK13, overexpressed in PDAC, in orchestrating these processes. Methods We utilized transcriptomic (RNA-seq), phosphoproteomic, and chromatin accessibility (ATAC-seq) profiling in PDAC cell lines and clinical specimens. Functional assays included gene knockdown/overexpression, site-directed mutagenesis, ChIP-qPCR, luciferase reporter assays, and in vivo metastatic models. Results CDK13 was overexpressed in PDAC and promoted tumor migration, invasion, and hepatic metastasis. Mechanistically, CDK13 phosphorylated the histone demethylase KDM2A at Ser692, triggering an H3K36me2-to-H3K36me1 switch at an intronic enhancer of NUP93—a nuclear pore component. This epigenetic activation upregulated NUP93, which facilitated nuclear translocation of phosphorylated STAT3. Nuclear p-STAT3 bound the HMGCR promoter to drive cholesterol biosynthesis. Genetic or pharmacological disruption of CDK13, KDM2A, or NUP93 suppressed cholesterol accumulation and metastatic progression in vitro and in vivo. Conclusions Our findings reveal an epigenetic-metabolic circuit wherein CDK13-mediated nuclear pore reprogramming via KDM2A phosphorylation and NUP93 activation drives cholesterol metabolism and metastasis in PDAC. This work suggests that co-targeting CDK13 and NUP93 may offer a promising therapeutic avenue for metastatic PDAC.

While premetastatic niche formation is known to affect primary tumors lung metastases, the role of lung stromal cells in this process remains unclear. Here, by performing multiomics sequencing, we identify interferon-regulated CD34+fibroblasts that reshape the immunosuppressive lung microenvironment via VLDLR-mediated lipoprotein metabolism activation. Increased lipoprotein uptake facilitates intracellular lipid accumulation, followed by CD155 expression in fibroblasts. CD155+fibroblasts strongly induce cytotoxic CD8+T and NK cell exhaustion, resulting in the formation of a premetastatic niche. The genetic disruption of the interferon-VLDLR-CD155 axis robustly reinstates immune surveillance and suppresses lung metastasis in multiple tumor models. Notably, interferon-based therapy is potentiated by specific silencing of the interferon response in fibroblasts or CD155 blockade. Moreover, the FTO-YTHDF2-mediated STAT1 m6A modification results in differences in the interferon response. Collectively, our findings reveal how interferon-induced metabolic rewiring in fibroblasts promotes metastatic competence via CD155-mediated immune evasion, suggesting stromal-targeted strategies for treating lung metastasis.

Metabolic plasticity driven by mitochondrial oxidative phosphorylation (OXPHOS) is increasingly recognized as a key determinant of therapeutic tolerance in hepatocellular carcinoma (HCC), but the upstream regulators that preserve electron transport chain stability during treatment remain poorly defined. In this study, we identified paraoxonase-1 (PON1) as a clinically relevant regulator of mitochondrial metabolism and lenvatinib response in HCC. PON1 was markedly upregulated in HCC and independently associated with poor overall and recurrence-free survival. Functionally, PON1 promoted tumor growth and conferred robust tolerance to lenvatinib. Mechanistically, PON1 directly interacted with and stabilized NDUFA4, a key component required for complex IV assembly, thereby maintaining mitochondrial membrane potential, complex IV integrity, and OXPHOS-dependent adenosine triphosphate production while limiting reactive oxygen species accumulation. Genetic silencing of PON1 or NDUFA4 impaired mitochondrial respiration, increased oxidative stress, and restored lenvatinib sensitivity in HCC cells and xenograft models. Structure-guided virtual screening identified the Food and Drug Administration-approved CFTR corrector lumacaftor as a potent modulator of PON1 that disrupted the PON1-NDUFA4 interaction and enhanced the antitumor efficacy of lenvatinib in vivo. These findings identify the PON1-NDUFA4 axis as a previously unrecognized metabolic vulnerability that sustains mitochondrial respiratory fitness and lenvatinib resistance in HCC. Targeting mitochondrial protein-stabilizing mechanisms such as PON1-NDUFA4 may offer a broadly applicable strategy for overcoming therapy resistance in liver cancer and other aggressive malignancies. Implications: These findings establish mitochondrial protein stabilization as an actionable therapeutic vulnerability and provide a rationale for combination strategies to overcome targeted therapy resistance in HCC.

In this article, we consider partially observable timed automata endowed with a single clock. A time interval is associated with each transition specifying at which clock values it may occur. In addition, a resetting condition associated to a transition specifies how the clock value is updated upon its occurrence. This work deals with the estimation of the current state given a timed observation, i.e., a succession of pairs of an observable event and the time instant at which the event has occurred. The problem of state estimation for a timed automaton is reduced to the reachability analysis of an associated zone automaton, which provides a purely discrete event description of the behavior of the timed automaton. An algorithm is formulated to provide an approach for state estimation of a timed automaton based on the assumption that the clock is reset upon the occurrence of each observable transition.

Glioblastoma (GBM) is a highly lethal malignant brain tumor with poor survival rates, and chemoresistance poses a significant challenge to the treatment of patients with GBM. Here, we show that transketolase (TKT), a metabolic enzyme in the pentose phosphate pathway (PPP), attenuates the chemotherapy sensitivity of glioma cells in a manner independent of catalytic activity. Mechanistically, chemotherapeutic drugs can facilitate the translocation of TKT protein from the cytosol into the nucleus, where TKT physically interacts with XRN2 to regulate the resolution and removal of R-loops. Depletion of TKT leads to increased R-loop accumulation and genome instability, increasing the susceptibility of glioma cells to chemotherapy. In conclusion, our study reveals a non-metabolic function of TKT in regulating R-loop dynamics, genome instability, and chemotherapy sensitivity in gliomas.

Pancreatic cancer is a highly malignant digestive system tumor characterized by covert onset and rapid progression, with a 5-year survival rate of less than 10%. Most patients have already reached an advanced or metastatic stage at the time of diagnosis. Therefore, it is particularly important to study the occurrence, development, and drug resistance mechanisms of pancreatic cancer. In recent years, the development of 3D tumor cell culture technology has provided new avenues for pancreatic cancer research. Patient-derived organoids (PDOs) are micro-organ structures that are obtained directly from the patient's body and rapidly expand in vitro. PDOs have the ability to self-renew and self-organize and retain the genetic heterogeneity and molecular characteristics of the original tumor. However, the use of organoids is limited because most patients with pancreatic ductal adenocarcinoma (PDAC) are inoperable. Endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/FNB) is an important method for obtaining tissue samples from non-surgical pancreatic cancer patients. This article reviews the factors that affect the formation of pancreatic cancer organoids using EUS-FNA/FNB. High-quality samples, sterile operations, and optimized culture media are key to successfully generating organoids. Additionally, individual patient differences and disease stages can impact the formation of organoids. Pancreatic cancer organoids constructed using EUS-FNA/FNB have significant potential, suggesting new approaches for research and treatment.

BACKGROUND:Gastric cancer, a globally prevalent malignant tumor, continues to exhibit high incidence and mortality rates. Although radical gastrectomy remains the primary treatment for this disease, postoperative complications frequently arise, negatively impacting short-term recovery and significantly reducing patients' quality of life. In this context, accurately predicting the risk of postoperative recurrence and metastasis, coupled with targeted interventions, could substantially improve patient outcomes. The C-reactive protein-triglyceride-glucose index (CTI), a composite biomarker that integrates metabolic disturbances and systemic inflammation, has garnered increasing attention in oncology. The prognostic nutritional index (PNI), a composite measure based on serum albumin and peripheral blood lymphocyte count, is used to evaluate both the nutritional status and systemic immune function of patients. In recent years, both the CTI and PNI have demonstrated significant prognostic value in predicting tumor outcomes, assessing treatment responses, and formulating personalized treatment strategies. AIM:To investigate whether the combined inflammation and insulin resistance marker, the CTI, can serve as a prognostic indicator for patients undergoing radical gastrectomy for gastric cancer. Additionally, it seeks to develop a predictive model by incorporating the PNI alongside CTI. METHODS:This retrospective study included a total of 300 patients who underwent radical gastrectomy. The patients were classified into high and low CTI groups based on their CTI index. Cox proportional hazards regression analysis was performed to identify independent prognostic factors influencing overall survival (OS) and disease-free survival (DFS), and two nomogram models were developed. RESULTS:Of the included patients, 131 had a high CTI and 169 had a low CTI. The DFS period of the low CTI group was significantly longer than that of the high CTI group. The number of postoperative adjuvant treatments, T stage, N stage, CTI, and PNI were identified as independent prognostic factors for DFS. The hazard ratio for CTI was 2.07 (95% confidence interval: 1.36-3.17, P < 0.001). In terms of OS, the OS period of the low CTI group was significantly longer than that of the high CTI group. Whether adjuvant treatment was administered, T stage, CTI, and PNI were independent prognostic factors for OS. The hazard ratio for CTI was 2.47 (95% confidence interval: 1.44-4.23, P = 0.001). The nomogram models for OS and DFS further emphasized the importance of CTI as a key predictor of patient prognosis. CONCLUSION:CTI is a long-term prognostic indicator for the outcome of radical gastrectomy for gastric cancer. Patients with lower CTI values have a better prognosis. The prediction models constructed by combining CTI with PNI has good predictive ability for DFS and OS after radical gastrectomy.

Lactate, initially considered a mere metabolic byproduct, has emerged as a pivotal metabolite in the tumor microenvironment (TME), playing critical roles across a range of pathological conditions. In tumors in particular, lactate contributes to disease progression through its multifaceted biological functions. Recent studies have further identified lactate as a central mediator in the regulation of tumor immune evasion. Tumor cells, via aerobic glycolysis, secrete large amounts of lactate, leading to acidification of the TME and suppression of antitumor immunity through various mechanisms, including immune cell inhibition, epigenetic reprogramming, and metabolic competition. These findings have fueled growing interest in targeting lactate as a therapeutic strategy against cancer, encompassing approaches such as LDHA inhibitors, MCT inhibitors, and novel nanomedicine-based therapies. In this review, we summarize lactate metabolism in the body, explore its impact on various immune cell populations, elucidate its functional roles in tumor biology, and highlight recent advances in antitumor strategies that target lactate.

Background and Aims: Many patients with HCC present inadequate responses to lenvatinib therapy. Therefore, it is important to elucidate the underlying mechanisms of resistance and to formulate effective reversal strategies. Approach and Results: We conducted transcriptome and proteome sequencing analyses of lenvatinib-resistant cell lines and patient-derived tissues, identifying microtubule-associated serine/threonine kinase-like (MASTL) as a critical factor associated with lenvatinib resistance in HCC. Then, we utilized subcutaneous mouse models, half maximal inhibitory concentration (IC 50 ) measurements, and colony formation assays to determine the biological function of MASTL in promoting tumor growth and mediating resistance to lenvatinib. To further elucidate the underlying mechanisms, we performed co-immunoprecipitation and mass spectrometry analyses, revealing that MASTL facilitates the phosphorylation of Y-box binding protein-1 (YBX1). Using chromatin immunoprecipitation assays, we subsequently confirmed that phosphorylated YBX1 transcriptionally activates PAK4, identifying PAK4 as a downstream effector of the MASTL pathway. Moreover, mass spectrometry and phosphorylation analysis indicated that serine/threonine protein kinase 24 (STK24), a stress-responsive kinase, can activate MASTL in HCC under lenvatinib exposure. Notably, disruption of the MASTL/YBX1/PAK4 signaling axis restored HCC sensitivity to lenvatinib. Conclusions: We propose that the MASTL/YBX1/PAK4 axis, which is activated by stress-induced STK24, plays a crucial role in lenvatinib resistance. Inhibiting this axis by targeting MASTL effectively overcomes lenvatinib resistance in HCC.

Objective: To elucidate the role and clinical potential of the lncRNA DLX6-AS1/miR-26a/PTEN axis in liver fibrosis. Methods: Systematic studies were conducted using cellular and animal models through causal validation, bivariate experiments, single-cell sequencing, ROC analysis of clinical samples, and humanized mouse models. Results: LncRNA DLX6-AS1 inhibited PTEN by adsorbing miR-26a, promoting hepatic stellate cell activation in a dose/time-dependent manner; the axis demonstrated excellent diagnostic performance (AUC > 0.9), and its inhibitors effectively reversed fibrosis in vivo. Conclusion: This study provides new biomarkers and targeted therapeutic strategies for liver fibrosis.

Hepatocellular carcinoma (HCC) represents the predominant form of primary liver cancer and is frequently identified at a late stage, necessitating systemic therapy. However, resistance to first-line tyrosine kinase inhibitor therapies, such as sorafenib and lenvatinib, remains a significant clinical challenge. Recent research has revealed a strong link between aerobic glycolysis and drug resistance in HCC. Key enzymes in the glycolytic pathway, such as hexokinase, phosphofructokinase, and pyruvate kinase M, play central roles in the metabolic reprogramming of HCC cells. Aberrant activation of these enzymes not only promotes swift proliferation of tumor cells but also boosts adaptability. Lactate, the final product of glycolysis, is also pivotal in contributing to drug resistance in HCC. Moreover, signaling pathways, such as AMPK, HIF-1, and c-Myc, play key roles in tumor metabolic regulation, influencing energy balance, gene expression under hypoxia, and metabolic pathway control. These mechanisms interact synergistically, allowing HCC cells to endure and proliferate despite targeted therapies, ultimately resulting in drug resistance. Therefore, a deeper understanding of these metabolic and signaling regulatory mechanisms will help reveal the fundamental causes of drug resistance in HCC and provide new targets and directions for future therapeutic strategies.

Salt stress, as a significant adverse consequence of global climate change, severely restricts the yield and quality of watermelon. In this study, salt-tolerant cultivar T23 and salt-sensitive cultivar B2 were subjected to a 200 mM NaCl treatment (0 h, 6 h, 24 h, 48 h, and 168 h) at the three-leaf stage, and the adaptation mechanisms of the watermelon roots to salt stress were systematically investigated at the phenotypic, physiological, and gene transcription levels. Phenotypic observations revealed that salt stress inhibited seedling growth, caused leaf curling, and induced root yellowing, with the damage being significantly more severe in B2 than in T23. Compared with B2, the activities of superoxide dismutase (SOD) were increased by -7.13%, 169.15%, 34.95%, 84.87%, and 39.87% under NaCl treatment at 0 h, 6 h, 24 h, 48 h, and 168 h, respectively. Compared to the 0 h NaCl treatment, the proline content in B2 increased by 4.25%, 14.39%, and 110.00% at 24 h, 48 h, and 168 h of NaCl treatment, respectively, while T23 showed increases of 93.74%, 177.55%, and 380.56% at the corresponding time points. The provided physiological data demonstrate that T23 exhibits superior antioxidant and osmoregulatory abilities relative to B2. The transcriptome analysis identified differentially expressed genes (DEGs) between the two cultivars under salt stress, with T23 showing the highest number of DEGs at 6 h, while B2 exhibited a significant increase in DEGs at 168 h. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that metabolic pathways such as plant hormone signal transduction, terpenoid biosynthesis, mitogen-activated protein kinase (MAPK) signaling pathways, transporter activity, and transcription regulator activity play important roles in the salt stress response. Furthermore, yeast overexpression experiments preliminarily validated the critical roles of the tonoplast dicarboxylate transporter gene ClCG01G010280 and the NAC transcription factor gene ClCG05G024110 in salt stress tolerance. This study provides new molecular insights into the salt tolerance mechanism of watermelon and offers potential genetic resources for breeding salt-tolerant varieties.

Although radiotherapy (RT) plays a crucial role in the local treatment of hepatocellular carcinoma, its therapeutic efficacy is often hindered by radiation resistance, the mechanisms of which remain poorly understood. Single-cell and bulk RNA sequencing analyses identified the DNA damage repair gene mortality factor 4-like 1 (MORF4L1) as a critical regulator of hepatocellular carcinoma progression and resistance to RT. This finding was further validated using clinical cohorts, patient-derived xenograft models, and in vitro experiments. Immunoprecipitation followed by mass spectrometry analysis revealed that partner and localiser of BRCA2 is an interaction partner of MORF4L1. Furthermore, MORF4L1 was demonstrated to acetylate partner and localiser of BRCA2 at lysine 628, inhibiting its ubiquitination and subsequent degradation. Additionally, MORF4L1 enhanced histone H3 acetylation at lysine 4, which facilitates DNA damage repair factor recruitment. Cross-priming assay and genetically engineered mouse model results indicated that MORF4L1 antagonist argatroban in combination with RT enhances anti-tumor immune responses by activating the cyclic GMP-AMP synthase–stimulator of interferon genes signaling pathway. This combination significantly improved the therapeutic efficacy of RT when used alongside immune checkpoint inhibitors. The study findings underscore the pivotal role of MORF4L1 in hepatocellular carcinoma progression and RT resistance, suggesting that combining argatroban with RT may overcome RT resistance and improve therapeutic outcomes.