PANoptosis is an integrated inflammatory cell death program that arises from the coordinated activation of apoptotic, pyroptotic, and necroptotic signaling pathways. Although it is increasingly recognized as a central determinant of immune defense, therapeutic response, and disease progression, PANoptosis remains largely undetectable using current molecular imaging and detection strategies. Most existing molecular probes are designed to interrogate individual cell death pathways, typically apoptosis, thereby reducing a multidimensional execution network to a single biochemical readout. Here, we critically examine why conventional cell death probes fail to resolve PANoptosis and systematically categorize current sensing strategies according to their apoptotic, pyroptotic, and necroptotic targets. We further highlight emerging multiplexed, logic-gated, and nanoplatform-based sensing architectures that partially address these limitations but remain mechanistically incomplete. Building on current insights into PANoptosome biology, we propose a set of design principles for next-generation PANoptosis probes that emphasize multi-axis molecular integration, temporal resolution, and conditional activation logic. By reframing PANoptosis as a measurable biological state rather than a conceptual abstraction, this review provides a roadmap for developing molecular probes capable of decoding inflammatory cell death in complex diseases. Such advances will be essential for translating PANoptosis from mechanistic insight into diagnostic and therapeutic applications.

ETV2 is a member of the ETS transcription factor family and has been shown to be necessary and sufficient for the hematoendothelial lineages. Genetic deletion in mice and pigs resulted in early embryonic lethality with complete absence of vasculature and blood. Studies support the notion that ETV2 functions as a pioneer factor to regulate the chromatin landscape and gene networks that govern essential functions, including cellular proliferation of endothelial progenitors. Here, in this mini-review, we highlight the regulatory mechanisms that have been defined by a number of laboratories to provide a roadmap for ETV2 modulation of cell cycle kinetics. These studies provide important new insights and establish a platform for the development of new therapies to promote angiogenesis and tissue regeneration.

Contemporary models of tumor progression highlight the key role of the tumor microenvironment (TME) and the extracellular matrix (ECM) in regulating angiogenesis, metastasis, and immune resistance. Among ECM components, oncofetal fibronectin (FN) isoforms containing the EDA and EDB domains are of particular interest because they are highly expressed in solid tumors but absent from normal adult tissues. This review article synthesizes current data on the pathophysiological functions of FN variants in oncogenesis. Particular attention was paid to their role in pathological vascular remodeling, the induction of epithelial-mesenchymal transition (EMT), the formation of pre-metastatic niches, and the generation of an immunosuppressive environment. The study also critically assesses the clinical significance of FN as a biomarker and a potential target for new therapies in breast cancer, ovarian cancer and glioblastoma. The prospects for the use of innovative stromal strategies - including antibody-drug conjugates (ADCs) and immunocytokines - to overcome resistance to standard immunotherapy are also highlighted.

NPC2 is a lysosomal cholesterol transporter involved in intracellular lipid trafficking and cholesterol homeostasis, processes that have been increasingly implicated in cancer biology. To quantify the clinical impact of NPC2 expression across human malignancies, we analyzed survival data from 2,097 patients evaluated for NPC2 expression in tumor tissues. We conducted a random-effects meta-analysis of four eligible studies assessing NPC2 expression by mRNA (RNA-seq, qRT-PCR) and protein-based methods (immunohistochemistry, Western blot).The cohort included 756 patients with gastric cancer (36.0%), 374 with hepatocellular carcinoma (17.8%), and 967 with gliomas (46.2%). Pooled analyses demonstrated that elevated NPC2 expression was significantly associated with worse overall survival across cancers (HR 1.29, 95% CI 1.10-1.52, p = 0.001; I[2] = 56%). In gastric cancer, this association was stronger and highly consistent (HR 1.37, 95% CI 1.18-1.60, p < 0.001; I[2] = 0%). These results suggest that NPC2 overexpression identifies a subset of tumors with increased aggressiveness and adverse clinical outcomes. Collectively, these findings support NPC2 as a candidate adverse prognostic biomarker and highlight lysosomal cholesterol trafficking as a pathway of translational interest in cancer biology. Further mechanistic and clinical studies are warranted to clarify the biological role of NPC2 and its potential therapeutic implications.

Cell division is an essential process required to maintain homeostasis. It must be tightly coordinated to allow the faithful transmission of the genetic material, and its regulation involves numerous partners. While some of them are well-characterized (e.g. Cyclin-Dependent Kinases, Aurora Kinases, …), others are still poorly understood. Citron Kinase (CitK) plays key roles during mitosis and cytokinesis, although its functions remain to be fully elucidated. In addition, its roles are not restricted to cytokinesis, and CitK also comes into play at earlier stages of cell division. Furthermore, emerging evidence suggests a role for CitK during tumorigenesis. Several studies have pointed to the potential of targeting CitK in the context of cancer treatment and hopefully this will bring attention to this largely understudied kinase. This review focuses on the different functions of Citron Kinase throughout the cell cycle to highlight its importance during cell division as well as its significance in cancer and its potential as a target for cancer therapy.

Breast cancer progression and therapeutic response are profoundly influenced by tumor immune interactions, yet the molecular regulators linking cell death pathways with immune modulation remain incompletely understood. Pyroptosis, a gasdermin-mediated inflammatory form of programmed cell death, has emerged as a key determinant of tumor immunity, while long non-coding RNAs are increasingly recognized as critical upstream regulators of cancer signaling. Recent transcriptomic analyses have identified numerous pyroptosis-associated lncRNAs and generated prognostic signatures that stratify patients into distinct risk groups with significantly different survival outcomes. These signatures are closely associated with the tumor immune microenvironment: low-risk tumors exhibit increased infiltration of CD8[+] T cells, NK cells, and B cells, together with elevated immune checkpoint expression, whereas high-risk tumors display immunosuppressive features, including M2 macrophage enrichment and higher tumor mutation burden. Mechanistic studies demonstrate that lncRNAs regulate pyroptosis through inflammasome activation, gasdermin-mediated signaling, and epigenetic modulation, thereby influencing tumor growth, metastasis, and therapeutic resistance. Despite these advances, clinical translation remains limited by dependence on retrospective transcriptomic datasets, insufficient mechanistic validation, lack of standardized assays, and scarce prospective clinical evidence. pyroptosis-associated lncRNAs represent a promising link between tumor progression and immune regulation, with considerable potential as prognostic biomarkers and therapeutic targets in breast cancer.

Gastrointestinal (GI) cancers, including colorectal, gastric, pancreatic, hepatocellular, and esophageal malignancies, remain a leading cause of cancer-related mortality worldwide. Emerging evidence identifies the gut microbiome as a critical regulator of GI carcinogenesis, influencing tumor initiation, immune evasion, therapeutic response, and clinical outcomes through inflammation, genotoxicity, metabolic reprogramming, and epithelial barrier disruption. Importantly, biological rationale, clinical evidence, and translational opportunities differ across GI tumor types. Specific taxa, including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, pks[+] Escherichia coli, and Helicobacter pylori, exhibit tumor-specific oncogenic roles with causal evidence ranging from associative to guideline-validated. Microbiome-based biomarkers, including composite multi-taxon models and signatures predictive of immune checkpoint inhibitor response, are evaluated using a four-tier framework (preclinical, associative, near-clinical, and validated). Microbiome-targeted therapies, including probiotics, fecal microbiota transplantation, dietary modulation, and engineered microbial therapeutics, are critically appraised according to clinical evidence and translational readiness. Advances in spatial microbiomics, single-cell analysis, multi-omics, and artificial intelligence may further accelerate microbiome-based precision oncology. This review provides a translationally stratified synthesis of microbiome-GI cancer interactions and their implications for precision oncology.

The tumor suppressor p53 plays a crucial role in preventing cancer development, and its dysfunction is frequently observed in various cancers. This study identifies a novel regulatory interaction between p53 and ITM2A. We found that p53 upregulates ITM2A expression, while ITM2A in turn inhibits p53 function, suggesting a negative feedback loop. ITM2A mRNA levels were reduced across multiple tumor types, particularly in those harboring mutant p53, and low ITM2A expression correlated with poor patient survival. Mechanistically, ITM2A physically interacts with p53, selectively modulates its phosphorylation (reducing Ser392 while enhancing Ser37), and promotes cytoplasmic accumulation of p53. These modifications collectively suppress p53-dependent transcription, an effect consistently observed across multiple cell lines under both basal conditions and upon physiological p53 activation by genotoxic stress. Conversely, ITM2A depletion enhances p53 nuclear accumulation and transcriptional activity. These findings reveal a novel autoregulatory circuit wherein p53 induces ITM2A expression, which then attenuates p53 activity, suggesting ITM2A as a potential prognostic marker and therapeutic target for cancers with dysregulated p53 signaling.

Hormesis is a biphasic dose-response, where mild stress triggers adaptive defense responses that increase cellular resilience. The hormesis is now recognized as a core concept with applications in toxicology, metabolism, aging, and evolutionary biology. A historical review, evolutionary explanations, and recent molecular insights led to the concept of hormesis as an anticipatory, "predict-and-prepare" strategy that allows organisms to adapt to changing conditions are addressed. The mitohormesis, autophagy, xenohormesis, epigenetic remodeling, and their interdependence with signaling pathways (Nrf2-KEAP1, AMPK-SIRT1, NF-κB, and heat-shock response). The stress-induced reversal of differentiation in basal metazoans also defy the irreversible aging concept demonstrate conservative plasticity programs. The relevance of translational research using toxin-derived therapeutics and lifestyle-based hormetic interventions are discussed, including challenges of the hormetic zone, inter-individual variability, and bioactivity cliffs. The future scope of integrating AI and ML into nonlinear modeling of precise hormetic dosing, with considerable applications in aging, regenerative medicine, and precision therapeutics.

Repeated implantation failure (RIF) remains a formidable challenge in in vitro fertilization-embryo transfer (IVF-ET). The etiology of RIF is multifactorial, involving complex interactions between embryo quality, the endometrium, and the maternal microenvironment. Adequate energy metabolism is pivotal for successful embryo implantation, supporting both embryonic development and the establishment of endometrial receptivity. Conversely, metabolic dysregulation contributes to RIF by arresting embryonic development, impairing endometrial receptivity, and disrupting the essential crosstalk between the embryo and the endometrium. Embryos and endometrial tissues from patients with RIF frequently exhibit distinct metabolomic abnormalities, including glycolysis utilization disorders, lipid metabolism disorders, and mitochondrial dysfunction. Clinical evidence suggests that therapeutic interventions involving antioxidants and specific metabolic modulators can enhance pregnancy rates in this population. This article reviews the critical role of energy metabolism in embryonic development and implantation, elucidates the pathological mechanisms linking metabolic dysfunction to RIF, and explores potential therapeutic strategies. We highlight that a comprehensive management strategy integrating diet, exercise, and targeted nutritional and antioxidant supplementation is expected to restore metabolic homeostasis in RIF patients and improve reproductive outcomes.

Insulin resistance (IR) is the core pathological basis of type 2 diabetes mellitus (T2DM). This study aimed to identify core lipid metabolism-ubiquitination-related feature genes in IR. Integrative transcriptomic and functional analysis screened differential genes via multiple machine learning models. Gene set enrichment analysis (GSEA), regulatory network prediction, and immune infiltration analysis were performed. C2C12 IR models were constructed, and ATG5 was knocked down to detect glucose-lipid metabolism, inflammation, and insulin signaling. Results showed that four feature genes were identified: Good genes Ankyrin Repeat And SOCS Box Containing 4 (ASB4)/ Low Density Lipoprotein Receptor (LDLR) and Bad genes ATG5/ CD36 molecule (CD36 blood group) (CD36). They were enriched in metabolism/inflammation pathways consistent with IR phenotypes. Regulatory network analysis predicted potential upstream microRNAs (miRNAs) and transcription factors (TFs) modulating these feature genes. IR/diabetes groups had lower ImmuneScores vs. insulin-sensitive groups. ATG5 was upregulated in IR models. Its knockdown inhibited autophagy, improved glucose and lipid metabolism, decreased inflammatory cytokines, and exerted no influence on cell viability. In conclusion, ASB4, LDLR, ATG5, and CD36 are potential IR biomarkers. ATG5 regulates IR via autophagy, insulin signaling, and metabolism, serving as a therapeutic target for metabolic diseases.

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disorder of intestine and a high risk for colorectal cancer; however, its precise etiology and pathogenesis remain poorly understood. Interleukin (IL)-37, a member of IL-1 family, exerts anti-inflammatory effects in various inflammatory diseases and cancers, and is generated by several epithelial cells and immune cells. Mechanistically, IL-37 mediates its anti-inflammatory either by translocating into nucleus in complex with small mother against decapentaplegic homolog 3 or binding to extracellular interleukin-18 receptor and IL-1 receptor-related receptor 8 (IL-1R8), which is abundantly expressed in the gastrointestinal tract. Recently, accumulating evidence has demonstrated that IL-37 expression is upregulated and plays protective roles in IBD and colitis-associated cancer (CAC). This review summarizes the recent advances regarding the expression, biological functions, molecular mechanism, and therapeutic potential of IL-37 in IBD and CAC, aiming to provide novel insights into its underlying mechanism and clinical application.

Glioblastoma (GBM) is defined by extreme lethality and transcriptomic plasticity, but the signatures driving the most aggressive tumors remain incompletely defined. In this exploratory in silico study, TCGA-GBM patients were stratified using a strict 1-year overall survival threshold. We integrated differential expression analysis, WGCNA, single-cell RNA-seq, spatial transcriptomics, and virtual knockout simulations. A high-risk signature centered on CCL2 and TIMP1 was identified. Single-cell and spatial mapping linked these genes to an inflammatory, macrophage-enriched microenvironment. The signature inversely correlated with neuronal synapse mimicry scores, suggesting that extreme aggressiveness involves a macroscopic shift from differentiated neuronal states toward an undifferentiated inflammatory phenotype. Virtual perturbation modeling confirmed CCL2 and TIMP1 as highly interconnected network hubs. Despite limitations inherent to computational and retrospective cohorts, our rigorous multi-omics validation identifies the CCL2/TIMP1 axis as a driver of potential prognostic indicator. These findings generate the hypothesis that these mediators reflect a critical inflammatory, mesenchymal-like tumor microenvironment shift, warranting independent cohort validation and experimental investigation.