Methylglyoxal in cancer: Bidirectional regulatory networks and precision intervention—From metabolic reprogramming to cross-disease synergistic targeting

As a major global health challenge with rising incidence and poor prognosis, head and continues to impose a significant clinical burden due to its aggressive biological behavior and frequent therapeutic resistance. Within this context, the atypical Hippo signaling pathway emerges as a crucial regulatory network, integrating diverse components including core kinases (TAO kinases, MAP4K family, NDR1/2 kinases), cell polarity determinants (CRUMBS, SCRIBBLE), junctional adhesion molecules (AMOT family), phosphorylation mediators (14-3-3 proteins), and tumor suppressors (NF2, RASSF family). This multifaceted system governs fundamental cellular processes spanning proliferation, apoptosis, migratory capacity, and immune microenvironment modulation. Notably, post-translational modifications (ubiquitination, acetylation, SUMOylation) of pathway components dynamically regulate the stability and activity of downstream effectors YAP/TAZ, whose sustained activation through molecular aberrations drives tumor progression and treatment resistance in head and neck malignancies.The pathway's extensive crosstalk with Wnt signaling, NF-κB cascades, and estrogen receptor networks creates context-dependent regulatory plasticity that contributes to tumor heterogeneity. Current therapeutic innovation focuses on molecular diagnostics and precision targeting approaches, including direct YAP/TAZ-TEAD complex inhibitors, upstream receptor modulators, and rational combinations with immune checkpoint blockade. Future investigations should employ multi-omics profiling to delineate tumor subtype-specific regulatory architectures while advancing novel drug delivery platforms. These efforts promise to translate mechanistic insights into multi-targeted therapeutic strategies capable of overcoming resistance mechanisms and improving survival outcomes for this therapeutically challenging malignancy.

Aristolochic Acid (AA) is a class of naturally occurring compounds characterized by potent genotoxicity and carcinogenicity, predominantly found in plants of theAristolochiagenus. The 1993 Belgian weight-loss incident and subsequent research unequivocally established the association between AA and "Aristolochic Acid Nephropathy" (AAN) as well as Balkan Endemic Nephropathy (BEN), prompting global regulatory actions. AA undergoes nitroreduction to generate highly reactive intermediates, which form persistent DNA adducts, inducing A:T to T:Atransversion mutations during DNA replication. In 2017, 78% (76/98) of hepatocellular carcinoma (HCC) samples collected from two Taiwanese hospitals exhibited the characteristic mutational signature COSMIC SBS22, sparking a global debate on whether AA contributes to liver carcinogenesis. This review systematically synthesizes the research progress on AA, encompassing its historical applications, metabolic mechanisms, genotoxic features, and its potential causal relationship with HCC. It highlights the necessity of employing multi-omics technologies to elucidate the regulatory networks of AA-metabolizing enzymes, developing non-invasive biomarkers, and rigorously validating carcinogenic mechanisms through animal models. Furthermore, strengthening the regulation of AA-containing herbal medicines and enhancing global exposure surveillance are imperative for mitigating the burden of liver cancer. This review provides a comprehensive perspective on the toxicological mechanisms and carcinogenic risks of AA, offering insights into precision prevention and intervention strategies.

Metabolic reprogramming is one of the fundamental characteristics of thyroid cancer (TC), which meets its energy and biosynthetic demands through mitochondrial dysfunction, glycolysis activation, lipid metabolism imbalance, and glutamine dependency, thereby promoting metastasis and reshaping the immune microenvironment. Exosomes, as extracellular vesicles, play a crucial role in TC by delivering bioactive molecules such as proteins, lipids, and nucleic acids. In the tumor microenvironment (TME) of TC, exosomes secreted by both tumor and non-tumor cells interact with each other, driving metabolic reprogramming and forming a bidirectional regulatory network. This significantly alters the biological characteristics of TC cells, including proliferation, invasion, metastasis, angiogenesis, and the acquisition of drug resistance and immune tolerance, ultimately influencing the process of immune escape in TC. This review systematically summarizes how exosomes in the TME of TC promote tumor progression through metabolic reprogramming, providing new diagnostic and therapeutic strategies for patients with locally advanced, radioiodine-refractory TC.

Long non-coding RNAs (lncRNAs) are pivotal regulators of gene expression across multiple biological contexts, including stress responses and cellular adaptation. Activating transcription factor 4 (ATF4) is a key transcriptional effector of the integrated stress response (ISR), modulating genes involved in redox balance, amino acid metabolism, autophagy, and apoptosis. Emerging evidence has uncovered complex interactions between ATF4 and lncRNAs in systemic diseases, where lncRNAs can act as either downstream targets or upstream modulators of ATF4 signaling. This bidirectional crosstalk influences critical processes such as tumor progression, metabolic reprogramming, immune evasion, and skeletal homeostasis. In this review, we comprehensively summarize the regulatory roles of ATF4–lncRNA interactions in four major physiological systems: digestive, respiratory, immune, and skeletal. Furthermore, we highlight the therapeutic potential of selectively targeting these lncRNAs to modulate ATF4-mediated stress responses in a disease- and context-dependent manner. Our insights provide a conceptual framework and translational perspective for future research and precision therapies targeting the ATF4–lncRNA regulatory axis.

In this study we examined the effect of interleukin 4 (IL 4) on T cell activation and proliferation via the alternative CD2 pathway. To this end highly purified human resting T cells were cultured with a stimulating pair of anti-CD2 monoclonal antibodies in the absence of accessory signals from monocytes. Addition of either recombinant (r)IL 2 or rIL 4 resulted in proliferation of the anti-CD2-stimulated T cells. The growth-promoting effect of rIL 4 on preactivated. T cells was shown to be partly a direct effect. rIL 4 also induced IL 2 production and, as a consequence, the effect of rIL 4 on T cell growth was enhanced by endogenously produced IL 2. Moreover, rIL 4 acted in synergy with exogenously added rIL 2 in promoting growth of anti-CD2-stimulated T cells. The synergistic effect of IL 2 and IL 4 could be explained by IL 2-induced up-regulation of IL 4 responsiveness. In contrast, preincubation with rIL 4 did not enhance IL 2 responsiveness and rIL 2 but not rIL 4 up-regulated IL 2R expression on anti-CD2-stimulated T cells. Finally we could demonstrate that monocyte-produced cytokines (IL 1 and IL 6) enhance the proliferative response to rIL 4 of anti-CD2-stimulated T cells. It can be concluded that IL 4 can act as a paracrine growth factor for T cells activated in the alternative CD2 pathway, and that it acts synergistically with IL 2, IL 1 and IL 6. Moreover, IL 4 is a helper signal for IL 2 production. Thus, IL 2 and IL 4 are involved in a bidirectional regulatory network, with IL 4 as an inducer of IL 2 production, and IL 2 as an enhancer of IL 4 responsiveness.

Stability and bifurcation of delayed bidirectional gene regulatory networks with negative feedback loops

microRNAs (miRNAs) are short non-coding RNAs with regulatory functions in various biological processes including cell differentiation, development and oncogenic transformation. They can bind to mRNA transcripts of protein-coding genes and repress their translation or lead to mRNA degradation. Conversely, the transcription of miRNAs is regulated by proteins including transcription factors, co-factors, and messenger molecules in signaling pathways, yielding a bidirectional regulatory network of gene and miRNA expression. We describe here a least angle regression approach for uncovering the functional interplay of gene and miRNA regulation based on paired gene and miRNA expression profiles. First, we show that gene expression profiles can indeed be reconstructed from the expression profiles of miRNAs predicted to be regulating the specific gene. Second, we propose a two-step model where in the first step, sequence information is used to constrain the possible set of regulating miRNAs and in the second step, this constraint is relaxed to find regulating miRNAs that do not rely on perfect seed binding. Finally, a bidirectional network comprised of miRNAs regulating genes and genes regulating miRNAs is built from our previous regulatory predictions. After applying the method to a human cancer cell line data set, an analysis of the underlying network reveals miRNAs known to be associated with cancer when dysregulated are predictors of genes with functions in apoptosis. Among the predicted and newly identified targets that lack a classical miRNA seed binding site of a specific oncomir, miR-19b-1, we found an over-representation of genes with functions in apoptosis, which is in accordance with the previous finding that this miRNA is the key oncogenic factor in the mir-17-92 cluster. In addition, we found genes involved in DNA recombination and repair that underline its importance in maintaining the integrity of the cell.

BackgroundEpitranscriptomics, the study of RNA modifications such as N6-methyladenosine (m6A), provides a novel layer of gene expression regulation with implications for numerous biological processes, including cellular adaptation to hypoxia. Hypoxia-inducible factor-1 (HIF-1), a master regulator of the cellular response to low oxygen, plays a critical role in adaptive and pathological processes, including cancer, ischemic heart disease, and metabolic disorders. Recent discoveries accent the dynamic interplay between m6A modifications and HIF-1 signaling, revealing a complex bidirectional regulatory network. While the roles of other RNA modifications in HIF-1 regulation remain largely unexplored, emerging evidence suggests their potential significance.Main bodyThis review examines the reciprocal regulation between HIF-1 and epitranscriptomic machinery, including m6A writers, readers, and erasers. HIF-1 modulates the expression of key m6A components, while its own mRNA is regulated by m6A modifications, positioning HIF-1 as both a regulator and a target in this system. This interaction enhances our understanding of cellular hypoxic responses and opens avenues for clinical applications in treating conditions like cancer and ischemic heart disease. Promising progress has been made in developing selective inhibitors targeting the m6A-HIF-1 regulatory axis. However, challenges such as off-target effects and the complexity of RNA modification dynamics remain significant barriers to clinical translation.ConclusionThe intricate interplay between m6A and HIF-1 highlights the critical role of epitranscriptomics in hypoxia-driven processes. Further research into these regulatory networks could drive therapeutic innovation in cancer, ischemic heart disease, and other hypoxia-related conditions. Overcoming challenges in specificity and off-target effects will be essential for realizing the potential of these emerging therapies.

Colorectal cancer (CRC) is a highly aggressive malignancy characterized by complex metabolic reprogramming, a hallmark that provides both biosynthetic precursors and signaling molecules to support tumor growth, invasion and therapeutic resistance. A key mechanism underlying this metabolic rewiring is the dynamic interplay between the host and gut microbiota. Gut microbiota derived metabolites, including short-chain fatty acids, secondary bile acids, polyamines and tryptophan derivatives, extensively reshape the CRC metabolic network and modulate the immune microenvironment, thereby influencing tumor progression and therapy response. This review systematically outlines the core features and molecular mechanisms of metabolic reprogramming in CRC, highlights the role of microbiota–host co-metabolism in regulating energy acquisition and immune-metabolic crosstalk, and discusses emerging therapeutic strategies that integrate metabolic targeting and microbiota modulation for precision intervention in CRC.

Acetylation modification and autophagy are fundamental mechanisms regulating cell fate and homeostasis, exhibiting a highly coordinated and dynamic interplay in cancer development. Emerging studies have revealed that acetylation modulates the activation and inhibition of autophagy by regulating the activity, stability, and subcellular localization of autophagy-related proteins. Conversely, autophagy reciprocally influences cellular acetylation levels through selective degradation of acetyltransferases and deacetylases, as well as modulation of acetyl-CoA metabolism, forming a complex bidirectional regulatory network. In cancer, this crosstalk critically contributes to metabolic reprogramming, migration and invasion, therapeutic resistance, and adaptation to the tumor microenvironment, thereby influencing tumor progression and prognosis. This review systematically summarizes the functional roles and interaction mechanisms of acetylation and autophagy across various cancer types, with a particular focus on small-molecule agents targeting this axis and their current status in clinical applications. Although these therapeutic strategies have demonstrated promising anti-tumor potential in both preclinical and clinical settings, challenges such as limited drug specificity, mechanistic heterogeneity, and acquired resistance remain to be addressed. Future research should explore non-canonical forms of acetylation, immune regulation within the tumor microenvironment, and personalized therapeutic models, aiming to identify key regulatory nodes in the acetylation–autophagy network and unlock their potential for precision cancer therapy.

Pulmonary arterial hypertension (PAH) is a fatal disease with extremely poor prognosis, primarily driven by persistent pulmonary vascular remodeling. The disease often presents insidiously and progresses rapidly. Although current targeted therapies may slow disease progression, they fall far short of reversing pathological changes, underscoring the urgent need for novel therapeutic breakthroughs and precise diagnostic approaches. Within this context, microRNA (miRNA) regulatory networks - key nodes of epigenetic regulation - have emerged as a potential bridge between basic science and clinical translation. Increasing evidence has shown that specific miRNAs, by targeting signaling pathways such as PI3K/AKT and TGF-β/Smad, orchestrate complex multi-target molecular cascades that critically regulate pathological processes, including endothelial dysfunction, abnormal proliferation and phenotypic switching of smooth muscle cells, inflammatory activation, and metabolic remodeling. These mechanisms ultimately drive irreversible vascular remodeling. Aberrant expression patterns of miRNAs are not only closely associated with disease severity but also hold great promise as non-invasive biomarkers, facilitating early detection, subtype classification, and prognostic assessment of PAH. Importantly, miRNA-targeted nucleic acid therapeutics have demonstrated therapeutic potential in preclinical models, including reversal of vascular remodeling and improvement of hemodynamics, highlighting their potential in future precision medicine strategies. However, clinical translation faces multiple barriers, such as poor targeting efficiency of delivery systems, unpredictable off-target effects, significant inter-individual variability, and lack of standardized efficacy evaluation frameworks. Therefore, systematic breakthroughs are urgently needed. This review aims to comprehensively summarize the role of miRNA regulatory networks in the pathogenesis, diagnosis, and treatment of PAH, with a particular emphasis on their central position in shaping early-stage precision intervention strategies.

This study looked into the underlying mechanisms and causal relationship between alcoholic liver disease (ALD) and the blood metabolite uridine using a variety of analytical methods, such as Mendelian randomization and molecular dynamics simulations. We discovered uridine to be a possible hepatotoxic agent aggravating ALD by using Mendelian randomization (MR) analysis with genome-wide association study (GWAS) data from 1416 ALD cases and 217,376 controls, as well as with 1091 blood metabolites and 309 metabolite concentration ratios as exposure factors. According to network toxicology analysis, uridine interacts with important targets such as SRC, FYN, LYN, ADRB2, and GSK3B. The single-cell RNA sequencing analysis of ALD tissues revealed that SRC was upregulated in hepatocytes and activated hepatic stellate cells. Subsequently, we determined the stable binding between uridine and SRC through molecular docking and molecular dynamics simulation (RMSD = 1.5 ± 0.3 Å, binding energy < −5.0 kcal/mol). These targets were connected to tyrosine kinase activity, metabolic reprogramming, and GPCR signaling by Gene Ontology (GO) and KEGG studies. These findings elucidate uridine’s role in ALD progression via immunometabolic pathways, offering novel therapeutic targets for precision intervention. These findings highlight the necessity of systems biology frameworks in drug safety evaluation, particularly for metabolites with dual therapeutic and toxicological roles.

Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. It is characterized by an extremely poor prognosis. Radiofrequency ablation (RFA) and microwave ablation (MWA) have become the main local therapies for early HCC. Nevertheless, the high recurrence rate is a key factor that limits the efficacy of thermal ablation. Numerous studies have suggested that HCC recurrence after thermal ablation involves many mechanisms. These include remodeling of immunosuppressive microenvironment, evasion of programmed cell death, metabolic reprogramming, reprogramming of metabolic adaptation, activation of epigenetic aberrations, acquisition of stemness traits, enhancement of epithelial-mesenchymal transition (EMT), induction of angiogenesis, and regulation by non-coding RNAs. To tackle these underlying mechanisms, precision intervention strategies have been gradually developed. These included, but were not limited to, immune-targeted therapy, modulation of cell death pathways, regulation of metabolic pathways, epigenetic therapeutic strategies, stem cell inhibition interventions, EMT reversal therapy, anti-angiogenesis interventions, and multi-target combination strategies. Our review systematically summarizes the research progress from 2017 to 2025, classifying the multidimensional molecular mechanisms and precision intervention strategies for HCC recurrence following thermal ablation. This provides a theoretical foundation for individualized comprehensive treatment and future research directions.

Atherosclerosis is a complex systemic inflammatory metabolic disease, which originates from endothelial dysfunction and progresses through plaque formation involving vascular smooth muscle cells (VSMCs) and macrophage uptake of modified low-density lipoprotein (LDL). These processes lead to vascular stenosis, plaque rupture, and potentially sudden death. Metabolic dysregulation and cellular remodeling are fundamental to the pathogenesis of atherosclerosis. In this review, we summarize recent advances in the metabolic reprogramming of major cell types (including endothelial cells, VSMCs, and macrophages) during atherosclerosis progression. Furthermore, we discuss the crosstalk among these cells mediated by such metabolic alterations. Finally, we highlight the implications of metabolic reprogramming for targeted therapeutic strategies, offering insights for precision intervention in aortic atherosclerosis.

Myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) exist among a spectrum of myeloid malignancies, governed by critical genetic dependencies, and propagated by a ripe pro-inflammatory niche. We previously identified elevated RPS6KA1 (RSK1) expression in myeloid malignancies associated with poor overall survival. Here, we demonstrate that RSK1 plays a fundamental role in mediating inflammation and serves as a central signaling node driving leukemogenesis. We further evaluate a novel therapeutic regimen utilizing a first-in-class RSK1 inhibitor, PMD-026, currently evaluated in Phase 1/1b clinical trials for breast cancer, for use in myeloid malignancies. Plasma analysis of 144 MPN patients and RNA-seq of CD14+ monocytes from 54 MPN patients revealed enrichment of inflammatory cytokines and hyperactive NFκB signaling. RSK1 inhibition by shRNA or PMD-026 in THP-1 monocytic AML cells potently suppressed this NFκB node, decreased TNF and NFKB1 mRNA, and reduced luminescence in cells expressing a NFκB-luciferase reporter. Immunoblotting and cytokine mass cytometry revealed suppression of RelA/p65 phosphorylation with reduction of TNF, IL-6, IL-8, CCL3, and CCL4 in MPN and CMML CD14+ monocytes. We also observed that RSK1 inhibition attenuated NFκB activation by TNF, LPS, and Pam3CSK4, while also suppressing monocyte differentiation to M1 macrophages. In the MPL W515L myelofibrosis (MF) model, mice treated with PMD-026 had significant reduction in TNF, IL-6, IL-1b, CCL3, and CCL5 by multiplex cytokine profiling and diminished disease burden (reduction of leukocytosis, splenomegaly, and bone marrow fibrosis). Finally, amelioration of disease was observed across MF and sAML patient-derived xenograft (PDX) models with PMD-026 treatment. We extended our findings to FLT3-ITD de novo AML models, in which RSK1 inhibition led to lethality in FLT3-ITD cells and PMD-026 potently suppressed leukemic engraftment in a MV4-11 mouse xenograft. Both genetic and pharmacological inhibition of RSK1 reduced FLT3 phosphorylation and revealed a novel, bi-directional regulatory network. Moreover, we found that RSK1 perturbation also attenuated FLT3 expression and altered protein stability, which was not observed with FLT3 inhibitor quizartinib. Mechanistically, RSK1 modulated FLT3 dynamics through deubiquitinase USP1, which was downregulated upon RSK1 perturbation. USP1 perturbation led to cell death and phenocopied FLT3 suppression observed with RSK1 inhibition. We further identified elevated USP1 expression associated with worse survival outcomes across the TCGA LAML, BeatAML, and Leucegene cohorts, thus indicating the potential of USP1 as a novel biomarker. We uncover a role for targeting RSK1 as a two-pronged approach in reducing disease burden across myeloid malignancies via: 1) suppressing driver signaling, and 2) dampening the pro-inflammatory milieu. These findings highlight a critical dependency along the RSK1-USP1-FLT3 axis that is potentially exploitable with RSK1 inhibitors such as PMD-026. Citation Format: Tim Kong, Angelo Laranjeira, Stephen Oh. RSK1 targeting impedes oncogenic driver and inflammatory cytokine signaling to attenuate myeloid neoplasms [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr PR02.