Growing evidence suggests that chronic substance use disrupts the gut microbiota composition and function, which can contribute to intestinal dysfunction, systemic inflammation, and gut-brain axis dysregulation. However, current evidence remains fragmented and heterogenous, with most studies focusing on individual substances rather than substance-specific microbial signatures. Therefore, this systematic review synthesizes recent evidence (2019-2025) to characterize the impact of chronic substance use, including alcohol, nicotine, opioids, cocaine, and methamphetamine, on the gut microbiota composition and functional integrity. Following the PRISMA 2020 guidelines, a total of 91,421 records were identified before screening through searches conducted across electronic databases and publisher platforms, including PubMed, Web of Science, ProQuest, and BSCOhost, among others. After duplication removal and application of the predefined eligibility criteria, 60 studies were selected for qualitative analysis. The findings revealed an interspecies similarity in which chronic substance exposure generally induced dysbiosis characterized by a depletion of beneficial short-chain fatty acid (SCFA)-producing taxa, such as Lactobacillus, Akkermansia, and Faecalibacterium, alongside the enrichment of opportunistic pathogens such as Escherichia-Shigella. Alcohol emerged as a particularly potent ecological driver, consistently reducing the richness and diversity of the microbial community. Mechanistically, these alterations are linked to impaired intestinal barrier function, increased lipopolysaccharide translocation, and the activation of systemic inflammatory pathways. Furthermore, substance-specific metabolic fingerprints were identified, including disruptions in glutamate pathways for cocaine and trimethylamine N-oxide precursors for methamphetamine. Preclinical evidence from fecal microbiota transplantation and germ-free models suggests that these microbial shifts actively modulate reward sensitivity and neuroplasticity through the gut-brain axis. Collectively, the data presented in this study support a shift from reductionist addiction models toward a systems-level framework, positioning the gut microbiome as a pivotal, modifiable component of addiction biology and a promising target for novel therapeutic interventions.
Addiction is a brain disorder marked by profound inter-individual heterogeneity, a factor that limits the clinical utility of group-level neuroimaging findings. To address this, we constructed a precision neuroimaging framework to capture individual variability. We quantified gray matter volume (GMV) deviations in 464 individuals with five substance-related and addictive disorders using a normative model derived from over 1000 healthy controls. Subsequently, we applied a dimensionality reduction technique to decompose these individual deviations into distinct spatial patterns. We observe a shared pattern involving the insula and prefrontal cortex that reflects common underlying biology across different addictions. In contrast, a pattern centered on the basal ganglia captures the differences between specific addiction types. Importantly, only transdiagnostic factors correlated with clinical measures, whereas the heterogeneity factor did not. By resolving neurobiological heterogeneity into distinct, structural atrophy subtypes, this framework offers insights into understanding structural heterogeneity as a local effect of common networks. Addiction affects the brain differently in every person. This study aimed to map these individualized brain changes. We compared brain scans of 464 people with various addictions against over 1000 healthy individuals to measure personalized patterns of brain shrinkage. We found that addiction involves both shared and highly specific physical brain changes. Recognizing these subtypes helps the public understand that addiction is a biologically diverse condition.
Nicotine addiction and toxicity are complex neurobiological conditions that exerts both toxicological and rewarding effects through nicotinic acetylcholine receptors (nAChRs), which are conventionally treated as separable phenomena, yet the relationship and shared overlapping neurobiological effects remains incompletely understood. This study combined biochemical profiling, transcriptomics, genetics, and olfactory conditioning to examine the mechanisms underlying nicotine's systemic toxicity, cellular stress responses, and addiction-like behavior in Drosophila melanogaster, with a focus on α7 and β2 nAChR subunits. Chronic dietary nicotine exposure (0.15, 0.25, and 0.35 mg/mL for 5 days) reduced survival and locomotor performance, increased reactive oxygen species levels, depleted total thiols, and suppressed acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymatic activities in control flies; these effects were attenuated innAChRα7-/- and nAChRβ2-/- In addition, transcriptomic re-analysis of a publicly available microarray dataset revealed a coordinated cellular stress response in nicotine-exposed flies, including the altered expression of detoxification genes, odorant-binding protein Obp56h and mechanosensory genes. Behaviorally, nicotine exposure during conditioning altered the innate odor valence and resulted in a persistent punishment-resistant odor preference, defined here as addiction-like behavior; this nicotine-induced reassignment was not observed in mutant flies. Collectively, these data suggest that α7- and β2-nAChR subunits function are mediators of nicotine's toxicological and behavioral effects, and support the use of Drosophila as a model the investigation of nicotinic effects, while recognizing that direct equivalence with mammalian addiction circuitry should not be assumed.
This study employed a network meta-analysis to evaluate and compare the efficacy of different exercise intensities (light, moderate and vigorous) on internet addiction and related psychological symptoms in adolescents and young adults. We systematically searched eight databases for relevant randomised controlled trials. A total of 22 studies with 1438 samples were included. A pairwise meta-analysis indicated that exercise interventions across all intensities were associated with improvements in internet addiction, anxiety and negative moods, with moderate-intensity additionally improving depression. The results of the network meta-analysis suggested that light-intensity exercise (SMD = -2.61, 95% CI [-4.29, -0.93], p = 0.002), moderate-intensity exercise (SMD = -2.74, 95% CI [-4.25, -1.22], p < 0.0001) and high-intensity exercise (SMD = -2.55, 95% CI [-4.88, -0.22], p = 0.032) may be associated with a reduction in adolescents' internet addiction. Only moderate-intensity exercise may be associated with a reduction in depression (SMD = -1.19, 95% CI [-2.20, -0.18], p = 0.021) and anxiety (SMD = -1.90, 95% CI [-3.50, -0.30], p = 0.02); light-intensity and high-intensity exercise were not significantly associated with a reduction in depression and anxiety. Light-intensity exercise (SMD = -1.63, 95% CI [-2.85, -0.41], p = 0.009) and moderate-intensity exercise (SMD = -1.55, 95% CI [-2.56, -0.54], p = 0.003) may be associated with reductions in other negative moods. According to the probability ranking of the likelihood of the optimal intervention effect, moderate-intensity exercise (SUCRA = 71) ranked highest for interventions in adolescents' internet addiction, depression (SUCRA = 70.2), anxiety (SUCRA = 68.4) and light exercise (SUCRA = 67.9) ranked highest for negative moods. However, owing to the limitations of sample size and the quality of individual studies, the strength of evidence needs to be further validated by more standardised, high-quality studies.
Breast cancer (BC) continues to pose a substantial clinical challenge due to acquired resistance induced by epithelial-mesenchymal transition (EMT). Nevertheless, this adaptive evolution, which frequently takes the form of a highly plastic, partial EMT (p-EMT) state, induces a profound lipidomic reconfiguration and iron dysregulation, thereby inadvertently revealing a targetable metabolic vulnerability: ferroptosis. In this Perspective, we outline the hierarchical molecular logic that governs this susceptibility, emphasizing the manner in which progressive p53 mutations (ranging from loss-of-function to gain-of-function) transform p-EMT cells from passive sensitization to an extreme "metabolic addiction." We argue that conventional "occupancy-driven" kinase inhibitors are unable to eliminate these resistant populations because they are unable to dismantle the essential non-catalytic scaffolding functions of core EMT-induced kinases (EIKs). As a result, we suggest a paradigm shift toward a chemical biology approach that is "event-driven." The p-EMT infrastructure can be irreversibly destroyed and resistant cells can be compelled to undergo catastrophic lipid peroxidation by deploying proteolysis targeting chimeras (PROTACs) against concealed scaffold super-hubs, particularly AXL and lemur tail kinase 3 (LMTK3), which are indispensable for stabilizing the hybrid p-EMT infrastructure. Additionally, we investigate the spatiotemporal modulation of this synthetic lethal axis by the tumor microenvironment (TME) through matrix mechanics and extracellular vesicles (EVs). Ultimately, we suggest a multimodal liquid biopsy strategy that couples specific oxidized phospholipid signatures with circulating tumor DNA (ctDNA) kinetics to precisely monitor in vivo ferroptotic events. This approach offers a transformative roadmap for eradicating minimal residual disease (MRD) and surmounting BC dormancy.
Although Rho kinase (ROCK) has been studied in tumor progression, the reliance of some cancer cells on ROCK-Myosin II for survival remains poorly understood. Using systematic analysis of ROCK inhibitor sensitivity in hundreds of cancer cell lines, we find that ROCK inhibition reduces survival of highly de-differentiated, invasive cancer cells from solid tumors. Transcriptomic analysis reveals enrichment in epithelial-to-mesenchymal transition, migration, proliferation, and inflammation genes, with reduced expression of differentiation and cell-cell junction genes like E-cadherin (CDH1). Acute myeloid leukemia (AML) shows high ROCK inhibitor response among hematological malignancies. Using in vitro and in vivo approaches, we validate biomarkers of ROCK inhibitor sensitivity in breast cancer, melanoma, and AML, demonstrating their unique addiction to Rho-ROCK-myosin II signaling for survival. Our work has important pre-clinical implications while cautions against wider use of ROCK inhibitors in patient-derived organoid cultures, where they may deplete important cancer cell populations.
Drug addiction is a complex, chronic, and relapsing neurological disorder characterized by persistent neuroadaptation and a substantial public health burden. Because of its simple nervous system, genetic tractability, short life cycle, transparent body, and quantifiable behavioral phenotypes, C. elegans (Caenorhabditis elegans) has become a useful complementary model for studying selected aspects of drug-induced behavioral adaptation. This review summarizes recent advances in the use of C. elegans to study opioids, amphetamine-type stimulants, cocaine, ketamine, ethanol, nicotine, and related anesthetic or depressant-type compounds. We discuss commonly used behavioral paradigms, including conditioned cue preference, swimming-induced paralysis, tolerance assays, withdrawal-like responses, chemotaxis, and locomotor adaptation, together with dopaminergic, cholinergic, serotonergic, gamma-aminobutyric acid (GABA)-mediated, neuropeptidergic, ion-channel, oxidative-stress, transcriptional, and epigenetic mechanisms. The main limitations of this model are also considered, including the lack of mammalian reward-circuit complexity, nematode-specific pharmacokinetic features, cuticle permeability, and limited direct translational validation. Overall, C. elegans is best used as a mechanistic and screening-level model to identify conserved pathways and candidate targets that require further validation in mammalian systems.
Brain insulin action was measured in adolescents with (cases) and without (controls) depression, by calculating the difference in resting-state functional connectivity (ΔrsFC) following an intranasal insulin challenge. A significant Group × Condition interaction effect was identified: controls exhibited greater ΔrsFC with intranasal insulin compared to cases in brain regions regulating cognitive/emotional processing.
Although opioids are effective analgesics, they can lead to problematic drug use behaviors that underlie opioid use disorder (OUD). Opioids also cause gut microbiota dysbiosis, which is linked to altered opioid responses. We used a longitudinal paradigm of voluntary oral morphine self-administration to capture multiple facets of drug seeking and preserve both individual behavioral responses and individual gut microbiota variation to investigate the role of the gut microbiota in a mouse model of OUD. Although all the mice consumed morphine, only a subset of the mice that transitioned to a state we defined statistically as compulsive. In compulsive mice, morphine constricted natural variability and fragmented the microbiota community networks, which convergently reorganized to form robust novel connections post-morphine. In contrast, the more variable communities of non-compulsive mice were highly interconnected during morphine disturbance and displayed more continuity post-morphine, suggesting greater flexibility and adaptability. Compulsive mice displayed a greater loss of functional diversity and a shift in favor of potential pathobionts, whereas non-compulsive mice better preserved genera associated with gut health and broader functional diversity. These findings highlight the potential role of persistent and stable opioid-induced microbiota dysbiosis in long-term behavioral changes underlying OUD and contributing to vulnerability to relapse.
Underage drinking has become a global public health concern. One of the major causes of underage drinking is stress. The orexin system has been reported to be involved in both alcohol addiction and stress. However, few studies have examined this system, especially among adolescents. Therefore, we constructed protein-protein interaction (PPI) networks to confirm that orexin receptors are connected to stress- and alcohol dependence-related genes, providing a theoretical basis for our experimental approach. Animal experiments employed the conditioned place preference (CPP), the foot-shock stress model and the enzyme-linked immunosorbent assay (ELISA), to elucidate the role of the orexin system in the stress-induced alcohol addiction-related behaviour among adolescent mice. Our results revealed that there were interactions among orexin system, chronic/acute stress and alcohol dependence related proteins. Otherwise, chronic stress can increase the animals' vulnerability to alcohol addition-related behaviour. Additionally, acute foot-shock can promote alcohol-seeking behaviour reinstatement and facilitate orexin concentrations in brain regions that have been shown to be associated with reward and addiction. Moreover, the inhibition of orexin receptors can attenuate the formation and reinstatement of alcohol addiction-like behaviour among adolescent mice. Collectively, our findings indicate that orexin system may be a pivotal target for preventing stress-induced alcohol addiction and reinstatement among the adolescents.
Sleep disturbances are common in individuals with Internet gaming disorder (IGD), yet the neurobiological links between poor sleep quality and addictive symptoms remain unclear. The glymphatic system contributes to cerebrospinal fluid-interstitial fluid exchange and metabolic waste clearance, processes that are closely related to sleep physiology. Diffusion tensor image analysis along the perivascular space (DTI-ALPS) provides a non-invasive MRI-based marker related to glymphatic system function. In parallel, middle frontal gyrus (MFG)-centred functional connectivity may reflect prefrontal network alterations associated with cognitive control and addiction severity in IGD. The study included 30 individuals with IGD and 37 demographically matched healthy controls (HCs). All participants underwent diffusion tensor imaging and resting-state functional MRI. DTI-ALPS was used to assess glymphatic system-related function. Resting-state functional connectivity analysis was performed using the MFG as the seed region. Group differences in ALPS indices were tested while controlling for age, education years and mean framewise displacement. Within the IGD group, correlation analyses were conducted to examine associations among ALPS indices, PSQI scores, MFG-centred functional connectivity and IAT scores. Individuals with IGD showed significantly lower mean and left ALPS indices than HCs. The right ALPS index showed a non-significant trend towards reduction. Within the IGD group, higher PSQI scores were associated with lower mean, left and right ALPS indices, suggesting that poorer subjective sleep quality was related to reduced glymphatic system-related function. MFG-centred functional connectivity analysis showed increased connectivity mainly involving medial and superior frontal regions and decreased connectivity involving subcortical regions. Stronger MFG-centred functional connectivity was positively correlated with IAT scores, indicating an association with greater addiction severity. This study integrates DTI-ALPS and MFG-centred resting-state functional connectivity to examine sleep-related glymphatic alterations and prefrontal network changes in IGD. Lower ALPS indices were associated with poorer sleep quality, whereas stronger MFG-centred connectivity was associated with greater addiction severity. These findings support a potential sleep-glymphatic-prefrontal network framework for understanding IGD. Longitudinal and interventional studies are needed to clarify the directionality of these associations.
Addiction is a chronic and relapsing disorder that affects millions of people worldwide; nonetheless, currently available FDA-approved treatments are limited in number and effectiveness. In past years, the gut-brain axis has emerged as a key modulatory factor associated with different psychiatric disorders, including addiction. Working in mice, we have shown that cocaine exposure alters the composition of the gut microbiome, increasing the abundance of Proteobacteria. This microbial shift, in turn, leads to a depletion in host glycine levels, altering cocaine-induced transcriptional changes in the Nucleus Accumbens (NAc) and facilitating the development of behavioral sensitization and conditioned place preference. Among the behavioral models to study psychostimulant use disorders, cocaine self-administration (SA) remains the most translational. Therefore, here we investigated whether Proteobacteria-induced glycine depletion can affect cocaine SA in mice. Using the human Escherichia coli HS and the glycine-uptake-deficient mutant E. coli HS ΔCycA, we build upon our previous findings and demonstrate that the ability of gut Proteobacteria to use glycine during cocaine SA shapes the trajectory and long-term neurobehavioral plasticity induced by the drug. Furthermore, we show that this bacterial-induced glycine depletion impacts the NAc proteome, altering its vulnerability to undergo molecular adaptations across different stages of the SA paradigm. Altogether, our findings show that the gut microbiome, and particularly the Proteobacteria phylum, is a crucial factor influencing short and long-term adaptation underlying motivation and cocaine-seeking behaviors.
Opioid use disorder (OUD) remains a critical global health challenge. The nucleus accumbens (NAc), a key region of the brain reward system, plays an essential role in opioid-induced neuroadaptations. Characterizing gene expression alterations in reward-system regions, such as the NAc, is essential for elucidating the molecular mechanisms underlying addiction. In recent years, bioinformatics has emerged as a rapidly advancing field and has played a pivotal role in elucidating molecular mechanisms and in advancing computational biology. This study aimed to characterize transcriptomic changes in the NAc of mice following chronic morphine administration using RNA sequencing and bioinformatic analysis. RNA sequencing (RNA-Seq) data from morphine- and saline-treated mice were obtained from the Gene Expression Omnibus database via the Sequence Read Archive. Following quality control and alignment, differentially expressed genes (DEGs) were identified using the DESeq2 package in R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, as well as protein-protein interaction (PPI) network analyses, were performed to evaluate the functional implications of these genes. Principal component analysis (PCA) revealed distinct transcriptomic profiles between the morphine and control groups. A total of 143 DEGs were identified, including 125 up-regulated and 18 down-regulated genes. Enrichment analyses indicated significant involvement in synaptic signaling, ion transport, and neurodegenerative pathways. Protein-protein interaction (PPI) network analysis identified several hub genes, including fgf3 (fibroblast growth factor 3), mki67 (marker of proliferation Ki-67), grin2a/grin2b (glutamate receptor NMDA subunits 2A/2B), gli1 (GLI family zinc finger 1), and ago2 (argonaute RISC catalytic component 2), which are associated with synaptic plasticity, neurogenesis, and epigenetic regulation. Chronic morphine exposure induces widespread gene expression changes in the NAc, engaging pathways associated with synaptic remodeling, neuronal excitability, and addiction-related neuroplasticity. These findings provide a molecular framework for understanding opioid-induced adaptations and identify candidate targets, including N-methyl-D-aspartate (NMDA) receptor subunits, fgf3, and ago2, for potential therapeutic intervention. Future studies should functionally validate these targets and evaluate their translational relevance in the context of OUD.
Acute myeloid leukemia (AML) pathogenesis is deeply rooted in the concept of clonal evolution, in which hematopoietic stem cells experience an initial genetic insult, followed by the sequential acquisition of mutations leading to various disease phenotypes. Through natural selection, a malignant clone can diversify and propagate with time. Aside from clonal evolution, a number of time-honored principles of molecular oncology account for the initiation and maintenance of AML. These principles include loss of heterozygosity, genomic instability, epigenomic disruption, deregulation of signaling pathways, anti-apoptotic mechanisms, and oncogene addiction. Such tenets of cancer biology not only explain AML cellular behavior but also may inform target validation in AML. Herein, we highlight the current state of targeted therapeutics, including the 14 novel agents (beyond 7+3 chemotherapy) approved by the Food and Drug Administration, in the context of these tenets and discuss future prospects by leveraging current knowledge of AML genomics. Such therapeutic concepts, including synthetic lethality, are especially relevant to TP53-mutant AML, as there are no unique therapies that have received regulatory approval for this subset to date. We emphasize the emerging role of single-cell genomics and multi-omics toward better understanding of AML biology and development of future successful AML therapies.
MicroRNAs, small noncoding RNA molecules, are pivotal regulators of gene expression and have been increasingly implicated in the molecular mechanisms underlying addiction. In this study, we investigated microRNA expression profiles in postmortem nucleus accumbens tissue, a key brain region for reward and addiction, from individuals with 6-monoacetylmorphine confirmed heroin-associated polysubstance intoxication (6-MAM-HAPI) (n = 20) compared with non-user individuals (n = 20). Total RNA was isolated from the tissues with "RNAzol®RT," and cDNA was obtained and measured by qRT-PCR. MicroRNA expression levels were calculated by the 2-ΔΔCT method. Our study revealed a distinct pattern of dysregulation, with downregulation of miR-132, miR-140, miR-181a, miR-206, miR-212, and miR-339-5p, alongside a significant upregulation of miR-133b in nucleus accumbens of 6-MAM-HAPI. These findings provide preliminary postmortem evidence suggesting possible miRNA expression changes in the nucleus accumbens in the context of 6-MAM-HAPI.
Proteasome inhibitors are approved to treat multiple myeloma and mantle cell lymphoma. Recent reports suggest sarcomas also display proteasome addiction. Mechanistic explanations cite proteotoxic stress. In sarcoma patients, we analyzed the impacts of 377 human E3 ubiquitin ligases on sarcoma patient overall survival (OS) and recurrence-free survival (RFS), identified substrates of E3 ligases with the most significant and robust effects, and performed enrichment analyses. High expression of 102 E3 ligases was associated with shortened OS. Thirteen of these shortened OS by >40 months, six with false-discovery rates (FDR) ≤ 5%. Nineteen showed correlation between increased expression and shortened RFS, two with FDR ≤ 5%. Overexpression of 73 E3 ligases significantly extended OS, with 18 extending OS by >40 months; six with FDR ≤ 5%. Elevated expression of 21 significantly extended RFS, one with FDR ≤ 5%. Enrichment analyses of substrates unique to the E3 ligases whose elevated expression most reliably shortened or extended OS by >40 months revealed non-overlapping functions: the E3 ligases associated with shortened OS uniquely targeted cell cycle, cell-cell communication, cellular responses to stimuli, chromatin organization, DNA repair, DNA replication, hemostasis, reproduction, and vesicle-mediated transport functions. Both OS-impacting E3 ligase sets targeted developmental biology, gene expression, immune system, metabolism of proteins, and signal transduction functions. Three specific functions were targeted by both groups. Functions uniquely targeted by each set of ligases could reveal therapeutic targets with a greater therapeutic index than the proteasome.
Reactive oxygen species (ROS) are important regulators of cancer biology, acting as tumor-promoting signaling mediators and inducers of oxidative cell death. Oncogenic signaling, mitochondrial dysfunction, metabolic rewiring, and microenvironmental stress lead to increased basal ROS levels in cancer cells, resulting in a state of chronic oxidative pressure. Tumors develop adaptive antioxidant programs such as glutathione and thioredoxin, NADPH regeneration pathways, and sustained activation of the Nrf2-Keap1 axis to adapt to these conditions, leading to redox plasticity and "Nrf2 addiction" in some cancers. This adaptive rewiring allows malignant cells to sustain proliferative signaling while evading ROS-induced cytotoxicity and contributes substantially to therapeutic resistance. Despite the great promise of ROS-targeted therapies in preclinical studies, their translation into the clinic has been challenging for decades. Large antioxidant trials failed or even increased cancer risk. Many pro-oxidant therapies have limited efficacy due to a narrow therapeutic window, systemic toxicity, poor tumor selectivity, and a dynamic ability of tumors to reprogram antioxidant defenses. The significant intra-tumoral and spatial heterogeneity of redox status further complicates these constraints, where different tumor regions and cellular subpopulations exhibit different metabolic states, ROS thresholds, and sensitivities to ferroptosis. Emerging evidence indicates that ferroptosis, an iron-dependent cell death triggered by lipid peroxidation, is a significant therapeutic liability of redox-adapted tumors, particularly when antioxidant buffering systems like GPX4, system Xc-, FSP1, or DHODH are impaired. This review discusses the molecular functions of ROS in tumor initiation, progression, immune regulation, metabolic adaptation, and therapeutic resistance and critically analyzes the reasons for clinical challenges in redox-targeted interventions despite extensive research. The review highlights the importance of adaptive antioxidant rewiring, redox-dependent metabolic flexibility, and the complexity of the tumor microenvironment in determining the therapeutic outcome. Finally, novel strategies in precision redox oncology are discussed, including biomarker-driven patient stratification, real-time redox profiling, ferroptosis-targeted therapies, and rational combination approaches with the aim to exploit tumor-specific redox vulnerabilities while minimizing toxicity to healthy tissues.
Tobacco use remains the leading cause of preventable death in the United States (U.S.) and worldwide. The U.S. Food and Drug Administration (FDA) has proposed a product standard to reduce nicotine in cigarettes and other combustible tobacco products to minimally or non-addictive levels, specifically, 0.7 milligrams of nicotine per gram of tobacco. To inform implementation of this standard and future policy directions, the American Thoracic Society's Tobacco Action Committee convened a multidisciplinary workshop that included experts in tobacco treatment, behavioral science, pharmacology, toxicology, pulmonology, cardiology, policy, public health, and advocacy from the U.S., United Kingdom, Lebanon, and Australia. Panelists reviewed the evidence and supported the proposed nicotine standard, citing its potential to reduce addiction, lower daily consumption of smoked tobacco, and increase smoking cessation rates. The panel emphasized that the policy's success depends on a comprehensive rollout strategy that includes complementary measures to protect public health and avoid unintended consequences. These include clear public messaging to prevent misperceptions about product safety, robust surveillance systems to monitor behavioral change and industry responses, and equitable access to FDA-approved cessation support, particularly for disproportionately affected populations. Panelists also addressed the anticipated shift toward non-combustible products, recommending harm minimization strategies, stronger monitoring and enforcement of industry marketing activities, and expanded regulatory authority over emerging products, including nicotine analogues and other addiction-enhancing substances. The panel highlighted the need for improved tools to assess real-world tobacco dependence and toxicant exposure to help ensure that evolving product landscapes are effectively regulated to protect public health.
Oral squamous cell carcinoma (OSCC), a highly prevalent and poor-prognosis malignancy, is closely associated with tumor metabolic reprogramming, particularly the glutamine-dependent metabolic phenotype. This study systematically investigates the role of N6-methyladenosine (m6A) modification in OSCC through integrated bioinformatics analysis and functional experiments, focusing on the tumor-suppressive function of the m6A reader YTHDC2 and its regulation of glutaminolysis. Analysis based on The Cancer Genome Atlas (TCGA) datasets revealed that YTHDC2 expression was significantly inversely correlated with OSCC malignancy and patient survival. Functional validation showed that YTHDC2 depletion promoted OSCC cell proliferation and stem-like properties, whereas YTHDC2 overexpression markedly suppressed these malignant phenotypes. Mechanistic studies demonstrated that YTHDC2 stabilized VHL mRNA by recognizing m6A modification sites, enhancing VHL protein expression. This promoted VHL-mediated ubiquitin-dependent degradation of HIF-1α, leading to transcriptional repression of its downstream target GLS1. Consequently, this blocked glutaminolysis, tricarboxylic acid (TCA) cycle-driven energy production, and glutathione (GSH)-mediated antioxidant pathways. Additionally, low YTHDC2 expression in OSCC tissues was closely associated with DNA hypermethylation at CpG islands in its promoter, an epigenetic silencing mechanism that sustains the glutamine-addicted phenotype. This study first uncovers the core role of the YTHDC2/m6A/VHL/HIF-1α/GLS1 signaling axis in metabolic regulation of OSCC, providing new insights into the molecular basis of glutamine addiction. YTHDC2 not only serves as a prognostic biomarker for OSCC but also highlights its-mediated metabolic pathway as a theoretical basis for developing targeted therapies against glutaminolysis.
Targeting transcriptional condensates is an emerging paradigm for cancer therapy. A key player is the transcriptional coactivator YAP (Yes-associated protein), which drives tumor-specific programs that fuel tumor progression and therapeutic resistance. Cyclin K, partnered with cyclin-dependent kinases (CDKs) CDK12/CDK13, is essential for transcription elongation, but its role in specific oncogenic programs was unclear. Here, we identify Cyclin K as an essential vulnerability across multiple cancer types. The CDK12/Cyclin K complex binds YAP via Cyclin K and forms a regulatory condensate to bridge YAP phosphorylation by CDK12. Such a phosphorylation at threonine-398 impedes YAP inhibition by its canonical LATS kinases, stabilizes YAP, and enables its further condensation with TEAD4 to stimulate YAP oncogenic activity. Coexpression of CDK12/Cyclin K and YAP predicts sensitivity to Cyclin K inhibitors in hepatocellular carcinoma cells and patient-derived xenografts. Thus, we define CDK12/Cyclin K as a critical regulator of YAP-driven transcriptional addiction and a biomarker for patient stratification who mostly benefit from therapies targeting the CDK12/Cyclin K-YAP axis.