Biochemical pharmacology最新文献

{"title":"Ginsenoside Rd: molecular mechanisms, pharmacological activities, and therapeutic potential.","authors":"Xiaoqin Tan, Rui Pu, Ning Zhang, Guangxia Cai, Tao Ye","doi":"10.1016/j.bcp.2026.118033","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118033","url":null,"abstract":"<p><p>Ginsenoside Rd (Rd), a major protopanaxadiol saponin from Panax species, is a pleiotropic candidate with potential relevance for treating ischemic, inflammatory, metabolic, and degenerative diseases. Over the past two decades, evidence from cellular systems, animal models, and early clinical studies indicates that Rd provides multi-level protection by modulating oxidative stress, inflammatory signaling, calcium dysregulation, mitochondrial dysfunction, and regulated cell death. Mechanistic studies implicate interconnected pathways, including PI3K/Akt, ERK, NF‑κB, Nrf2‑mediated antioxidant programs, NLRP3 inflammasome signaling, and context‑dependent regulators such as PARP‑1/AIF, DAPK1-NR2B, and AMPK/SIRT1 in the effects of Rd. Recent work further links Rd to ferroptosis and pyroptosis control, preservation of blood-brain and blood-retinal barrier integrity, and immune microenvironment remodeling. However, despite broad preclinical support, translation remains limited by low oral bioavailability, microbiota‑dependent metabolic variability, and heterogeneity in experimental design and reporting. Intravenous Rd has shown favorable pharmacokinetics and acceptable tolerability in healthy volunteers, while randomized stroke trials have reported signs of functional benefit, supporting continued indication‑focused optimization rather than extrapolation to class‑wide efficacy. Therefore, this review critically synthesizes evidence from the chemical origin and biotransformation of Rd to its molecular pharmacology and disease‑specific efficacy, integrates legacy and emerging data into a unified mechanistic framework, evaluates translational readiness by indication, and proposes a development strategy centered on exposure optimization, biomarker‑guided stratification, and indication‑appropriate trial design. Overall, Rd remains a promising natural‑product scaffold whose clinical value depends on rigorous pharmacologic standardization and precision‑oriented development.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118033"},"PeriodicalIF":5.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological targeting of cholesterol biosynthesis in cancer: Sterol intermediates, oxysterols, and sterol flux rewiring.","authors":"Philippe de Médina, Julio Buñay, Silia Ayadi, Sandrine Silvente-Poirot, Marc Poirot","doi":"10.1016/j.bcp.2026.118003","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118003","url":null,"abstract":"<p><p>Cholesterol metabolism has emerged as an important regulator of tumor cell biology. Beyond its structural role in membranes, the cholesterol biosynthetic pathway generates sterol intermediates and oxidized derivatives able to modulate signaling pathways controlling proliferation, differentiation, and survival. Early studies mainly emphasized the requirement of the mevalonate pathway for cholesterol synthesis and for production of non-sterol isoprenoid intermediates involved in protein prenylation, but increasing evidence indicates that the biological effects of inhibiting cholesterogenesis cannot be explained solely by cholesterol depletion. Blocking specific enzymatic steps frequently causes accumulation of sterol precursors that differ structurally from cholesterol and are highly susceptible to oxygenation under conditions of oxidative stress commonly observed in tumor cells, leading to formation of bioactive oxysterols. Among these metabolites, cholesterol-5,6-epoxides represent a central metabolic node linking sterol imbalance, lipid peroxidation, and sterol signaling. Depending on the enzymatic context, these epoxides can be converted into metabolites with tumor-promoting or tumor-suppressive properties, indicating that inhibition of cholesterol biosynthesis redistributes sterol metabolic flux rather than simply reducing cholesterol levels. Identification of sterol metabolites formed after perturbation of cholesterogenesis remains difficult because many derivatives differ only by subtle structural modifications or exist as stereoisomers, often requiring chemical synthesis of reference compounds and dedicated analytical methods. These observations support the concept of sterol flux rewiring, in which the biological outcome of targeting cholesterol biosynthesis depends on the nature of accumulated intermediates, the oxidative environment, and the enzymatic context of the cell, with important implications for pharmacological targeting of sterol metabolism in cancer.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"250 Pt 2","pages":"118003"},"PeriodicalIF":5.6,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alternative splicing fuels the functional diversity of GPCR in neurological and psychiatric disorders: An emerging path toward RNA-targeted neurotherapeutics.","authors":"Enkai Wang, Yulin Kang, Daichuan Chen, Rongmeng Tian, Yiyue Hu, Hong Wang, Liu Jun, Ziyun Zhou, Tian Tian, Hanli Xu, Jiaqiang Huang","doi":"10.1016/j.bcp.2026.118026","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118026","url":null,"abstract":"<p><p>Dysfunction in intricate neural circuits contributes to numerous neurological and psychiatric disorders, affecting a substantial portion of the global population and significantly contributing to the global disease burden. This highlights the urgent need for more precise therapeutic targets. G protein-coupled receptors (GPCRs) are the predominant targets commonly utilized in the development of novel therapeutics for nervous system disorders. Alternative splicing (AS) generates numerous tissue- and cell type-specific GPCR isoforms that are regulated by cis-acting elements, trans-acting factors, and underlying epigenetic modifications. These isoforms exhibit distinct distributions, leading to signaling bias and conformational diversity. However, their role in GPCR signaling heterogeneity is often overlooked due to limited data on expression and function in various neuropathological conditions. This review examines GPCR splicing variants (SVs) in neurodegenerative diseases such as Alzheimer's and Parkinson's, neuropsychiatric disorders including depression, anxiety, autism spectrum disorder, and schizophrenia, as well as pain and addiction. It emphasizes how alternative splicing shapes tissue-specific GPCR expression and diverse biological functions. Emerging technologies and AI-based structural modeling are underscored as powerful tools for resolving GPCR variant structures and enabling isoform-specific drug development. The review aims to provide new insights into GPCR functional heterogeneity and promote an isoform-focused therapeutic strategy based on GPCR-ligand interactions to guide future treatments.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118026"},"PeriodicalIF":5.6,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832956","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological and neurobehavioral evaluation of the bifunctional opioid peptide Gluten exorphin B5.","authors":"Vishwadeep Asokan, Deepak Kumar Jha, V Aranganathan","doi":"10.1016/j.bcp.2026.118013","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118013","url":null,"abstract":"<p><p>Depression is a prevalent neuropsychiatric disorder that remains inadequately managed by current pharmacotherapies due to delayed onset of action, treatment resistance, and adverse effects. A growing body of evidence implicates the endogenous opioid system in mood regulation, highlighting opioid peptides as potential targets for novel antidepressant strategies. Exogenous opioid peptides (exorphins) derived from dietary proteins have attracted interest for their neuropsychopharmacological properties. In this study, the pharmacological and neurobehavioral profile of the bifunctional opioid peptide gluten exorphin B5 (GE-B5; YGGWL), derived from wheat gluten, was investigated. Opioid receptor activity was evaluated using isolated tissue bioassays, namely the mouse vas deferens (MVD) and guinea pig ileum (GPI), to assess δ- and μ-opioid receptor agonism, respectively. GE-B5 exhibited pronounced μ-opioid agonist activity in the GPI assay (IC₅₀ = 4.96 mM) and moderate δ-opioid agonist activity in the MVD assay (IC₅₀ = 3.50 mM), with inhibitory effects on acetylcholine-induced contractions that were reversible by naloxone. The in vivo neurobehavioral effects of GE-B5 were further assessed following intravenous administration using established behavioural paradigms, including the elevated plus maze, open field test, tail suspension test, and forced swim test. GE-B5 produced behavioural responses indicative of anxiolytic- and antidepressant-like effects across these models. Collectively, these findings suggest that gluten exorphin B5 exhibits μ-opioid receptor-mediated pharmacological activity accompanied by measurable neurobehavioral effects.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118013"},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genistein and the immune system: experimental evidence, key challenges, and future perspectives.","authors":"Ravichandran Vishwa, Babu Santha Aswani, Anjana Sajeev, Mohamed Abbas, Mohammed S Alqahtani, Gautam Sethi, Ajaikumar B Kunnumakkara","doi":"10.1016/j.bcp.2026.118024","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118024","url":null,"abstract":"<p><p>Genistein (GEN), a soy-derived isoflavonoid and phytoestrogen, exhibits diverse biological activities against allergic and hypersensitivity reactions, autoimmune disorders, infectious diseases, and cancer. Its immunomodulatory properties are crucial to these effects however, clinical translation remains limited due to the complexity and pronounced context dependence of its immune actions. This review critically summarizes experimental evidence on GEN-mediated immunomodulation across innate and adaptive immune compartments, including its effects on cytokine regulation and key molecular signaling pathways. GEN has been shown to modulate dendritic cells, mast cells, macrophages, T cells, B cells, and natural killer cells through both estrogen receptor-dependent and -independent mechanisms, involving pathways such as ERK, NF-κB, p53, and IL-18 receptor signaling. Notably, these immunomodulatory effects are influenced by multiple variables, including cell type, dose, sex, hormonal milieu, and developmental stage, presenting significant challenges for clinical translation. While GEN demonstrates substantial immunomodulatory potential, its highly context-specific actions necessitate disease-relevant preclinical validation and carefully tailored therapeutic strategies that account for dosage, target immune cells, hormonal status, and patient sex. Addressing these factors, together with advances in formulation approaches to improve bioavailability, will be essential for the rational development of GEN as a precision immunomodulatory agent.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118024"},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic AAV8-SIL1-TAT therapy improves motor function in a mouse model of Marinesco-Sjögren syndrome.","authors":"Fabio Bellia, Anna Giulia Ruggieri, Laura Amodei, Francesca Potenza, Beatrice Dufrusine, Valeria Panella, Francesco Del Pizzo, Alessia Lamolinara, Manuela Iezzi, Luca Federici, Michele Sallese","doi":"10.1016/j.bcp.2026.118014","DOIUrl":"10.1016/j.bcp.2026.118014","url":null,"abstract":"<p><p>Marinesco-Sjögren Syndrome (MSS) is a rare genetic disorder characterized by cerebellar ataxia, congenital cataracts, and progressive myopathy. Approximately 60% of cases result from SIL1 gene mutations, causing endoplasmic reticulum stress and neuromuscular degeneration. We investigated AAV8-mediated SIL1 gene replacement combined with TAT peptide-mediated protein delivery in the woozy (Sil1^wz) mouse model. Thirty-two female Sil1^wz mice received either AAV8-SIL1-TAT vector (5 × 10¹² genome copies) or saline intravenously at 4 weeks of age. The construct enabled liver-produced SIL1 protein uptake by peripheral tissues. Motor performance, cognitive behaviour, and molecular changes were monitored over 20 weeks. Treated mice showed significant motor improvement versus controls. Accelerating rotarod testing revealed delayed motor deficit onset by approximately 3 weeks, with significantly higher performance from weeks 10-14 (p < 0.001). Beam walking assessment showed reduced traversal time and contralateral falls from week 9 onwards. Western blotting and immunohistochemistry confirmed intracellular SIL1 localization in hepatocytes and muscle fibres, but not cerebellum. Quadriceps SIL1 delivery peaked at 2 weeks post-treatment, then gradually declined. Treatment normalized peIF2α and LC3 expression in quadriceps, indicating reduced ER stress and autophagy in skeletal muscle. This study provides proof-of-concept evidence for liver-based protein production combined with cell-penetrating peptides as a viable approach for treating peripheral manifestations of multisystemic disorders, while highlighting the need for alternative CNS delivery strategies for comprehensive therapeutic coverage in MSS.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118014"},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GSK2879552 inhibits NLRP3 inflammasome-mediated pyroptosis and acute lung injury through NOX2-ROS signalling axis.","authors":"Guo-Dong Wu, Sen Guo, Shiyi Chen, Jiacheng Jiang, Xueping Wei, Zhuo Zhang, Tongfu Li, Yakun Weng, Dong Sun, Long Shuang Huang","doi":"10.1016/j.bcp.2026.118021","DOIUrl":"10.1016/j.bcp.2026.118021","url":null,"abstract":"<p><p>Acute lung injury (ALI) is a severe inflammatory disease, and NLRP3 inflammasome plays a crucial role in the initiation and progression of ALI. To date, there are no effective drug treatments for ALI. Thus, it is urgent to develop new therapeutic options to cure ALI. Our study found a new molecule, GSK2879552, which directly suppressed reactive oxygen species (ROS) generation and NLRP3 inflammasome activation, resulting in decreased inflammatory cytokine release and pyroptosis in macrophage. GSK2879552 treatment effectively mitigated the excessive inflammatory response, tissue injury, NLRP3 inflammasome activation, pyroptosis and accumulation of ROS in mouse lung tissue during ALI caused by lipopolysaccharide (LPS) or heat stroke. Meanwhile, GSK2879552 also inhibited the activation of NF-κB pathway and oxidative stress. The molecular docking analysis and in vitro experiments suggested that GSK2879552 suppressed ROS generation may through directly inhibition of NOX2 during NLRP3 inflammasome activation. Taken together, our results suggested that GSK2879552 would be a potential therapeutic option to ALI.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118021"},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147833008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Niacin accelerates skeletal muscle regeneration and enhances C2C12 differentiation by activating the PI3K/Akt signaling pathway.","authors":"Lizhi Dai, Jingxuan Wang, Zheyuan Cao, Tong Yu, Jia Liu, Youchong Li, Yuhao Zhang, Jianhua Xiao","doi":"10.1016/j.bcp.2026.118016","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118016","url":null,"abstract":"<p><p>Skeletal muscle injury is prevalent in clinical practice and sports medicine, and efficient regeneration is crucial for restoring motor function. Niacin (vitamin B3, NIA), a water-soluble essential nutrient and key precursor of nicotinamide adenine dinucleotide (NAD + ), regulates muscle metabolism and mitochondrial function, but its role and underlying mechanisms in skeletal muscle injury repair remain unclear. In this study, a mouse model of acute skeletal muscle injury was established via intramuscular injection of bupivacaine hydrochloride, and C2C12 myoblasts were used as an in vitro model to explore NIA's effects on muscle regeneration and myogenic differentiation. In vivo experiments showed that oral NIA supplementation (73 m g/kg/day for 8 weeks) significantly promoted repair of the injured tibialis anterior (TA) muscle: compared with the NC group, NIA-treated mice had increased TA muscle mass, larger myofiber cross-sectional area, a higher proportion of centrally nucleated fibers, and improved muscle function. Western blot analysis revealed that NIA upregulated the expression of myogenic regulatory factors (MRFs) including Pax7, MyoD, and MyoG in injured tissues. In vitro assays demonstrated that NIA promoted C2C12 myoblast differentiation dose-dependently, with 1 mM as the optimal concentration, confirmed by increased MyoD and MyoG expression and a higher myotube fusion index. Bioinformatics analyses predicted the PI3K/Akt signaling pathway as a potential downstream target. Mechanistically, NIA increased Akt phosphorylation (p-Akt) in C2C12 cells, while PI3K inhibition by LY294002 eliminated NIA-induced p-Akt upregulation, MRFs expression, and myotube fusion. In conclusion, NIA accelerates skeletal muscle regeneration and enhances C2C12 myoblast differentiation by activating the PI3K/Akt signaling pathway. This study clarifies NIA's molecular mechanism in muscle regeneration and provides a theoretical basis for its clinical application in treating skeletal muscle injury.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"250 Pt 2","pages":"118016"},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and therapeutic potential of the cGAS-STING signaling pathway in macrophage activation and polarization.","authors":"Hua Liu, Xucheng Zhu, Jie Wang, Xinlei Yao, Zhanzhan Li, Chuli Zhu, Jiacheng Sun, Xia Li, Lei Qi, Hualin Sun","doi":"10.1016/j.bcp.2026.118031","DOIUrl":"https://doi.org/10.1016/j.bcp.2026.118031","url":null,"abstract":"<p><p>The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway is a central component of the innate immune system. It primarily senses cytosolic double-stranded DNA and initiates immune responses against pathogen infection and cellular damage. Recent studies have revealed its critical role in macrophage activation, polarization, and functional regulation. Macrophages are key immune cells with high plasticity; they can polarize into pro-inflammatory M1 or anti-inflammatory and reparative M2 phenotypes under different microenvironmental signals. This polarization influences various pathophysiological processes, including inflammation, tissue repair, fibrosis, and cancer. This review systematically summarizes the central role and molecular mechanisms of cGAS-STING signaling in macrophage polarization and activation. It further explores the interplay between this pathway and cellular processes such as pyroptosis, ferroptosis, and autophagy. Current technical challenges and biological complexities are analyzed. Potential therapeutic strategies targeting this pathway and their clinical prospects are also discussed. The article highlights the dual role of cGAS-STING signaling in macrophage function-it acts as both a guardian of immune defense and a driver of inflammatory imbalance under pathological conditions. Precise regulation of this pathway is crucial for developing novel immunotherapies. This review also provides multi-dimensional perspectives on future research directions.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":"250 Pt 2","pages":"118031"},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting purinergic signaling and MTAP-associated metabolism in cancer: A functional immunometabolic convergence framework.","authors":"Vandriel Pedone da Rosa, Michelli Fontana, Carine Raquel Richter Schmitz, Maike Valentim Buzatto, Iuri Raiel Giacomelli, Walter Antônio Roman Junior, Detlev Boison, Margarete Dulce Bagatini, Sarah Franco Vieira de Oliveira Maciel","doi":"10.1016/j.bcp.2026.118030","DOIUrl":"10.1016/j.bcp.2026.118030","url":null,"abstract":"<p><p>Cancer progression is closely associated with metabolic reprogramming and immune evasion. Extracellular adenosine (eADO) metabolism regulates adenosine receptor activation within the tumor microenvironment (TME). Predominantly through the adenosine A2A receptor, and, in some contexts through the adenosine A2B receptor, eADO signaling suppresses antitumor immune responses and contributes to resistance to immunotherapy. Production of eADO is largely driven by ecto-5'-nucleotidase (CD73), which catalyzes the conversion of eADO monophosphate (AMP) into eADO. In parallel, methylthioadenosine phosphorylase (MTAP) deletion - frequently co-occurring with loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) - does not increase eADO levels but, instead, leads to intracellular accumulation of methylthioadenosine (MTA), reshaping methylation homeostasis and creating selective metabolic dependencies involving protein arginine methyltransferase 5 (PRMT5) and methionine adenosyltransferase 2A (MAT2A). Recent evidence further indicates that nucleoside transport dynamics, particularly via equilibrative nucleoside transporter 1 (ENT1), regulate intracellular adenosine (iADO) availability in T cells, and represent an additional regulatory layer, linking extracellular purinergic signaling with intracellular immunometabolic control. Accordingly, we propose a functional immunometabolic convergence framework in which CD73-dependent extracellular eADO signaling, ENT1-regulated iADO handling, and MTAP loss-associated metabolic rewiring function as parallel yet cooperative processes that stabilize tumor immune escape.</p>","PeriodicalId":8806,"journal":{"name":"Biochemical pharmacology","volume":" ","pages":"118030"},"PeriodicalIF":5.6,"publicationDate":"2026-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147832964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}