Pharmacological Reports最新文献

{"title":"Nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-), and pyrin domain-containing protein 3 (NLRP3) inflammasome and snake venoms/toxins: mechanisms, pathophysiological relevance, and translational perspectives.","authors":"Charles Nunes Boeno, Mauro Valentino Paloschi, Milena Daniela Souza Silva, Juliana Pavan Zuliani","doi":"10.1007/s43440-026-00913-y","DOIUrl":"https://doi.org/10.1007/s43440-026-00913-y","url":null,"abstract":"<p><p>Snake envenoming triggers a complex inflammatory response that substantially contributes to local tissue destruction and systemic complications. Among the innate immune pathways implicated in venom-induced injury, the nucleotide-binding oligomerization domain (NOD-), leucine-rich repeat (LRR-), and pyrin domain-containing protein 3 (NLRP3) inflammasome has emerged as a key sensor-effector platform linking tissue damage, ionic imbalance, reactive oxygen species (ROS), lipid mediators, and cytokine maturation. Experimental studies indicate that crude venoms and isolated snake toxins, including Lys49 and Asp49 phospholipase A₂ (PLA₂), metalloproteinases, and C-type lectin/C-type lectin-like proteins, can activate NLRP3 inflammasome-dependent signaling, leading to caspase-1 activation, interleukin (IL)-1β release, and, in some settings, pyroptotic cell death. These findings position the NLRP3 inflammasome as a promising adjunctive therapeutic target in snakebite envenoming, although causal evidence remains restricted to selected toxin models and broader validation across venom classes is still required. This review summarizes the current understanding of NLRP3 inflammasome biology in the context of snake venoms and toxins, discusses the molecular mechanisms proposed for inflammasome priming and activation, and highlights unresolved questions relevant to toxinology, immunology, and adjunctive therapy development. Recent literature also places venom-derived molecules within the broader framework of NLRP3 inflammasome modulation, reinforcing the idea that venoms may serve both as drivers of pathology and as sources of pharmacological leads.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLS2 reshapes glycolytic metabolism and bioenergetic homeostasis in glioblastoma cells.","authors":"Juan De Los Santos-Jiménez, José A Campos-Sandoval, Jessica Sudderth, Lauren G Zacharias, João Santos Patricio, Francisco J Alonso, Javier Márquez, Thomas P Mathews, Ralph J DeBerardinis, José M Matés","doi":"10.1007/s43440-026-00908-9","DOIUrl":"https://doi.org/10.1007/s43440-026-00908-9","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma (GBM) exhibits extensive metabolic reprogramming, including glucose and glutamine (Gln) addiction, with Gln being converted into glutamate by glutaminase, encoded by the GLS and GLS2 genes. GLS2 acts as a context-dependent tumor suppressor, although the underlying mechanisms remain poorly understood. GLS2 is silenced in GBM, and we previously showed that its re-expression modulates pyruvate dehydrogenase (PDH) activity and tricarboxylic acid cycle (TCAC) metabolism, suggesting a distinct metabolic rewiring associated with its tumor-suppressive function.</p><p><strong>Methods: </strong>LN229 and T98G GBM cell lines were used as experimental models. Metabolomic profiling by liquid chromatography-mass spectrometry was performed to compare changes in central metabolic pathways following GLS2 or GLS overexpression. Glutaminase and PDH enzymatic activities were measured, and Western blotting was performed to assess GLS, GLS2, and PDHA1 protein levels and PDHA1 phosphorylation. A Seahorse analyzer was employed to quantify real-time ATP production derived from glycolysis and oxidative phosphorylation.</p><p><strong>Results: </strong>Overexpression of GLS2, but not GLS, in LN229 cells caused the accumulation of TCAC-related metabolites, except for citrate, whose depletion is attributed to GLS2's effect on PDH phosphorylation, causing reduced PDH activity. This was accompanied by decreased levels of several acyl-carnitines. Furthermore, GLS2 induced the accumulation of glucose/fructose, while reducing levels of glucose-6-phosphate and pentose-phosphates, consistent with altered glycolysis. GLS2 also diminished the ATP/AMP ratio, confirmed by a reduced ATP synthesis rate, particularly glycolytic ATP, whereas mitochondrial ATP production remained unaltered.</p><p><strong>Conclusions: </strong>GLS2 exerts an isoenzyme-specific effect on Gln and glucose metabolism in GBM, likely modulating the glycolysis/pentose-phosphate pathway (PPP)-TCAC-axis.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dexamethasone-mediated modulation of the renin-angiotensin system: current insights.","authors":"Katarzyna Gajewska, Anna Wosiak, Natasza Wiertek-Płoszaj, Weronika Broszkiewicz, Kamila Domińska","doi":"10.1007/s43440-026-00915-w","DOIUrl":"https://doi.org/10.1007/s43440-026-00915-w","url":null,"abstract":"<p><p>Dexamethasone (DEX) exerts pleiotropic effects that extend beyond classical glucocorticoid receptor signaling and include interactions with the renin-angiotensin system (RAS). Growing evidence indicates that DEX regulates both systemic and tissue-specific RAS activity through genomic and non-genomic mechanisms, affecting the expression and activity of key components, including angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin receptors AT1 and AT2. This mini-review summarizes current evidence on DEX-induced RAS modulation and its physiological and pathological implications. Depending on dose, duration, and biological context, DEX may exert both beneficial and adverse effects. Short-term exposure can suppress renin activity and aldosterone secretion and may provide protective effects in selected acute pathological conditions. In contrast, prolonged or high-dose treatment may promote hypertension, electrolyte imbalance, cardiac remodeling, and tissue dysfunction through dysregulation of RAS signaling. DEX also alters local RAS activity in bone, contributing to osteoporosis and osteonecrosis by enhancing osteoclast activity and impairing osteoblast function. In the kidney and lung, DEX-mediated RAS modulation affects fluid homeostasis, inflammatory responses, and susceptibility to tissue injury. Prenatal exposure to DEX may further induce long-term RAS programming, increasing the risk of cardiovascular, renal, and skeletal disorders in adulthood. Collectively, DEX-RAS interactions represent an important but often overlooked aspect of glucocorticoid pharmacology and may contribute to both the therapeutic and adverse effects of DEX.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149183828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Linking preclinical models with functional imaging and artificial intelligence to decode tumor angiogenesis.","authors":"Lenka Varinská, Pieter Koolwijk","doi":"10.1007/s43440-026-00912-z","DOIUrl":"https://doi.org/10.1007/s43440-026-00912-z","url":null,"abstract":"<p><p>Tumor angiogenesis is a hallmark of cancer, influencing oxygen delivery, immune cell trafficking, and therapeutic response. Although anti-angiogenic therapies have achieved clinical relevance, their efficacy remains limited by tumor heterogeneity, adaptive resistance, and insufficient functional assessment of tumor vasculature. In this review, we evaluate preclinical models of tumor angiogenesis with a focus on their ability to generate quantitative and physiologically relevant readouts. We discuss established assays such as tube formation, fibrin bead assay, aortic ring, and chorioallantoic membrane (CAM) models, alongside emerging systems including vascularized organoids and organ-on-a-chip platforms, as well as zebrafish and murine tumor models. Particular emphasis is placed on advanced imaging modalities enabling longitudinal assessment of perfusion, permeability, and vascular remodeling, as well as on the growing role of artificial intelligence (AI) in automated and quantitative data interpretation. We further highlight the integration of single-cell and multi-omics approaches for resolving endothelial heterogeneity and tumor-stroma interactions. By linking biologically relevant models with functional imaging and computational analysis, this review outlines strategies to improve the predictive power and translational relevance of angiogenesis research.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-dependent and long-term effects of cisplatin on bone mineral density in juvenile mice.","authors":"Héctor Fabián Torres-Rodríguez, Santos Adrián Pérez-Reyes, Denisse Arlette Santiago-Méndez, Carla Gabriela Aguilar-Campos, Laura Yanneth Ramírez-Quintanilla, Arisai Martínez-Martínez, Enriqueta Muñoz-Islas, Juan Miguel Jiménez-Andrade","doi":"10.1007/s43440-026-00914-x","DOIUrl":"https://doi.org/10.1007/s43440-026-00914-x","url":null,"abstract":"<p><strong>Background: </strong>Cisplatin is an anti-neoplastic treatment widely used to treat pediatric cancers. Negative effects of cisplatin treatment on bone mass have previously been reported; however, long-term effects of cisplatin on skeletal health and potential sex differences have largely been unexplored.</p><p><strong>Methods: </strong>Four-week-old BALB/c mice were treated with cisplatin (4 mg/kg, intraperitoneally, twice weekly for four weeks). At 13 weeks of age, we assessed structural changes in the tibiofemoral region using microcomputed tomography. We also quantified, using immunohistochemistry and confocal microscopy, the density of tartrate-resistant acid phosphatase⁺ (TRAcP⁺) osteoclasts, sclerostin⁺ osteocytes, and osterix⁺ (OSX⁺) osteoblasts, within the femoral metaphysis of female and male mice treated with cisplatin during the juvenile period.</p><p><strong>Results: </strong>At 13 weeks of age, both female and male mice treated with cisplatin showed a significantly greater decrease in trabecular, but not cortical, bone mass in the tibiofemoral region than saline-treated mice. This decrease in trabecular bone mass was significantly greater in females than in males. The density of TRAcP⁺ osteoclasts on the trabecular surfaces of the femur was higher in mice treated with cisplatin than in those in the saline group, independent of sex. Cisplatin treatment did not alter the density of sclerostin⁺ osteocytes or OSX⁺ osteoblasts in the femoral metaphyseal bone marrow compared with the saline group.</p><p><strong>Conclusion: </strong>These findings suggest that cisplatin induced sex-dependent and long-term complications in the skeletal system, which may partially explain the greater incidence of fractures in childhood cancer survivors.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149137795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tryptamide (nicotredole) revisited: re-examining a forgotten anti-inflammatory agent by large-scale target profiling and ADMET studies.","authors":"Katarzyna Szczepańska, Tadeusz Karcz, Ryszard Bugno, Katarzyna Kaczorowska, Beata Duszyńska, Andrzej J Bojarski","doi":"10.1007/s43440-026-00907-w","DOIUrl":"https://doi.org/10.1007/s43440-026-00907-w","url":null,"abstract":"<p><strong>Background: </strong>Tryptamide (nicotredole) is a clinically investigated small molecule that was previously reported to possess anti-inflammatory, antirheumatic, and sedative properties, yet its molecular targets and mechanism of action remain poorly understood. Moreover, despite historical pharmacokinetic studies, its absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile has not been comprehensively evaluated using contemporary methodologies.</p><p><strong>Methods: </strong>Tryptamide was resynthesized and subjected to a panel of in vitro ADMET assays, including PAMPA permeability, Caco-2 transport, P-glycoprotein interaction, CYP3A4 inhibition, metabolic stability in human liver microsomes, and hepatotoxicity assessment in HepG2 cells. To investigate its mechanism of action, the compound was profiled against 135 biological targets using Eurofins CNS Target Panel™ and InflamEnzyme Panel™ platforms, followed by selected concentration-response studies and additional assays relevant to neuroinflammation and neurodegeneration.</p><p><strong>Results: </strong>Tryptamide exhibited favorable in vitro developability characteristics, including high intestinal permeability, limited interaction with P-glycoprotein, high metabolic stability in human liver microsomes, and low cytotoxicity in HepG2 cells under the tested conditions. The compound inhibited CYP3A4 (IC₅₀ = 2.30 ± 0.39 µM), whereas follow-up evaluation of the thromboxane synthase screening hit revealed weak inhibitory activity (IC₅₀ = 78 µM). Broad target profiling revealed remarkably limited pharmacological activity, with only four targets showing > 50% inhibition at 10 µM: CYP2C19, CYP3A4, thromboxane synthase, and the serotonin 5-HT_2C receptor. Additional studies demonstrated no meaningful activity toward FAAH, TNFα-induced necroptosis, or β-amyloid aggregation.</p><p><strong>Conclusions: </strong>Contemporary re-evaluation revealed a favorable in vitro ADMET profile but failed to identify a convincing molecular mechanism underlying the reported pharmacological effects of tryptamide. The findings highlight both the utility and limitations of modern target profiling approaches in the reassessment of historical drug candidates.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081823","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isoflavones as multi-target modulators in glioma and neuroblastoma: a mini-review.","authors":"Wojciech Paździora, Agnieszka Galanty","doi":"10.1007/s43440-026-00903-0","DOIUrl":"https://doi.org/10.1007/s43440-026-00903-0","url":null,"abstract":"<p><p>Brain tumors, including gliomas and neuroblastoma (NB), remain among the most aggressive and therapeutically challenging malignancies of the nervous system. Despite multimodal treatment, prognosis for high-grade gliomas and high-risk NB remains poor, largely due to pharmacological barriers and intrinsic therapy resistance. Isoflavones are plant-derived phytoestrogens that have attracted increasing attention because of their pleiotropic anticancer, anti-inflammatory, and neuroprotective properties. In this review, we focus on the molecular and cellular mechanisms that determine the biological activity of isoflavones in brain tumors, including estrogen receptor-dependent signaling, modulation of oncogenic pathways, and limitations related to blood-brain barrier permeability. We discuss how modulation of phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPK), and nuclear factor kappa B (NF-κB) pathways contributes to antiproliferative and pro-apoptotic effects, and how limited brain bioavailability represents a major barrier to effective application. We identify key limitations of the current literature, including inconsistent epidemiological findings, poor standardization of experimental models, and limited pharmacokinetic characterization. Available data suggest that isoflavones represent promising adjuncts in brain tumor therapy, but their clinical relevance will depend on improving brain delivery and defining receptor-selective mechanisms of action.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lithium pretreatment does not affect pilocarpine-induced seizure-like activity in zebrafish larvae.","authors":"Marta Marszałek-Grabska, Monika Hułas-Stasiak, Saadat Bekenova, Anna Grenda, Michał Szulc, Camila V Esguerra, Sohee Kim, Waldemar A Turski, Kinga Gaweł","doi":"10.1007/s43440-026-00905-y","DOIUrl":"https://doi.org/10.1007/s43440-026-00905-y","url":null,"abstract":"<p><strong>Background: </strong>Recently, it has been reported that pilocarpine (PILO) induces seizures in zebrafish larvae. It has also been shown that acute PILO-induced convulsions result in unprovoked seizure-like discharges 24 hours later. Since lithium (Li) pretreatment potentiates the convulsions induced by PILO in rodents, this study was undertaken to evaluate the effect of Li on PILO-induced seizures in zebrafish larvae.</p><p><strong>Methods: </strong>Experiments were conducted on zebrafish larvae up to 5 days post-fertilization. Larvae were pre-exposed to Li and then exposed to PILO. Local field potentials from the optic tectum were recorded and subjected to quantitative spectral analysis, including power spectral density estimation, band-specific power analysis, and automated ictal-event detection based on root mean square thresholding. Locomotor activity, followed by quartile-based population analysis as a potential behavioral correlate of seizure activity, was investigated. TUNEL-based apoptosis quantification and mRNA expression of neuronal activity markers npas4α and c-fos were examined.</p><p><strong>Results: </strong>It was found, that pre-exposure to Li does not affect PILO-induced seizures. PILO induced seizure-like discharges in Li-pretreated larvae comparable to those evoked by PILO alone, and similarly to PILO, resulted in spontaneous, unprovoked paroxysmal brain activity 24 hours post-exposure. Spectral analysis revealed persistent increases in theta, alpha, and beta band power at the 24-hour time point, accompanied by brain apoptosis. At this time, an increase in npas4α expression was found in naïve larvae exposed to PILO. Results of quartile-based locomotor analysis, but not aggregate distance measures, correlate with seizure-like activity.</p><p><strong>Conclusions: </strong>Both PILO and Li+PILO zebrafish paradigms offer a reproducible, ethically advantageous platform for conducting research related to early-onset epilepsy and for antiseizure medication screening targeting this age group.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149081663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the allosteric landscape of 5-HT₂ receptors: integrated molecular dynamics and fragment molecular orbital analyses of activation mechanisms.","authors":"Paweł Śliwa, Karina Pakosz, Aleksandra Banach","doi":"10.1007/s43440-026-00909-8","DOIUrl":"https://doi.org/10.1007/s43440-026-00909-8","url":null,"abstract":"<p><strong>Background: </strong>The 5-HT₂ receptor subfamily (5-HT_2A, 5-HT_2B, and 5-HT_2C) is a cornerstone of neuropsychiatric drug design, yet the precise molecular determinants of their activation and biased signaling remain only partially elucidated. This study aimed to investigate the conformational transitions and energetic landscapes across diverse functional states to provide a refined structural blueprint of the allosteric signaling mechanisms.</p><p><strong>Methods: </strong>We integrated Molecular Dynamics (MD) simulations, Dynamical Network Analysis (DNA), and Fragment Molecular Orbital calculations combined with Pair Interaction Energy Decomposition Analysis (FMO/PIEDA). By applying FMO/PIEDA to MD-derived representative structures, we performed an ab initio evaluation of receptor-ligand complexes, quantifying individual residue-ligand pair interaction energies (PIE).</p><p><strong>Results: </strong>Our results demonstrate that signal transduction is governed by a cooperative allosteric network rather than a single toggle switch, with the conserved R3.50 residue serving as a mandatory endpoint of ligand-induced communication. While agonists initiate the shift toward active-like states, G protein coupling acts as a directional amplifier, focusing communication pathways toward R3.50 and effectively stabilizing the E/DRY ionic lock against disruption. Subtype-specific analyses reveal that the 5-HT_2B receptor possesses the most intrinsically pre-organized communication network, while 5-HT_2A exhibits the highest sensitivity to perturbations in signal transmission. Furthermore, FMO analysis identified the highly conserved D3.32 as the primary stabilizing anchor, while residues such as S5.46 and W6.48 were found to be critical energetic determinants of ligand efficacy.</p><p><strong>Conclusions: </strong>These integrated insights provide a refined structural blueprint of the TM5-TM6-TM7 allosteric landscape, moving beyond isolated residue descriptions. The findings facilitate the rational design of next-generation, non-hallucinogenic agonists or selective modulators by targeting specific energetic and dynamic pathways within the serotonin receptor family.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 ferroptosis in cancer: mechanisms, tumor immunity, and translational challenges.","authors":"Aleksandra Zdanowicz, Bhaskar Pradhan, Beata Pyrzyńska, Dagmara Otto-Ślusarczyk, Marta Struga","doi":"10.1007/s43440-026-00910-1","DOIUrl":"https://doi.org/10.1007/s43440-026-00910-1","url":null,"abstract":"<p><p>Ferroptosis is an iron-dependent form of regulated cell death driven by phospholipid peroxidation and the failure of cellular antioxidant defenses. Its close integration with iron metabolism, lipid remodeling, and redox homeostasis has identified ferroptosis as a potentially exploitable vulnerability in cancer. This review critically examines the molecular and pharmacological determinants of ferroptotic sensitivity, including iron handling, acyl-CoA synthetase long-chain family member 4 (ACSL4)/lysophosphatidylcholine acyltransferase 3 (LPCAT3)-dependent lipid remodeling, and the glutathione peroxidase 4 (GPX4)-glutathione, ferroptosis suppressor protein 1 (FSP1)-coenzyme Q10, mitochondrial dihydroorotate dehydrogenase (DHODH), and GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin defense systems. We discuss experimental ferroptosis inducers and clinically used drugs with reported ferroptosis-modulating activity, emphasizing differences in their mechanisms, strength of evidence, and translational relevance. Particular attention is given to the bidirectional interactions between ferroptosis and the tumor immune microenvironment. Although cytotoxic lymphocytes and interferon-gamma (IFN-γ) signaling may sensitize malignant cells to ferroptosis, excessive lipid peroxidation in cluster of differentiation 8-positive (CD8⁺) T cells, natural killer cells, dendritic cells, and other immune populations may impair antitumor immunity. These context- and cell-type-dependent effects support combination strategies involving immunotherapy, radiotherapy, and conventional or targeted anticancer treatments, but also define potential toxicities. We further discuss candidate biomarkers related to iron metabolism, lipid composition, antioxidant capacity, and immune context, as well as the need for patient stratification and targeted drug delivery. Successful clinical implementation will require selective induction of ferroptosis in malignant cells while preserving normal tissues and antitumor immune function. Ferroptosis should therefore be regarded as a conditional therapeutic vulnerability rather than a universally beneficial anticancer mechanism.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149063814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}