Pharmacological Reviews[JOURNAL]
Sun
200 papers
Machine learning-driven discovery of potent isocitrate dehydrogenase 1 mutant inhibitors from ultralarge ligand libraries for targeting malignant glioma.
Zaka M, Asaad F, Özkanca Ş … +6 more , Çelebi A, Zhou R, Kim H, Kılıç T, Avşar T, Durdağı S
J Pharmacol Exp Ther · 2026 Apr · PMID 41880802 · Publisher ↗
Glioblastoma (GBM) represents one of the most lethal and therapy-resistant forms of brain tumors, characterized by high heterogeneity, metabolic reprogramming, and recurrence. In the current study, we aimed to identify n...
Glioblastoma (GBM) represents one of the most lethal and therapy-resistant forms of brain tumors, characterized by high heterogeneity, metabolic reprogramming, and recurrence. In the current study, we aimed to identify novel small molecule inhibitors targeting mutant isocitrate dehydrogenase 1 (IDH1), a crucial enzyme involved in GBM tumor metabolism. For this aim, machine learning-based quantitative structure-activity relationships modeling was combined with structure-based e-Pharmacophore screening to virtually screen ultralarge chemical libraries containing around 157 million compounds. The best hits were selected based on docking score, predicted pIC value, and molecular mechanics/generalized Born surface area binding energy calculations. Furthermore, molecular dynamics (MD) simulations were conducted to validate the selected hit compounds. In total, 36 compounds were subjected to short MD simulations (10 ns), and 16 molecules showing low binding free energies (below -90 kcal/mol) were further analyzed through long MD simulations (100 ns). Among these, 11 synthetically available hits were ordered and experimentally tested on human glioblastoma U87 and U251 cell lines. Our experimental results showed that 5 of the tested compounds (hits 1, 4, 5, 6, and 7) reduced spheroid formation by nearly 80%-90% and inhibited cell proliferation. Moreover, these hits decreased the oxygen consumption rate and extracellular acidification rate (ECAR), by up to 62% and 55%, respectively, indicating inhibition of both mitochondrial respiration and glycolysis. Furthermore, Western blot and quantitative real-time polymerase chain reaction analyses revealed downregulation of glycolytic enzymes and stemness markers. Moreover, steered MD and free energy perturbation analyses confirmed the stable interactions of these compounds at the IDH1 mutant active site. This multistage in silico-in vitro approach allowed the identification of metabolically disruptive novel mutant IDH1 inhibitors that suppress glycolysis, mitochondrial respiration, and cancer stemness in glioblastoma cells. These compounds represent promising scaffolds for the development of next-generation GBM therapeutics. SIGNIFICANCE STATEMENT: This study integrate machine learning-guided quantitative structure-activity relationships modeling with structure-based pharmacophore screening to discover small molecule inhibitors of mutant IDH1, a central mediator of metabolic reprogramming in glioblastoma. Lead compounds identified through this pipeline inhibit mutant IDH1 activity, disrupt metabolic pathways required for glioblastoma cell viability, and concomitantly reduce stem-like phenotypes in vitro, consistent with a dual mechanism of action that targets both bulk tumor cells and cancer stem-like populations.
Targeting of kinases to treat neurodegenerative diseases.
Shomali T, Trempe JF
Pharmacol Rev · 2026 May · PMID 41880688 · Full text
Neurodegenerative diseases, including Alzheimer, Parkinson, and multiple sclerosis, represent a growing global health crisis with limited therapeutic options that address disease progression. Protein kinases, which are c...
Neurodegenerative diseases, including Alzheimer, Parkinson, and multiple sclerosis, represent a growing global health crisis with limited therapeutic options that address disease progression. Protein kinases, which are crucial regulators of diverse cellular processes such as endolysosomal trafficking, neuroinflammation, and mitochondrial homeostasis, are frequently dysregulated in these conditions, making them attractive drug targets. This review explores the therapeutic potential of targeting key kinases implicated in neurodegeneration, specifically p38 MAPK, BTK, c-Abl/ABL1, CDK5, GSK3, JNK, LRRK2, and PINK1. We delve into their specific roles in disease pathophysiology, current therapeutic strategies, and the structural insights guiding our understanding of these kinases and the development of more selective inhibitors. Although significant challenges remain, particularly regarding selectivity and drug delivery to the brain, the advancements in our understanding of kinase biology and novel therapeutic modalities offer substantial promise for developing disease-modifying treatments. This review highlights the urgent need for continued research to identify new targets and translate these scientific breakthroughs into effective therapies for patients. SIGNIFICANCE STATEMENT: This review outlines the roles of protein kinases in neurodegenerative diseases and highlights emerging strategies for their therapeutic modulation. By integrating current knowledge of kinase signaling, drug development, and pharmacokinetics, this work provides a timely and practical framework to guide the development of disease-modifying treatments in an area of pressing clinical need.
A mu-opioid receptor positive allosteric modulator provides opioid-sparing antinociception without enhancing opioid side effects.
Kochan KE, Clements BM, Prince TD … +4 more , Demery C, White AD, Levitt ES, Traynor JR
J Pharmacol Exp Ther · 2026 Apr · PMID 41875797 · Publisher ↗
Opioids that act at the mu-opioid receptor (MOR) are the gold standard for pain management, but can induce serious unwanted effects, including addiction liability and respiratory depression. 2-(3-bromo-4-methoxyphenyl)-3...
Opioids that act at the mu-opioid receptor (MOR) are the gold standard for pain management, but can induce serious unwanted effects, including addiction liability and respiratory depression. 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine is a positive allosteric modulator of MOR that increases the actions of small-molecule opioids and opioid peptides in vitro. In vivo, 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine enhances the action of endogenously released opioid peptides to provide MOR-mediated antinociception, but not constipation, reward, or respiratory depression. However, the effects of positive allosteric modulators of MOR on the behavioral actions of opioid drugs such as morphine and fentanyl have not been studied. Here, we show that 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine enhances opioid drug-induced antinociception in assays for acute and inflammatory pain but not the adverse effects of constipation, respiratory depression measured by blood oxygen levels and respiration rate, or reward as determined by conditioned place preference. These data support the potential of positive allosteric modulators of MOR as effective and safe opioid-sparing agents for pain management. SIGNIFICANCE STATEMENT: The undertreatment of pain and the addiction liability of opioids necessitate new strategies to improve pain management. Here, we demonstrate that the mu-opioid receptor modulator 2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl) sulfonyl]-thiazolidine enhances opioid drug-mediated analgesia in mice without enhancing constipation, reward, or respiratory depression.
G protein-coupled receptors and inflammation resolution signaling networks in the heart: Pharmacology and potential for innovative therapeutics.
Sosnowski DK, Hébert TE, Dobrev D … +1 more , Nattel S
Pharmacol Rev · 2026 May · PMID 41875505 · Full text
Chronic, unresolved inflammation, and immune system activation contribute to the development and progression of human cardiovascular disease. Specialized proresolving mediators (SPMs), primarily the lipoxins and resolvin...
Chronic, unresolved inflammation, and immune system activation contribute to the development and progression of human cardiovascular disease. Specialized proresolving mediators (SPMs), primarily the lipoxins and resolvins, demonstrate potent inflammation-resolving effects. SPMs bind to their respective G protein-coupled receptors (GPCRs) to transduce intracellular events and exert proresolving actions. Given the importance of immune cells in the cardiovascular system, the involvement of nonimmune cardiac cell-types in chronic cardiac inflammation, and the inflammation-resolving effects of SPMs, SPM-GPCR interactions may present efficacious new therapeutic targets for heart disease. In this review, we discuss the mechanisms potentially underlying these GPCR-mediated responses. We begin by providing a brief overview of SPM biosynthesis and the GPCRs implicated in SPM signaling. We then discuss literature demonstrating protective effects of SPMs in models of heart disease. We look in detail at the pharmacology of SPM-GPCR interactions, with a primary focus on formyl peptide receptor 2, GPR32, GPR18, and chemerin receptor 1. We then consider SPM-GPCR downstream signaling pathways in various cell models, including heterologous cell systems overexpressing human SPM-GPCR constructs, SPM-GPCR interactions in endogenous immune cells and effects in nonimmune cell types of the heart including cardiomyocytes, cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells. We end by considering knowledge gaps and discussing future directions in SPM-GPCR interaction research. SPM-GPCR signaling networks and actions vary widely in different cell-types and disease contexts, and knowledge of the detailed pharmacology in the heart is quite limited, so extensive additional work on SPM-GPCR signaling is needed to capitalize on the rich therapeutic potential. SIGNIFICANCE STATEMENT: Inflammation resolution is a critical process in cardiac healing after injury or disease. Understanding of the pharmacology and G protein-coupled receptor-dependent signaling mechanisms of inflammation-resolving molecules in the heart is limited, heavily dependent on cell type, and sometimes conflicting. The knowledge gained about these signaling mechanisms in more basic cell systems can be used to facilitate future investigation of how these molecules work within the diverse cardiac cellular milieu as potential targeted therapeutics for heart disease.
Contextual Influences on Naltrexone Sensitization During Daily Morphine Exposure.
Paronis CA, Bergman J
J Pharmacol Exp Ther · 2026 Apr · PMID 41863974 · Publisher ↗
Naltrexone-precipitated withdrawal in animals that receive morphine daily can include decreases in operant responding. However, naltrexone also can decrease operant responding in untreated animals, depending on prior nal...
Naltrexone-precipitated withdrawal in animals that receive morphine daily can include decreases in operant responding. However, naltrexone also can decrease operant responding in untreated animals, depending on prior naltrexone exposure and reinforcer contingencies. The present study was conducted to further evaluate changes in the behavioral effects of naltrexone consequent to morphine exposure and changes in behavioral context. Tolerance to the effects of both μ- (morphine, heroin, buprenorphine, methadone) and κ-opioid (U50,488) agonists during daily chronic morphine also was evaluated. Squirrel monkeys (n = 4) responded under a multiple schedule consisting of 4 18-minute cycles, each comprising a 10-minute timeout period followed by 3-minutes during which fixed-ratio responding was maintained by food presentation, a 2-minute timeout period, and 3-minutes during which fixed-ratio responding was maintained by stimulus-shock termination (SST). Control response rates were comparable under both schedule conditions. All drugs decreased food-maintained responding and, albeit requiring 0.5-1 log unit higher doses, morphine, heroin, methadone, and U50,488 also decreased SST-maintained responding. Daily morphine (3.2 mg/kg/day) produced tolerance to the rate-decreasing effects of μ-opioid agonists in the absence of sensitization to naltrexone's rate-decreasing effects. Doubling the daily dose of morphine and eliminating components of SST-maintained responding resulted in a 1.5-log unit leftward shift of the naltrexone dose-effect function. Full sensitization to naltrexone's ability to decrease food-maintained responding (3-log unit leftward shift) emerged after reintroducing SST-maintained performance into daily sessions. These results indicate that naltrexone's effects on operant responding during morphine maintenance can be influenced by behavioral context as well as the level of dependence. SIGNIFICANCE STATEMENT: Repeated administration of high naltrexone doses in nonopioid dependent individuals may result in behaviorally disruptive effects of low doses (naltrexone supersensitivity). Low doses of naltrexone also have disruptive effects during opioid dependence. These studies show that the expression of naltrexone effects during opioid dependence is a product of both pharmacological and behavioral factors.
Therapeutic potential of liraglutide in rheumatoid arthritis: Modulation of inflammation, apoptosis, and metabolic dysfunction in a rat model.
Nematalla HA, Sheta E, Ghareeb AZ … +3 more , Abo Saree MM, Ghoneim AI, Elharoun M
J Pharmacol Exp Ther · 2026 Apr · PMID 41863197 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by joint inflammation and systemic symptoms. This study evaluates the efficacy of liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, in RA ma...
Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by joint inflammation and systemic symptoms. This study evaluates the efficacy of liraglutide (LIRA), a glucagon-like peptide-1 receptor agonist, in RA management, particularly in conjunction with methotrexate (MTX), a standard RA therapy on complete Freund's adjuvant (CFA)-induced arthritis. Rats were injected with 0.12 mL of CFA (10 mg/1 mL) intradermally on day 1. Rats were divided into 6 groups, Normal group, Model group, MTX group (methotrexate 1 mg/kg/wk/i.p.), LIRA protection group (liraglutide 75 μg/kg/day/i.p. from day 1 to day 56), LIRA group (liraglutide 75 μg/kg/day/i.p. from day 15 to day 56), LIRA + MTX group (liraglutide 75 μg/kg/day/i.p. + methotrexate 1 mg/kg/wk/i.p. from day 15 to day 56). The arthritic rats developed significant joint destruction accompanied by alterations in metabolic parameters, elevated inflammatory cytokines, and enhanced apoptosis and autophagy. Liraglutide treatment and protection significantly showed metabolic hexokinase 2-succinate-hypoxia-inducible factor 1α axis modulation, inflammasome NOD-like receptor family, pyrin domain containing 3 suppression, apoptosis and autophagy flux normalization and joint pathology improvement. Liraglutide produced more pronounced effects when administered in combination with methotrexate. In conclusion, liraglutide demonstrated significant therapeutic and protective efficacy in a CFA-induced rat model of RA. The mechanism involves metabolic reprogramming where liraglutide downregulated the hexokinase 2-succinate-hypoxia-inducible factor 1αaxis, correcting disease-associated metabolic dysregulation. Similarly, liraglutide inhibited key proinflammatory signaling cascades, specifically the nuclear factor κB/NOD-like receptor family, pyrin domain containing 3/interleukin-1β and tumor necrosis factor-α/P38 mitogen-activated protein kinase pathways. SIGNIFICANCE STATEMENT: Rheumatoid arthritis is a chronic immuno-inflammatory disorder causing joint damage. Liraglutide presents opportunities for repurposing metabolic agents in the treatment of autoimmune illnesses. Liraglutide modulates metabolic dysfunction, normalizes autophagy markers, inflammatory pathways, and lower apoptotic signals in complete Freund's adjuvant-induced arthritis in rats.
Regenerative therapeutics for chronic obstructive pulmonary disease.
van der Koog L, Showell HRD, Nugraha DF … +21 more , Lehmann M, Conlon TM, Yildirim AÖ, Fuentes-Mateos R, Baarsma H, Ng-Blichfeldt JP, Melgert BN, Dost AFM, Burgess JK, Yam SLS, Heijink IH, Ahmed S, Paschini M, Jansen EM, Hinrichs WLJ, Johnson JR, Wu X, Nagelkerke A, Frijlink HW, Kim CF, Gosens R
Pharmacol Rev · 2026 May · PMID 41856010 · Full text
Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases worldwide, characterized by an accelerated loss of lung function. A key problem underlying COPD is increased tissue destruction in comb...
Chronic obstructive pulmonary disease (COPD) is one of the most common lung diseases worldwide, characterized by an accelerated loss of lung function. A key problem underlying COPD is increased tissue destruction in combination with defective lung tissue repair. As current therapies do not modify the progression of the disease, new therapies aimed at restoring lung tissue repair in COPD need to be developed. In an attempt to address this major unmet need, there has been a surge in both preclinical and clinical studies, aiming to identify key mechanisms underpinning defective lung repair and the ability to inhibit or even reverse this defect. This includes small molecules such as retinoids, as well as advanced therapy medicinal products such as cell therapies or therapies with cell-derived products such as extracellular vesicles, or secreted proteins. The results of these endeavors have been variable with failures as well as successful proof-of-concepts. In this review, we provide an overview of the current state of the field, including modes of action of the therapeutics that are or have been considered for lung regeneration, including a discussion on the reasons for failure where relevant. In addition, we discuss hurdles in the clinical development of regenerative therapeutics for COPD including clinical outcomes, route of administration and formulation as these are pivotal considerations moving forward. SIGNIFICANCE STATEMENT: Chronic obstructive pulmonary disease is characterized by progressive alveolar destruction and defective epithelial regeneration. Targetable mechanisms, including cellular senescence, altered mesenchymal-epithelial signaling, and chronic inflammation, impair progenitor function and niche integrity. Therapeutic strategies that restore epithelial repair, including small molecules, biologics, and cell-based approaches, represent a promising path toward disease modification and long-term lung function restoration.
Comparison of naloxone, naltrexone, nalmefene, and methocinnamox for preventing and reversing the discriminative stimulus effects of buprenorphine and carfentanil in rats discriminating fentanyl from saline.
Hiranita T, Grisham AK, Mijares AE … +3 more , Alvarez MA, Patel MN, France CP
J Pharmacol Exp Ther · 2026 Mar · PMID 41849982 · Publisher ↗
Naloxone and nalmefene are μ opioid receptor (MOR) antagonist medications for reversing opioid overdose and naltrexone is a MOR antagonist medication for treating opioid use disorder (preventing relapse). MOR agonist med...
Naloxone and nalmefene are μ opioid receptor (MOR) antagonist medications for reversing opioid overdose and naltrexone is a MOR antagonist medication for treating opioid use disorder (preventing relapse). MOR agonist medications for treating opioid use disorder include methadone and buprenorphine. The magnitude of effect of buprenorphine can be less than the effect of higher efficacy MOR agonists with some effects of buprenorphine (eg, ventilatory depression) resistant to reversal by naloxone, compared with reversal of the effects of other MOR agonists. Drug discrimination was used to compare the ability of naloxone, naltrexone, nalmefene, and methocinnamox (MCAM) to prevent and reverse the effects of buprenorphine and the ultrapotent fentanyl analog carfentanil in male and female rats discriminating fentanyl from saline. Naloxone, naltrexone, nalmefene, and MCAM (0.01-0.1 mg/kg) were equipotent at preventing the discriminative stimulus effects of 0.01 mg/kg buprenorphine and 0.0001 mg/kg carfentanil. Compared with their potencies to prevent discriminative stimulus effects, naloxone, naltrexone, and nalmefene were ≥92-fold less potent in reversing the discriminative stimulus effects of buprenorphine and ≥31-fold less potent in reversing the discriminative stimulus effects of carfentanil. In contrast, MCAM was equipotent in preventing and reversing the discriminative stimulus effects of buprenorphine and carfentanil. There was no significant difference in the onset of action of naloxone, naltrexone, nalmefene, or MCAM. The greater potency of MCAM, compared with naloxone, naltrexone, and nalmefene for reversing the effects of buprenorphine and carfentanil might translate to MCAM reversing adverse effects of a wide range of MOR agonists in patients. SIGNIFICANCE STATEMENT: Buprenorphine, a μ opioid receptor (MOR) agonist used to treat opioid use disorder, can produce adverse effects that are reportedly more difficult to reverse with naloxone, compared with reversal of the effects of other MOR agonists. This study provides evidence for the potential utility of the MOR antagonist methocinnamox to reverse the adverse effects of buprenorphine by demonstrating the relatively greater potency of methocinnamox, compared with currently available MOR antagonists, to reverse the discriminative stimulus effects of buprenorphine and carfentanil.
Pharmacokinetic and pharmacodynamic properties of cannabigerol in male mice.
Mabou Tagne A, Ahmed F, Tran A … +8 more , Galvani F, Debbaneh L, Perranoski ER, Sarlah D, Das A, Pabon E, Cooper Z, Piomelli D
J Pharmacol Exp Ther · 2026 Apr · PMID 41833244 · Full text
Cannabigerol (CBG) is a nonintoxicating phytocannabinoid gaining popularity as a self-medication for anxiety and other conditions; however, its pharmacological properties remain poorly defined. Here, we report the develo...
Cannabigerol (CBG) is a nonintoxicating phytocannabinoid gaining popularity as a self-medication for anxiety and other conditions; however, its pharmacological properties remain poorly defined. Here, we report the development of a rapid and sensitive liquid chromatography-tandem mass spectrometry method for quantifying CBG and its primary oxidative metabolite, cyclo-CBG. This platform enabled the characterization of CBG's pharmacokinetic and biotransformation profile after intraperitoneal administration (10 mg/kg) in male mice. CBG exhibited rapid systemic distribution and clearance, with relatively low brain penetration (brain-to-plasma ratio = 0.26). In contrast, cyclo-CBG accumulated in brain tissue to a surprising extent (brain-to-plasma ratio = 7.1), suggesting local formation and a potentially important role in mediating central effects. Despite prior reports of anxiolytic effects, we found that CBG administered at its peak brain concentration produced anxiogenic-like effects in mice, as assessed using the elevated plus maze. This response was not affected by the CB cannabinoid receptor inverse agonist, rimonabant (3 mg/kg, i.p.), indicating a mechanism independent of CB signaling. As interest in CBG continues to rise, the analytical and pharmacokinetic framework presented here provides a valuable foundation for advancing preclinical and clinical investigations into its efficacy, safety, and mechanism of action. SIGNIFICANCE STATEMENT: Application of a new liquid chromatography-tandem mass spectrometry method to quantify cannabigerol reveals key pharmacokinetic properties of this phytocannabinoid in mice, including unexpectedly high brain accumulation of its metabolite cyclo-cannabigerol, which was accompanied by anxiogenic-like effects. The results offer valuable tools for advancing preclinical and clinical investigations into cannabigerol pharmacology.
From neuroimmune circuits to targeted therapy of chronic pruritus.
Ramcke T, Kaplan DH
Pharmacol Rev · 2026 Mar · PMID 41831428 · Full text
Chronic pruritus (CP) is a debilitating symptom of various human diseases and significantly reduces quality of life, underscoring its clinical relevance. CP can accompany non-skin-borne diseases such as chronic kidney di...
Chronic pruritus (CP) is a debilitating symptom of various human diseases and significantly reduces quality of life, underscoring its clinical relevance. CP can accompany non-skin-borne diseases such as chronic kidney disease, but it is also a hallmark of many dermatological diseases. Most pruritic skin diseases are characterized by dysregulated immune responses, indicating a close relationship between CP and skin inflammation. Major breakthroughs over the last 2 decades have transformed our understanding of how immune cells and the nervous system interact to promote itch and scratching behavior in pruritic inflammatory skin diseases such as atopic dermatitis. This bidirectional neuroimmune crosstalk is fundamental for understanding the mechanistic basis of CP and opens new avenues for targeted treatment strategies. This translational review provides an up-to-date overview of the biological basis of itch, its clinical implications, and modern therapeutic options for CP; pruritic inflammatory skin diseases constitute a central focus. The first part summarizes the anatomical structures and physiological processes underlying itch transmission, with emphasis on neuroimmune communication. Endogenous itch-inducing molecules, or pruritogens, are a central element of this crosstalk and drive CP at the neurocutaneous interface. The second part of the review discusses these pruritogens in detail, with particular attention to their clinical relevance for the treatment of CP across dermatological and selected nondermatological conditions. SIGNIFICANCE STATEMENT: Chronic pruritus is a debilitating symptom of many human diseases, including pruritic inflammatory skin diseases such as atopic dermatitis. This review provides an up-to-date overview of the biological basis of itch, highlights neuroimmune crosstalk in particular, and discusses the clinical and therapeutic relevance of pruritogens acting at the neurocutaneous interface.
Positron emission tomography-based radiopharmaceuticals for imaging the expression and function of multidrug resistance P-glycoprotein.
Muralidhar D, Kumar P
J Pharmacol Exp Ther · 2026 Apr · PMID 41831271 · Publisher ↗
Multidrug resistance is a major reason for drug resistance in patients undergoing chemotherapy or other drug therapy. The overexpression of efflux proteins, such as multidrug resistance protein or P-glycoprotein (P-gp),...
Multidrug resistance is a major reason for drug resistance in patients undergoing chemotherapy or other drug therapy. The overexpression of efflux proteins, such as multidrug resistance protein or P-glycoprotein (P-gp), has been recognized as a major cause of the drugs' efflux from the brain. P-gp expression is not only responsible for drug resistance, but underactivity leads to the accumulation of amyloid proteins and may become one of the reasons for Alzheimer disease. Hence, measuring the activity of the efflux proteins can indicate whether the candidate is suitable for chemotherapy. Therefore, several radiotracers have been developed to image P-gp activity. Positron emission tomography imaging can assess P-gp function and, therefore, plays a crucial role in informing clinicians' decisions to adjust treatment. This review article discusses advancements in radiopharmaceuticals for imaging P-gp function and expression, particularly at the blood-brain barrier. It highlights the significance of various radiolabeled tracers, including verapamil, metoclopramide, and MC225, in assessing P-gp-mediated drug delivery to the brain and its role in various neurodisorders. This article discusses the outcomes of various radiopharmaceuticals used in imaging P-gp expression and function. SIGNIFICANCE STATEMENT: This review article highlights the evolution of radiopharmaceuticals for imaging P-gp in various disorders, including drug resistance, Alzheimer disease, and epilepsy. P-gp imaging can play a crucial role in drug development and aid in identifying tumors that are responsive or resistant to chemotherapy. It may help clinicians decide whether a patient is suitable for chemotherapy. Positron emission tomography imaging can provide information on P-gp activity, which can be assessed before and during chemotherapy.
Disulfidptosis: A novel cell death mechanism with pathological significance and therapeutic potential in diseases.
Qian S, Pan L, Chen G … +5 more , Qiu F, Ma Y, Li R, Mehta JL, Wang X
Pharmacol Rev · 2026 May · PMID 41818911 · Publisher ↗
Programmed cell death participates in diverse physiological and pathological processes. The identification of disulfidptosis reveals that disulfide stress-induced cytoskeletal disintegration constitutes a targetable biol...
Programmed cell death participates in diverse physiological and pathological processes. The identification of disulfidptosis reveals that disulfide stress-induced cytoskeletal disintegration constitutes a targetable biological process mediated through pathways such as SLC7A11-dependent cystine metabolism, offering potential therapeutic avenues for disease intervention. Disulfidptosis involves activation of specific molecular pathways, including SLC7A11-mediated cystine uptake, NADPH depletion, aberrant intracellular disulfide accumulation, filamentous actin collapse, and dysregulation of the antioxidant system, ultimately leading to cell death and contributing to disease progression. Furthermore, comparison between disulfidptosis and other established cell death modalities, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cuproptosis, further underscores its unique biological characteristics and research significance, enabling intervention in disease progression. By targeting these pathways, we systematically integrated pharmacological agonists and inhibitors of key targets, such as SLC7A11-dependent cystine metabolism, to promote or inhibit disulfidptosis, thereby restoring cellular homeostasis disrupted by diseases including cancer, neurodegeneration, ischemia/reperfusion injury, autoimmune diseases, metabolic syndrome, and sepsis. This highlights the potential of disulfidptosis as a therapeutic target. We identified that therapeutic strategies targeting disulfidptosis converge on the core pathogenic axis of "redox imbalance, disulfide stress, actin cytoskeleton collapse." These strategies exhibit disease-dependent bidirectionality-inducing disulfidptosis to selectively eliminate cancer cells in neoplastic diseases while suppressing this process to protect functional cells in non-neoplastic conditions. This review explores the current understanding of the molecular mechanisms and key regulatory nodes of disulfidptosis, deepening our comprehension of the role of disulfidptosis in human health and disease while revealing actionable targets and future research directions. SIGNIFICANCE STATEMENT: The discovery of disulfidptosis enriches understanding of programmed cell death, providing a foundation for targeting SLC7A11-mediated cystine metabolism and other key pathways to treat various diseases and offering new approaches for managing pathological processes previously considered intractable. As molecular mechanistic understanding advances, these emerging therapeutic strategies may open new research avenues, although clinical translation and efficacy require further validation.
Targeting cholangiocyte sphingosine-1-phosphate (S1P) receptor 1 signaling alleviates cholestatic liver injury: Mechanistic insight into S1P/phosphorylated signal transducer and activator of transcription 3 axis.
Yuan Z, Wang J, Zhang H … +8 more , Miao Y, Chai Y, Li A, Tang Q, Chen Q, Zhang L, Yu Q, Jiang Z
J Pharmacol Exp Ther · 2026 Apr · PMID 41818851 · Publisher ↗
Effective first-line treatments for cholestasis are limited, leading to poor outcomes and liver transplantation after ursodeoxycholic acid/obeticholic acid intolerance. We investigated the role of cholangiocyte sphingosi...
Effective first-line treatments for cholestasis are limited, leading to poor outcomes and liver transplantation after ursodeoxycholic acid/obeticholic acid intolerance. We investigated the role of cholangiocyte sphingosine-1-phosphate receptor 1 (S1PR1) in cholestasis pathogenesis to identify new therapeutic targets. We generated cholangiocyte-specific S1pr1 knockout mice (S1pr1). Cholestasis models included bile duct ligation (BDL) (14 days) and 0.5% cholic acid (CA) diet (4 months). The level of sphingosine-1-phosphate (S1P) and its receptor, especially S1PR1 in cholangiocytes were significantly increased in both BDL or 0.5% CA diet models. Sphingosine kinase 1-derived sphingosine-1-phosphate from hepatic stellate cells/endothelial cells activated cholangiocyte S1PR1, promoting signal transducer and activator of transcription 3 phosphorylation and releasing interleukin-6/C-C motif chemokine 7, which remodeled the inflammatory microenvironment and exacerbated liver injury. S1PR1 deletion significantly reduced liver injury, fibrosis, and inflammation. Likewise, treatment with a specific inhibitor of cholangiocyte S1PR1, W146, slightly improved liver injury induced by BDL. The functional effect of S1PR1 in cholangiocyte was further strengthened by our design of the nanoparticle-delivered W146. This demonstrated that cholangiocytes-specific deletion of S1PR1 can alleviate liver fibrosis and injury caused by biliary obstruction or chronic cholestasis, which helps to develop S1PR1 as a target for the treatment of liver fibrosis and cholestasis. SIGNIFICANCE STATEMENT: This study identifies elevated sphingosine-1-phosphate as a potential cholestasis biomarker. High sphingosine-1-phosphate binds sphingosine-1-phosphate receptor 1, activating signal transducer and activator of transcription 3 in cholangiocytes and creating proinflammatory microenvironment. Cholangiocyte-specific sphingosine-1-phosphate receptor 1 inhibition via nanocrystal agents alleviates cholestatic liver injury.
The evolving landscape of pharmacogenomics: Current achievements and future directions.
Lauschke VM, Ingelman-Sundberg M
Pharmacol Rev · 2026 Mar · PMID 41806469 · Full text
Pharmacogenomics investigates how inherited and acquired genetic variation shapes drug efficacy, toxicity, and treatment failure. The major therapeutic areas for pharmacogenomics-assisted drug therapy include oncology, c...
Pharmacogenomics investigates how inherited and acquired genetic variation shapes drug efficacy, toxicity, and treatment failure. The major therapeutic areas for pharmacogenomics-assisted drug therapy include oncology, cardiology, psychiatry, neurology, infectious diseases, pain management, and metabolic disorders. Next-generation sequencing has revealed the extensive landscape of pharmacogenetic polymorphisms at the population scale. As a result, the field has evolved from early single-gene pharmacogenetics to genome-wide approaches that encompass the entirety of pharmacogenetic variability. However, much of the heritable variation in drug response remains unexplained, reflecting rare and structural variants, complex haplotypes, and the importance of polymorphisms in factors that regulate pharmacogenes in trans. A recently emphasized factor is the importance of considering differences in substrate specificities between enzymes and transporters that carry amino acid changes. Allele frequencies of actionable genetic variants are often low, requiring large, well powered studies that carefully account for key confounders, including patient adherence, placebo effects, comorbidities, hepatic and renal dysfunction, inflammation, and drug-drug and food-drug interactions. At the same time, emerging in silico variant-effect predictors, deep mutational scanning, population biobanks, and organotypic 3-dimensional human tissue models provide scalable platforms for functionally annotating variants and modeling human drug disposition and toxicity. A major effort moving forward is the continued identification and accurate classification of clinically important drug-gene pairs, along with improved implementation of pharmacogenomics in clinical practice. Artificial intelligence can accelerate this process by enabling rapid genome interpretation, prioritizing clinically relevant variants, and translating complex data into actionable recommendations. It can also integrate pharmacogenomic findings with other omics and help mitigate bias, thereby improving equity in treatment outcomes. In conclusion, the field will continue to expand, but its success will require large, rigorously designed ancestrally diverse trials, harmonized international regulatory standards, robust cost-effectiveness evidence, and the seamless integration of artificial intelligence-supported pharmacogenomic decision tools into global clinical practice. SIGNIFICANCE STATEMENT: Pharmacogenomics is a rapidly evolving field. Here, we review its foundational background, the most important clinical applications, and future perspectives with respect to methodological advances, the role of artificial intelligence, and its translation into clinical practice.
Laxative use and acute kidney injury risk: Analysis of a Japanese hospital-based database.
Mitsuboshi S, Tsuchiya M, Kizaki H … +2 more , Hori S, Imai S
J Pharmacol Exp Ther · 2026 Mar · PMID 41806409 · Publisher ↗
Although a potential association between laxative use and the development of acute kidney injury (AKI) has been proposed, it remains inadequately investigated. Therefore, the objective of this study was to elucidate the...
Although a potential association between laxative use and the development of acute kidney injury (AKI) has been proposed, it remains inadequately investigated. Therefore, the objective of this study was to elucidate the association between the use of each laxative and the risk of developing AKI. Data were obtained from the JMDC hospital-based administrative claims database, covering the period from April 2014 to August 2022. Laxatives were defined as lubiprostone and linaclotide (secretory drugs), senna (a stimulant), and magnesium oxide (a nonabsorbed substance). AKI was defined in accordance with the recommendations of the Kidney Disease: Improving Global Outcomes working group. After screening, 159,630 patients were eligible for inclusion. AKI occurred in 693 patients (94/1000 patient-years) in the magnesium oxide group, 67 (153/1000 patient-years) in the lubiprostone group, 194 (109/1000 patient-years) in the senna group, and 22 (161/1000 patient-years) in the linaclotide group. Cox regression analysis revealed that the use of lubiprostone (adjusted hazard ratio, 0.96; 95% CI, 0.74-1.24), senna (adjusted hazard ratio, 1.08; 95% CI, 0.91-1.27), and linaclotide (adjusted hazard ratio, 1.42; 95% CI, 0.92-2.17) did not decrease the risk of AKI compared with magnesium oxide. The findings suggest that there is no difference in AKI risk among the various laxatives studied. SIGNIFICANCE STATEMENT: The results indicate that there were no differences in the risk of acute kidney injury among lubiprostone, linaclotide, senna, and magnesium oxide, suggesting that the use of these laxatives might not impact the risk of acute kidney injury.
Lomitapide reduces viability and clonogenicity in hepatocellular carcinoma cells but enhances xenograft growth: The importance of the tumor microenvironment.
Comanzo CG, Buatti Fagalde F, Vera MC … +9 more , Oviedo Bustos L, Palma NF, Capiglioni AM, Hesse L, Pisani GB, Ferretti AC, Ceballos MP, Alvarez ML, Quiroga AD
J Pharmacol Exp Ther · 2026 Apr · PMID 41795398 · Publisher ↗
Lomitapide, a microsomal triglyceride transfer protein inhibitor approved for the treatment of homozygous familial hypercholesterolemia, has recently attracted interest as a potential anticancer agent because of its effe...
Lomitapide, a microsomal triglyceride transfer protein inhibitor approved for the treatment of homozygous familial hypercholesterolemia, has recently attracted interest as a potential anticancer agent because of its effects on lipid metabolism. Given the central role of lipid handling in hepatocellular carcinoma (HCC), we investigated the impact of lomitapide-mediated microsomal triglyceride transfer protein inhibition using complementary in vitro and in vivo models. Lomitapide induced intracellular lipid accumulation and reduced cell viability and clonogenicity in human HCC cell lines (Huh7 and HepG2) in a dose-dependent manner, without affecting cell migration. However, in a subcutaneous xenograft model, lomitapide treatment paradoxically promoted tumor growth, increasing tumor volume, weight, and proliferative markers, whereas apoptosis-related proteins remained unchanged. Tumors from lomitapide-treated mice exhibited enhanced extracellular signal-regulated kinase (ERK) signaling and increased lipid accumulation, alongside reduced systemic lipoprotein levels. To reconcile these opposing effects, we examined the contribution of the tumor microenvironment. Coculture experiments revealed reduced sensitivity of HCC cells to lomitapide in the presence of nonparenchymal cells. Conditioned media studies identified hepatic stellate cells as key mediators of this resistance, associated with increased secretion of interleukin 8 and vascular endothelial growth factor after lomitapide exposure. These factors are known activators of proliferative signaling pathways in HCC. Collectively, our findings demonstrate that lomitapide exerts direct antiproliferative effects on HCC cells under simplified conditions, but promotes tumor growth in vivo through microenvironment-dependent mechanisms. This study highlights the critical influence of stromal-tumor interactions on therapeutic outcomes and urges caution in repurposing lipid-modulating drugs for cancer treatment without accounting for tissue context. SIGNIFICANCE STATEMENT: This study demonstrates that inhibition of microsomal triglyceride transfer protein exerts opposite effects on hepatocellular carcinoma depending on biological context, suppressing tumor cell growth in vitro while promoting tumor expansion in vivo. These findings reveal a decisive role for the tumor microenvironment, particularly stromal cell-derived protumorigenic signals, in shaping therapeutic responses to lipid-modulating drugs.
Adiponectin deficiency and high fat and sucrose diets impair pancreatic islet adaptations to pregnancy and contribute to gestational hyperglycemia.
Moyce Gruber BL, Fonseca MA, Trivedi K … +2 more , Doucette CA, Dolinsky VW
J Pharmacol Exp Ther · 2026 Mar · PMID 41793898 · Full text
Gestational diabetes mellitus is characterized by hyperglycemia and impaired glucose tolerance with first onset in pregnancy. Clinical research shows an association between low circulating adiponectin levels and gestatio...
Gestational diabetes mellitus is characterized by hyperglycemia and impaired glucose tolerance with first onset in pregnancy. Clinical research shows an association between low circulating adiponectin levels and gestational diabetes mellitus diagnosis. Adiponectin is a fat-derived cytokine which is postulated to improve insulin secretion and survival of pancreatic β-cells; however, the role of adiponectin in the regulation of late pregnancy glucose homeostasis requires investigation. We investigated metabolic, morphological, and functional adaptations of pancreatic islets to pregnancy in adiponectin knockout and wild-type female mice and the interaction with low fat (LF) or high fat and sucrose (HFS) diets. Pregnant wild-type mice fed a HFS diet exhibited elevated fasting glycemia and glucose intolerance, accompanied by impaired insulinogenic index at gestational day 18.5 compared to LF-fed controls, and interestingly both LF and HFS-fed adiponectin knockout mice exhibited similar impairments. Pregnancy-induced pancreatic β-cell expansion was largely preserved during late pregnancy, though the HFS diet attenuated β-cell mass at gestational day 18.5 and adiponectin deficiency triggered a similar level of impairment. Glucose stimulated insulin secretion was significantly attenuated in islets isolated from pregnant wild-type mice fed HFS diet and both LF and HFS-fed pregnant adiponectin knockout mice showed a similar level of impaired despite similar basal secretion and insulin content. Gene expression analysis of islets from pregnant mice revealed reduced Nkx6.1 and downregulation of metabolism genes (Ppargc1a, Cpt1a) and Adipor1, without changes in insulin synthesis/secretion genes or mitochondrial electron transport chain components in both the HFS-fed wild-type and both LF- and HFS-fed adiponectin knockout mice compared to wild-type LF-fed controls. These findings demonstrate that HFS feeding and adiponectin deficiency trigger a similar level of impaired insulin secretion during pregnancy that contributes to hyperglycemia, which suggests increasing adiponectin levels during pregnancy has potential therapeutic benefit. SIGNIFICANCE STATEMENT: We show that in late pregnancy, the absence of adiponectin elicits a similar level of impaired insulin secretion as high fat/sucrose diet-induced obesity, but without a synergistic effect. This suggests interventions to enhance adiponectin could improve insulin secretion and prevent gestational diabetes mellitus.
Multiomics and experimental validation reveal theophylline's mechanism targeting IL1A/ACTB/TLR4 and identify synergistic drugs in hepatocellular carcinoma.
Gao Y, Chen W, Zarogoulidis P … +8 more , Yallapu MM, Nikolic MV, Vaishnani DK, Zheng J, Nedeljkovic N, Ye K, Guo Y, Xu Q
J Pharmacol Exp Ther · 2026 Mar · PMID 41763175 · Publisher ↗
This study aimed to investigate the mechanism by which theophylline influences hepatocellular carcinoma (HCC) through the regulation of core targets and to identify its potential synergistic drugs. Integrated network pha...
This study aimed to investigate the mechanism by which theophylline influences hepatocellular carcinoma (HCC) through the regulation of core targets and to identify its potential synergistic drugs. Integrated network pharmacology, multiomics data (transcriptomics, single-cell, and spatial transcriptomics), and multiple machine learning algorithms (a total of 113 diagnostic models combined with SHapley Additive exPlanations, least absolute shrinkage and selection operator, and artificial neural network analyses) were used to screen core targets linking theophylline, gut microbiota, and HCC. Enrichment analyses (Disease Ontology, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes) were conducted to elucidate their biological functions. Molecular docking and molecular dynamics simulations were used to evaluate the binding patterns and stability between theophylline (and potential synergistic drugs) and the core targets. Databases including The University of ALabama at Birmingham CANcer data analysis Portal, Gene Expression Profiling Interactive Analysis, Comparative Toxicogenomics Database, and gutMGene were used to analyze the clinical relevance of core targets, their regulatory roles in the immune microenvironment, and their connections within the "theophylline-target-HCC chemical-gut microbiota" network. Finally, in vitro cell experiments (proliferation, migration, invasion, quantitative reverse transcription polymerase chain reaction, and Western blot) and in vivo xenograft models were used to validate the findings. Seventeen shared targets were screened, and 3 core targets, interleukin 1α, actin β, and toll like receptor 4, were further identified. Molecular docking and dynamics simulations demonstrated that theophylline could stably bind to these core targets. Multiple drugs including chlorogenic acid (PubChem CID: 1794427), losartan (PubChem CID: 3961), and estrone sulfate (PubChem CID: 3001028), were found to potentially exhibit synergistic effects with theophylline. The expression of core targets was significantly associated with clinical stage, prognosis, immune cell infiltration (eg, monocytes and macrophages), and immune checkpoints (including programmed death-ligand 1 and cytotoxic T-lymphocyte associated protein 4) in patients with HCC. Single-cell and spatial transcriptomic analyses revealed heterogeneous expression of core targets within the tumor microenvironment. Experimental validation confirmed that theophylline significantly inhibited HCC cell proliferation, migration, and invasion, downregulated core target expression, and effectively suppressed tumor growth in vivo. Theophylline may exert anti-HCC effects by regulating the core targets interleukin 1α, actin β, and toll like receptor 4, thereby influencing the tumor immune microenvironment, malignant biological behaviors of cells, and the gut microbiota-liver axis. This study provides a theoretical foundation for theophylline as a potential therapeutic or adjuvant agent for HCC and suggests directions for its combined application with specific drugs. SIGNIFICANCE STATEMENT: The research uncovers a new target and mechanism for the classic drug theophylline in treating hepatocellular carcinoma. This finding provides a key scientific basis for repurposing the drug. Furthermore, a drug combination discovered through multiomics analysis and laboratory tests offers a direct and practical new path for developing new combination therapies for hepatocellular carcinoma in the clinic.
Downregulation of osteoclast differentiation and activation by the soluble epoxide hydrolase inhibition.
Martins G, Oliveira D, Rivas CA … +5 more , Clemente-Napimoga JT, Hammock BD, Van Dyke TE, Napimoga MH, Abdalla HB
J Pharmacol Exp Ther · 2026 Mar · PMID 41763174 · Full text
This study aimed to investigate the effects of soluble epoxide hydrolase (sEH) inhibition on osteoclast differentiation and activity in vitro and in vivo, as well as to elucidate the signaling pathways associated with os...
This study aimed to investigate the effects of soluble epoxide hydrolase (sEH) inhibition on osteoclast differentiation and activity in vitro and in vivo, as well as to elucidate the signaling pathways associated with osteoclastogenesis. Primary murine bone marrow monocytes were stimulated with macrophage colony-stimulating factor and receptor activator of nuclear factor kappa B ligand to induce osteoclastogenesis and treated with the sEH inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU) (0.1-10 μM). Tartrate-resistant acid phosphatase staining, gene expression analyses, and immunofluorescence were used to evaluate osteoclast formation, transcriptional regulation, and cell fusion. A murine model of ligature-induced periodontitis was used to assess in vivo effects of sEH inhibition (TPPU 10 mg/kg). Alveolar bone loss was quantified by histomorphometry, and gingival gene expression was analyzed. In vitro, sEH inhibition significantly reduced tartrate-resistant acid phosphatase-positive multinucleated osteoclast formation, downregulated the expression of key transcription factors and osteoclast activity-related genes. Immunofluorescence analysis revealed attenuation of mitogen-activated protein kinase signaling and reduced dendritic cell-specific transmembrane protein expression, indicating impaired cell fusion. In vivo, TPPU treatment preserved alveolar bone structure, reduced osteoclast-like cell numbers, and decreased the expression of osteoclastic markers in gingival tissues during experimental periodontitis. sEH acts as a crucial regulator of osteoclast differentiation and function. Pharmacological inhibition of sEH suppresses osteoclastogenesis and protects against inflammatory bone loss. Therefore, targeting sEH may represent a novel therapeutic approach to modulate osteoclast activity and prevent bone destruction in periodontitis and other bone-resorptive diseases. SIGNIFICANCE STATEMENT: This study provides direct evidence that soluble epoxide hydrolase inhibition modulates osteoclast differentiation and fusion, contributing to reduced inflammatory bone loss. By demonstrating effects on osteoclast-intrinsic pathways while also influencing the inflammatory microenvironment, our findings support soluble epoxide hydrolase as a pharmacological target for chronic inflammatory bone-resorptive diseases.
Carbon dots for drug delivery: Insights into their potential in nanopharmacology.
Iannazzo D, Celesti C, Cardo L … +2 more , Prato M, Bitto A
Pharmacol Rev · 2026 Mar · PMID 41759375 · Publisher ↗
Carbon dots (CDs), a remarkable class of novel nanomaterials, have attracted significant attention in the biomedical field owing to their extraordinary chemical, physical, and biological properties. Among their diverse a...
Carbon dots (CDs), a remarkable class of novel nanomaterials, have attracted significant attention in the biomedical field owing to their extraordinary chemical, physical, and biological properties. Among their diverse applications, CDs stand out as highly promising nanocarriers for drug delivery owing to their ability to cross cell membranes efficiently and deliver therapeutic agents directly to damaged cells or tissues. What makes CDs truly unique is their intrinsic photoluminescence and the abundance of reactive groups on their surface, allowing for extensive multifunctionalization. This versatility enables the conjugation of various functional groups, therapeutic molecules, biomolecules, and targeting ligands, paving the way for an integrated approach to diagnosis and therapy. This review highlights the latest advancements in the application of CDs for drug delivery, focusing on their use in anticancer and antiviral therapies, as well as in the treatment of osteoarticular diseases and neurological disorders. Particular attention is given to the critical aspects of biocompatibility and toxicity, which remain key challenges for their translation into clinical practice. These promising developments position CDs as cutting-edge tools in nanopharmacology, offering exciting opportunities for future therapeutic innovations. SIGNIFICANCE STATEMENT: Carbon dots represent a transformative class of nanomaterials whose tunable chemistry, intrinsic photoluminescence, and high biocompatibility make them highly promising for next-generation drug delivery. By enabling targeted, multifunctional, and trackable therapeutic strategies across cancer, viral infections, osteoarticular, and neurological diseases, carbon dots offer a unique platform that bridges diagnostics and therapy, with the potential to significantly advance precision medicine while addressing current limitations of conventional drug carriers.
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