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.

The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor that serves as a classical and central regulator of xenobiotic metabolism and endogenous metabolic homeostasis. Recent studies have revealed that PXR plays critical roles in the pathogenesis and progression of diseases across multiple organ systems, including hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine disorders. Notably, PXR activation can exert protective effects by improving metabolic balance, reducing inflammation, and preventing fibrosis; however, it may promote disease progression in certain settings, highlighting its dual roles. Advances in pharmacological research have led to the identification of numerous PXR agonists and antagonists, including endogenous ligands, natural products, and synthetic compounds, many of which show therapeutic potential. This review summarizes recent progress on the pharmacological roles of PXR in organ-specific diseases and provides an overview of current strategies targeting PXR, offering new insights into its potential as a therapeutic target. SIGNIFICANCE STATEMENT: The pregnane X receptor (PXR, NR1I2) is a ligand-activated nuclear receptor traditionally recognized as a master regulator of xenobiotic metabolism. Growing evidence demonstrates that PXR plays important roles beyond drug metabolism, regulating the pathogenesis and progression of hepatic, gastrointestinal, renal, cardiovascular, central nervous system, and reproductive-endocrine diseases. This review summarizes current knowledge on PXR's organ-specific functions and pharmacological modulation, highlighting PXR as a promising drug target across multiple disease contexts.

Methotrexate (MTX) was among the first steroid-sparing agents introduced for the treatment of inflammatory bowel disease (IBD). Its efficacy is well established for Crohn's disease, though studies of its use in ulcerative colitis have largely reported negative results, with only some, although inconsistent, findings suggesting limited benefit. In this review, we provide a comprehensive and up-to-date evaluation of MTX's use in IBD, including its key mechanisms of action(s), therapeutic value, as well as emerging targets that underscore the complexity of this drug and the biological landscape it alters. Despite its longstanding use, the full spectrum of MTX's effects contributing to its efficacy in IBD remains incompletely understood. Although multiple pathways have been implicated, the relative importance of each remains nebulous, and additional, unidentified functions may play a role, particularly in contexts not pertaining to immunomodulation. We highlight recent findings that poise MTX as an unexpected but promising agent for mucosal healing. We also provide a detailed evaluation of clinical studies, encompassing randomized controlled trials and observational data, highlighting MTX's effectiveness, differences in route of administration, safety profile, and limitations as they pertain to the management of IBD. As therapeutic targets for IBD evolve, we discuss MTX's future positioning by exploring clinical perspectives regarding its utility and examine the latest evidence that indicates there may be novel, previously unexplored, therapeutic potential. By bridging mechanistic insights with clinical evidence, this review underscores MTX's enduring, albeit niche, position in IBD therapy and highlights key areas for future investigation to optimize its use. SIGNIFICANCE STATEMENT: Methotrexate remains a valuable, though underutilized, therapeutic option for the management of inflammatory bowel disease. This review provides a comprehensive overview of methotrexate's pharmacology, integrating emerging mechanistic insights and clinical data to reframe its role beyond immunomodulation, particularly at the gastrointestinal mucosal interface, thereby identifying novel avenues for future research that may expand its clinical utility in inflammatory bowel disease.

We are arguably experiencing the greatest disruption to higher education in modern history. High-quality education research has demonstrated that active learning and other innovations are significantly more effective than traditional methods. The recent pandemic forced educators to adapt in previously unimaginable ways. Generative artificial intelligence now presents great challenges and opportunities for our approaches to teaching, support of learning and assessment, such as streamlining personalized feedback while raising concerns about academic integrity. This article provides a research informed, expert commentary to support new pharmacology educators in navigating this complex environment. The article is neither a systematic review by design and methodology, nor is it offering comprehensive coverage of the pertinent literature (an insurmountable task, given the breadth of the topic). We highlight how educators in basic and clinical pharmacology are transforming their teaching and curricula to enhance student success in current and future settings. Global initiatives, such as those sponsored by the International Union of Basic and Clinical Pharmacology, including the Pharmacology Education Project and Core Concepts-based curricula, are offering opportunities to enhance pharmacology education by standardizing key concepts, providing open-access learning resources, and fostering international collaboration. These efforts are intended to support alignment of curricula, improve student engagement through interactive materials, facilitating a global exchange of best practices, and supporting educators in adopting innovative teaching methodologies. These initiatives require contributions from pharmacology experts across multiple countries, languages, and cultures. Consequently, this article serves as a call to action to advance innovation and inclusivity in pharmacology education. SIGNIFICANCE STATEMENT: Recent disruptions in higher education have forced educators to adapt in ways that would have previously been unthinkable. The article provides an evidence-based, expert commentary for new pharmacology educators that will assist them to thrive in this complex environment.

Obesity is a multifactorial metabolic condition characterized by dysregulated lipid accumulation and systemic energy imbalance with escalating global prevalence. This chronic disease drives a spectrum of life-threatening comorbidities, including metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), which now represent a primary cause of liver-related morbidity and transplantation. Both conditions share pathophysiological underpinnings such as insulin resistance, chronic inflammation, and mitochondrial dysfunction, creating a vicious cycle where obesity exacerbates hepatic steatosis and fibrosis. Although US Food and Drug Administration-approved antiobesity agents such as glucagon-like peptide-1 receptor agonists (eg, semaglutide) demonstrate weight loss efficacy, their long-term utility is constrained by gastrointestinal intolerance and variable effects on hepatic outcomes. Similarly, the recent approval of resmetirom for MASH, though groundbreaking, leaves unresolved challenges in durability, accessibility and some adverse effects including gastrointestinal reaction. The intricate molecular crosstalk linking adipose and hepatocyte dysfunction necessitates innovative therapeutics targeting shared pathophysiological pathways or novel molecular targets. Natural products, with inherent structural diversity and multitarget potential, offer a promising avenue for dual intervention in the obesity-MASH continuum. This review systematically evaluates emerging endogenous metabolites and plant-derived compounds, elucidating their directly validated molecular targets and preclinical evidence for metabolic reprogramming against obesity and MASLD/MASH. Furthermore, it synthesizes translational insights from natural product research and clinical trial experiences of related synthetic agonists. By integrating mechanistic discovery with a critical assessment of developmental challenges, this review aims to advance strategic frameworks for the concurrent management of obesity and MASLD/MASH. SIGNIFICANCE STATEMENT: Obesity-driven metabolic dysfunction-associated steatotic liver disease and steatohepatitis are leading causes of liver morbidity with limited treatment options. This review systematically evaluates natural products as multitarget therapeutics for these interconnected conditions. By integrating evidence of their efficacy and target mechanisms with modern discovery approaches, this study emphasizes pathways for clinical translation and aims to stimulate future research into novel, mechanism-based interventions.

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.

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.

Adhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly apparent. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in this field and provides a comprehensive assessment of the current understanding of aGPCR biology, including a focus on human and mammalian aGPCRs, their evolutionary origins, methodological approaches, and model systems for their investigation, as well as emerging approaches for their therapeutic targeting. SIGNIFICANCE STATEMENT: Adhesion G protein-coupled receptors are versatile cell-surface proteins that integrate structural, biochemical, and physiological functions, with major roles in health and disease. This review summarizes current knowledge of their molecular features, functions in diverse model systems, and emerging opportunities for therapeutic targeting, providing a comprehensive resource that connects basic biology with translational applications across multiple scientific disciplines.

Parenteral anticoagulants are mainstay therapies in critical care and perioperative settings because of their unique pharmacological properties, but they have a narrow therapeutic window. This emphasizes the need to thoroughly understand their pharmacodynamics effects on hemostasis. Thrombin generation assays provide a comprehensive measure of coagulation and can characterize class-specific anticoagulant effects. We reviewed the literature with a focus on parenteral anticoagulants to define the role of thrombin generation as a pharmacodynamic measure of anticoagulation status. We contextualize these results in light of findings from a prior review on the effects of oral anticoagulants on thrombin generation and consider our findings in view of results stemming from comparative anticoagulation-focused epidemiologic research. This review provides proof of principle that, from a pharmacodynamics perspective, not all anticoagulants are the same. They exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects, such as unfractionated or low-molecular-weight heparins, are better able to suppress thrombin generation than selective direct inhibitors, such as bivalirudin, argatroban, direct oral anticoagulants, or factor XI(a) inhibitors. We propose a conceptually valid theoretical framework, grounded in mechanistic rationale, supported by experimentation, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants. The knowledge reviewed herein may support the future development of more personalized approaches to anticoagulation treatment. Our findings contribute a foundation upon which future anticoagulation research can be based and warrant further investigation. SIGNIFICANCE STATEMENT: From a pharmacodynamic perspective, not all anticoagulants are the same. Oral and parenteral anticoagulants exert class-specific effects on thrombin generation, and these divergent effects reflect differing mechanisms of action on coagulation initiation, amplification, and propagation. Anticoagulants with multiple downstream effects are better able to suppress thrombin generation than selective direct inhibitors. This review proposes a theoretical framework, grounded in mechanistic rationale, and leveraging thrombin generation as a common measure to compare and examine the pharmacodynamic impact of different anticoagulants.

The apelin receptor binds 2 families of endogenous peptide, apelin and Elabela, but unusually these share little sequence similarity in the N-terminal sequences of the binding domains. Cryo-electron microscopy, X-ray crystallography combined with AlphaFold has yielded a molecular map of the interaction of amino acids with the apelin receptor in complex with endogenous peptides and biased ligands. In the early embryo, the apelin signaling pathway is essential for cardiovascular development, with receptor knockout models displaying severe cardiovascular defects. In adults, the principal short-term effects of [Pyr1]apelin-13, infused into healthy volunteers was increased cardiac output and decreased peripheral resistance without side effects. Importantly, these beneficial effects of systemic apelin were retained in patients with heart failure and pulmonary arterial hypertension. In chronic kidney disease, [Pyr1]apelin-13 showed additional therapeutic potential, increasing glomerular filtration rate while reducing proteinuria. Identification of these favorable actions in disease has sparked the development of more effective agonists with improved pharmacokinetics and pharmacodynamics profiles. Among these are G protein-biased peptide agonists, designed to minimize receptor desensitization by reducing internalization via the β-arrestin pathway. These have shown efficacy in proof-of-concept studies and in animal models of pulmonary arterial hypertension, one of the most promising therapeutic targets. This review focuses on the clinical pharmacology of the apelin receptor, exploring the pathophysiology of diseases where the apelin signaling pathway is dysregulated that have emerged during the last 5 years. SIGNIFICANCE STATEMENT: This review focuses on the pharmacology of the apelin receptor where structural analysis has generated a molecular map of interaction with endogenous ligands, apelin and Elabela, as well as with peptide and small molecule agonists. Novel unbiased and biased apelin agonists are progressing through the clinic targeting pathophysiological conditions where the apelin signaling pathway is dysregulated.