G protein–coupled receptors (GPCRs) are best known for initiating signaling at the plasma membrane, yet a substantial and functionally distinct subset of these receptors localize to the primary cilium, a highly specialized cell-surface organelle. Over the past decade, the primary cilium has emerged as a privileged signaling compartment that concentrates GPCRs, signaling effectors, and second messengers within a physically constrained and biochemically unique environment. In this review, we synthesize current knowledge of GPCR signaling from a primary cilium perspective, with emphasis on receptor repertoire, trafficking mechanisms, and compartment-specific signal transduction. We discuss how ciliary entry and exit are regulated by dedicated transport systems, how canonical GPCR signaling components - G proteins, GRKs, β-arrestins, RGS proteins, and AKAPs - are organized within cilia, and how the ciliary geometry, membrane composition, voltage, pH, and cytoskeletal architecture shape signaling outcomes. We further highlight how cilia support autonomous and highly sensitive microdomains of cAMP and Ca2+ signaling, enabling integration and hierarchical control of multiple GPCR inputs. Finally, we examine the physiological consequences of ciliary GPCR signaling in neural, renal, adipose, and pancreatic, and developmental tissues, where defects in ciliary signaling contribute to metabolic disease, impaired morphogenesis and tissue homeostasis, and ciliopathies – a range of human disorders arising from primary cilium dysfunction. Together, these studies establish the primary cilium as a dynamic and modular GPCR signaling hub and underscore the importance of subcellular localization in determining receptor function and signaling specificity.
The critical involvement of hepatic transporters in both physiological and pathological processes, including metabolic diseases, drug metabolism and toxicity, represent key issues in pharmacology. The expression and localization of transporters involved in hepatic functions are especially important in new drug development and toxicology studies. The value of animal experiments, because of major specific differences in transporter expression, localization and substrate recognition, is limited in this regard, and human liver cell preparations are already available to allow relevant in vitro studies. Currently the gold standard for in vitro studies is the primary human liver cell preparation. However, the inter-individual heterogeneity, low reproducibility and high price of such preparations are prohibiting in their wide-spread use. Hepatocytes derived from liver tumors are widely used in toxicology studies, while each of these cell lines has specific advantages and shortcomings. Stem cell-based liver cell preparations, especially spheroids and organoids derived from human induced pluripotent stem cells, may serve as a new toolbox for studying a variety of membrane transporters and complex metabolic interactions in human hepatocytes. These advanced preparations, while currently somewhat premature, should provide an excellent basis for comprehensive in vitro functional assays. The present paper provides a comparative review of our current understanding of the pharmacological relevance of hepatic transporters, their interactions with the key players of general drug metabolism, their complex regulation, as well as the recent methodologies to apply human-relevant in vitro systems in drug development and toxicology studies.
In 1987 the human mineralocorticoid receptor (MR) was cloned and verified as a high affinity, low abundance corticosteroid receptor and the primary mediator of mineralocorticoid activity. Shortly thereafter the role of the MR in the pathology of cardiac and renal failure was characterised and the cardioprotective effects of the MR antagonists (MRA) spironolactone demonstrated in preclinical models and patients with all-cause heart failure. While MRA are now established therapies for heart failure, the therapeutic success of MRA is tempered by an increased risk of hyperkalaemia and reduced renal function. However, the MR remains an attractive therapeutic target and several non-steroidal MRA have now been developed and may have a reduced effect on serum potassium. The MR is also well-recognised for important physiological roles across a broad range of epithelial and non-epithelial tissues. New insights into MR biology arise from recent demonstration of the structural mechanisms within the receptor that switch progesterone from MR agonist in fish to antagonist in mammals, identification of MR-specific response sequences and the contribution of MR to timekeeping of the molecular circadian clock. This review will summarise the breadth of physiological actions of the MR, the molecular and cellular mechanisms that define MR signalling, and how cell context can switch MR actions from physiological regulation of homeostasis in many tissues to induction of tissue injury and remodelling. We also review new developments in MR-targeted therapies and recent clinical trials that seek to mitigate the pathological actions of the MR in an increasing number of diseases.
Recombinant proteins represent a critically important class of biopharmaceuticals and are indispensable for the prevention and treatment of various clinical diseases. However, their in vivo disposal is far more complex than those of small-molecule drugs. Unfortunately, pharmacokinetic (PK) studies of recombinant proteins still lag far behind those of small molecules, and most investigations are limited to the determination of overall PK parameters, with insufficient exploration at the cellular and subcellular levels or in-depth mechanistic insights. Inadequate understanding of the PK and metabolic characteristics of recombinant proteins frequently leads to limited or diminished efficacy and suboptimal safety profiles in clinical practice. Moreover, with the emergence of a growing number of novel recombinant proteins in recent years, such as monoclonal antibodies and fusion proteins, the PK research of recombinant proteins has become increasingly extensive while also facing mounting new challenges. Therefore, this article focuses on the PKs and metabolic characteristics of both classical and novel recombinant proteins, as well as factors affecting their in vivo disposal, in order to enhance their therapeutic efficacy and safety through optimization of their PKs. To our knowledge, no comprehensive review has systematically summarized the PK properties and metabolic mechanisms of recombinant proteins, which highlights the necessity of this review. Furthermore, mechanistic insights into the PK of recombinant proteins, particularly their metabolic mechanisms, remain scarce and outdated. We hope this review can draw more attention to this vital yet understudied area and promote further in-depth exploration.
Neuronal Kv7 (KCNQ) voltage-gated potassium channels are key regulators of membrane excitability, primarily through their contribution to the M-current, a slowly activating and non-inactivating potassium conductance that stabilizes the resting membrane potential and limits repetitive firing. Given the central role of the M-current in regulating critical central nervous system functions, it is not surprising that Kv7 channel dysfunction contributes to the onset and progression of a wide range of neuropsychiatric disorders and that Kv7 channels are primary targets for pharmacological intervention in all these conditions. In this review, we provide a comprehensive overview of the physiological roles of neuronal Kv7 subunits (Kv7.2–Kv7.5) with particular emphasis on their expression patterns during development and across distinct neuronal populations. We also discuss the complex regulatory mechanisms governing Kv7 channel expression, trafficking, and function, including modulation by intracellular signaling pathways and interacting proteins. Particular attention is devoted to the involvement of Kv7 channel dysfunction in epileptic encephalopathies, pain syndromes, and neuropsychiatric conditions, as well as neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, where altered neuronal excitability is a common pathogenic hallmark. Furthermore, we examine the evolving pharmacological landscape of Kv7 channel modulators, from first-generation openers such as retigabine to next-generation agents, repurposed drugs, natural products and Kv7 modulators currently in clinical development, highlighting both their therapeutic promise and existing challenges. Collectively, available evidence identifies Kv7 channels as versatile and highly attractive pharmacological targets for the treatment of central nervous system disorders characterized by maladaptive changes in neuronal excitability.
The kidneys are highly metabolically active organs that undergo a progressive, intrinsic decline in renal function with aging, a process that can be further exacerbated by chronic exposure to oxidative stress, inflammation, hypertension, and various toxins. Studies have shown that the prevalence of acute kidney injury and chronic kidney disease is significantly higher in the elderly. This suggests that the age-related reduction in baseline renal function, rather than advanced age itself, increases the susceptibility to and severity of these disorders after nephrotoxic insults. We comprehensively discuss the emerging recognition of shared molecular and cellular mechanisms underpinning fibrosis and cellular senescence, 2 hallmark features of functional decline seen in renal aging, acute kidney injury, and chronic kidney disease, as well as proposing the interconnection between these events. Furthermore, we highlight therapeutic strategies aimed at mitigating kidney damage and counteracting the effects of aging. These include lifestyle modifications, small-molecule inhibitors, and senotherapeutic approaches such as senolytics and senomorphics. Overall, this work aims to establish a foundation for understanding the pathogenesis of renal aging and related diseases, while also identifying promising avenues for effective therapeutic intervention. SIGNIFICANCE STATEMENT: Cellular senescence and fibrosis intersect in renal aging, acute kidney injury, and chronic kidney disease, highlighting shared pathways that may be targeted to slow disease progression and providing insights into the underlying mechanisms, current interventions, and future strategies for age-related kidney disorders.
Experimental and clinical evidence continues to accumulate, supporting the critical role of dysregulated inflammation, immunity, and redox signaling in the pathophysiology of various age-related cardiometabolic and neurodegenerative diseases. While ongoing research is investigating novel anti-inflammatory and immunomodulatory therapies for such conditions, available antirheumatic drugs may serve a similar purpose. One such drug, methotrexate, has been successfully used at high doses since the 1940s as an anticancer agent and, more recently, at lower doses in patients with autoimmune diseases. Although the effects of methotrexate have traditionally been attributed to its antiproliferative activity via folic acid modulation, additional targets have been identified, including AMP-activated protein kinase, Janus kinase/signal transducer and activator of transcription, high mobility group box 1 protein, the gut microbiota, and additional pharmacological effects of adenosine, a key mediator of methotrexate. The beneficial effects of modulating these targets on downstream inflammatory and immune pathways, cellular senescence, and vascular, metabolic, and brain homeostasis have been increasingly investigated in experimental models. Furthermore, studies conducted over the past 20 years suggest an association between low-dose methotrexate and a decreased risk of certain age-related cardiometabolic and neurodegenerative diseases, particularly in patients with autoimmune conditions. The results of these studies support the potential protective role of methotrexate against age-associated cardiometabolic and neurodegenerative diseases through multiple mechanisms, unlike targeted immunomodulatory and anti-inflammatory drugs, thereby providing a robust framework for investigating its repurposing in future intervention studies. SIGNIFICANCE STATEMENT: New treatments are essential to address the burden of age-related diseases. The important roles of dysregulated inflammation, immunity, and redox signaling in these conditions have spurred research into developing new therapies or repurposing existing drugs to target these dysfunctions. The disease-modifying antirheumatic drug methotrexate has shown potential protective effects against cellular senescence and certain age-related cardiometabolic and neurodegenerative diseases. This knowledge will encourage further research into the repurposing of methotrexate for the treatment of these diseases.
G-quadruplexes (G4s), a specialized nucleic acid secondary structure, have been found in recent years to be widely distributed in gene promoter regions. Growing evidence has highlighted the significance of G4 structures of promoter region in regulating various biological processes, including transcription and epigenetic regulation. In this review, we first proposed the 8 main characteristics of G-quadruplexes in the promoter region: widespread distribution, positional specificity, structural diversity, precise regulation, genetic modifiability, dynamic reversibility, signal responsiveness, and synergistic regulation. Common G4 regulators were then categorized as natural products, transcription factors and other binding proteins, small molecule ligands, and nucleic acids, which were fully summarized. Then different types of characterization methods for promoter region G4 and its ligands are summarized. Finally, the directions of promoter region G4 applications, including disease diagnosis, bioimaging, synthetic biology, targeted therapies, and antiviral potentials, which have been the focus of recent studies, are sorted out and presented. SIGNIFICANCE STATEMENT: Promoter G-quadruplexes (G4s) are emerging as dynamic and multifunctional regulatory elements that shape transcription, epigenetic states, and cellular responses to environmental cues. By pioneering the definition of 8 key features and corresponding regulatory mechanisms, this review highlights their significant potential as novel targets for therapeutic intervention and provides a comprehensive framework that advances both fundamental understanding and translational exploration of promoter G4s in disease diagnosis, imaging, synthetic biology, and targeted therapy.
The transforming growth factor-β (TGF-β) superfamily of signaling molecules is involved in normal development and homeostasis. However, aberrant signaling among members of the TGF-β superfamily plays an important pathogenic role in numerous diseases. Increased expression of the pleiotropic cytokine and growth factor TGF-β leads to aberrant signaling associated with numerous diseases, including fibrosis of multiple tissues, a wide variety of cancers, obesity and diabetes, and glaucoma, among others. Normally, the profibrotic effects of TGF-β are regulated by concurrent signaling through bone morphogenetic proteins (BMPs). Unfortunately, many disease states exhibit increased expression of the BMP antagonist Gremlin-1 (GREM1), which suppresses this protective effect of BMPs. Targeting TGF-β is challenging as a therapeutic target because TGF-β is still needed for basal signaling required for normal tissue/cell functions. GREM1 is a more attractive therapeutic target because its expression in most tissues is limited after development. However, targeting GREM1 has been very challenging and long considered an "undruggable" target. Fortunately, several new approaches, including the discovery of GREM1-directed aptamers, proteolysis targeting chimera small molecules, and neutralizing antibodies, as well as the design of protein-protein interaction inhibitors, are being explored to directly target and inhibit GREM1 pathogenic functions and activities, thereby restoring homeostasis. SIGNIFICANCE STATEMENT: Gremlin-1 (GREM1) is a secreted bone morphogenetic protein antagonist re-expressed in numerous diseases fibrosis, glaucoma, and cancer. Once deemed "undruggable," GREM1 has recently become a validated therapeutic target, exemplified by the current clinical development of GREM1-neutralizing antibodies. Additional experimental strategies represent promising, although still preclinical, approaches to suppress GREM1 activity or enhance its degradation, offering new avenues to restore transforming growth factor-β/bone morphogenetic protein signaling balance in disease.
The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that has emerged as a key modulator of several physiological and pathological processes. Historically, AHR has been studied for its role as a mediator of the toxic responses of environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Because of this, its potential as a therapeutic target was overlooked. AHR is now regarded as a multifunctional regulator of inflammation, immunity, barrier tissue integrity, metabolism, and cancer biology. AHR signaling is modulated by an array of structurally diverse endogenous, microbial, dietary, pharmaceutical, and xenobiotic ligands. AHR exhibits extensive crosstalk with many signaling pathways, which contributes to highly context-specific biological outcomes. Recent advances and enhanced interest in AHR pharmacology have accelerated the development of therapeutically relevant AHR ligands, including the clinically approved AHR agonist, tapinarof, for the treatment of psoriasis and atopic dermatitis, as well as emerging AHR antagonist strategies in cancer immunotherapy. Structural efforts have succeeded in providing valuable insight into ligand-AHR interactions that will further contribute to improved and rational design of AHR ligands. However, significant challenges remain, including AHR ligand promiscuity, complex negative feedback regulation, extensive signaling crosstalk, and long-term safety concerns. Here, we review the molecular mechanisms of AHR activation, its physiological and pathological functions, and the current advances of its therapeutic targeting. Significance Statement The aryl hydrocarbon receptor (AHR) has emerged from its origins in toxicology to become a promising clinically relevant target for the treatment of dermatological, gastroenterological, and autoimmune diseases as well as cancer. This review summarizes the current knowledge of AHR pharmacology, including molecular signaling, endogenous and exogenous ligands, physiological and pathological functions, present and emerging therapeutic targeting strategies, as well as challenges that remain for translation into safe clinical therapies.
Mast cells (MCs) are versatile, multifunctional immune cells with broad roles in physiological homeostasis and pathogenic processes. MCs are found in most tissues, including skin, lungs, intestines, and peritoneum, and they vary in numbers, types, and biological functions. MCs are implicated in host defense against various pathogens, including bacteria, viruses, and fungi. Additionally, MCs are crucial in protecting against toxins, including those present in venoms from multiple species, such as honeybees, snakes, scorpions, and lizards. Although MCs play an essential role in host defense, they are mostly known for their detrimental actions in allergic reactions, such as asthma, food allergy, anaphylaxis, mastocytosis, and various inflammatory skin conditions. Under such conditions, MCs are activated (via IgE-mediated or other mechanisms) and release a range of potent proinflammatory mediators, including tumor necrosis factor α. In addition to cytokines, they are major producers of histamine and various proteases, including chymase, tryptase, and carboxypeptidase A3. As a result, these mediators contribute to the pathological manifestations associated with inflammatory conditions and other disorders. This review focuses mainly on the biological role of MCs and their proteases, with a focus on chymase and tryptase, as well as their inhibitors as candidate therapies for MC-driven diseases. Significance Statement Mast cells (MCs) and their proteases are central regulators of tissue homeostasis, barrier defense, and inflammation across multiple organs, but are also associated with numerous diseases. Ongoing research has shown that the function of MCs is highly dependent on their tissue location, where the local tissue environment shapes their phenotype, protease expression, and, consequently, their biological functions. However, further investigation is required to more precisely understand the physiological conditions governing the transition of MCs from maintaining tissue homeostasis to acquiring pathogenic functions, particularly with respect to their protease-dependent activities. By profiling MC heterogeneity using multiomics approaches to map protease-driven signaling networks, it will be possible to gain deeper insight into their functional roles and establish a conceptual framework to guide the development of next-generation, mechanism-based therapeutics that selectively modulate MC activity in human diseases.
Chronic pain conditions affect a large proportion of the global population and pain has tremendous personal and economic impact, affecting quality of life and ability to work while imposing a significant burden on families and health care systems. Neurological disorders and painful conditions are frequently accompanied by chronic pain, which is often jointly diagnosed with age-related neurodegenerative diseases, however, many patients do not receive adequate treatment. This review aims to create a working framework around the issue of under-recognized/undertreated chronic pain in Alzheimer disease by offering an in-depth overview of the mechanisms driving chronic pain and how we can leverage this knowledge to advance therapeutics approaches for these patients with an emphasis on the immune system. SIGNIFICANCE STATEMENT: Chronic pain conditions are prevalent among the aging population, and they positively associate with dementia. The incidence of chronic pain is associated with neuropsychiatric symptoms of dementia and pain management should aim for effective treatments regardless of cognitive status.
Peptide hormones play a central role in maintaining metabolic homeostasis by integrating complex signaling pathways to coordinate interorgan crosstalk. Aberrant production and/or dysfunction of peptide hormones are important contributors to the pathophysiology of a cluster of interrelated chronic metabolic diseases (CMDs), including obesity, type 2 diabetes mellitus, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and cardiovascular diseases. These CMDs often co-occur, ranking among the top causes of death and disability in the rapidly aging population. Peptide hormone-based pharmacotherapies are the mainstay of treatment for these CMDs. Analogs and agonists of peptide hormones produced by classical endocrine cells, especially insulin and glucagon-like peptide-1, are cornerstones in managing diabetes and obesity. Furthermore, peptide hormones released from nonclassical endocrine organs, such as liver-secreted fibroblast growth factors 21 and growth differentiation factor 15, have emerged as highly promising therapeutic candidates for obesity-related metabolic comorbidities. These peptide hormones act synergistically and/or complementarily to exert pleiotropic metabolic benefits through their distinct receptors in different target organs/tissues. Combination pharmacotherapies with these peptide hormones are much more effective than monotherapy and hold promise to address the multimorbidity issue in patients with CMDs. This review summarizes recent advances in the pharmacoengineering and pharmacology of these peptide hormone-based long-acting analogs and coagonists and discusses their synergistic and antagonistic interactions in the treatment of CMDs. Furthermore, we highlight major challenges and future perspectives in the clinical development of multiple peptide hormone-based coagonists as safe and effective pharmacotherapy for the management of metabolic comorbidities. SIGNIFICANCE STATEMENT: This review highlights recent clinical advances in combination peptide hormone therapies for chronic metabolic diseases, emphasizing their superior efficacy over monotherapies in addressing metabolic multimorbidity. Summarizing the latest developments in long-acting analogs and coagonists of peptide hormones provides critical insights into their synergistic mechanisms, clinical potential, and future challenges, offering a comprehensive perspective for improving the management of complex metabolic disorders.
The prevalence of methamphetamine use disorder (MUD) remains discouragingly high. Relatively few clinical trials have focused on identifying new pharmacotherapies for MUD, and no medications have received US Food and Drug Administration approval. The lack of available pharmacotherapies may be due to failure to follow a rational, translational medications development pipeline progressing from preclinical work to the human laboratory to clinical trials. Our review thus has 2 primary goals: to (1) assess the scope of the literature evaluating candidate medications for MUD and (2) identify drugs screened to treat MUD across research domains, analyzing concordance across contexts. We identified 36 randomized, double-blind, placebo-controlled clinical trials that evaluated 25 candidate medications for MUD. Only 5 of these putative treatments (aripiprazole, bupropion, d-amphetamine, modafinil, and naltrexone) had also been evaluated in human laboratory and preclinical laboratory contexts. Overall, most studies showed no change in methamphetamine use (ie, no effects of treatment) across contexts. Although literature from these contexts imply a high degree of negative predictive validity, we encountered limitations at each level of analysis that prevented us from fully confirming concordance (eg, lack of positive predictive validity). These trends and limitations highlight the extent to which methamphetamine treatments are under-researched relative to other substance use disorders, such as cocaine use disorder. To address this gap in the literature, we advocate for future work that identifies therapeutic targets and, by consequence, classes of medications (repurposed or novel) to treat MUD. We conclude this review with additional comments about future research directions and treatment considerations. SIGNIFICANCE STATEMENT: Investment in methamphetamine use disorder (MUD) medications development remains poor. To date, no pharmacotherapies have received US Food and Drug Administration (FDA) approval to treat MUD, and few candidate medications have been systematically evaluated using a translational medications development pipeline (eg, beginning with preclinical research and progressing to human laboratory research and clinical trials). Adhering to the translational pipeline while incorporating new FDA guidance, such as evaluating nonabstinence outcomes, may be useful in facilitating MUD medications development.
Coronary and peripheral artery bypass graft surgery remain cornerstones of cardiac and vascular surgery, respectively. They utilize the saphenous vein as the preferred conduit, although it suffers from poor midterm and long-term outcomes, with the grafted vein often becoming occluded. Current therapeutic approaches aim to manage complications rather than prevent graft failure directly, and despite progress, failure rates have remained unchanged in decades, meaning there remains an unmet clinical need for novel therapeutic approaches. As access to the grafted tissue is available at the time of surgery, coronary and peripheral artery bypass graft are particularly suited to perioperative therapeutic manipulation and intervention that can be delivered locally and directly to the tissue immediately before grafting. Ongoing research attempts to uncover novel genes driving bypass graft failure that can be targeted for such therapies. In addition to protein-coding genes, multiple examples of noncoding genes driving graft failure are now described, including microRNAs and long noncoding RNAs with cell type-specific roles. The increasing wealth of single cell, single nuclei and spatial transcriptomic data related to cardiovascular pathologies are revealing novel target loci that could facilitate greater specificity for target manipulation in specific pathogenic cell types. In parallel, extensive research continues to develop advanced imaging techniques that can be used to monitor the patency of grafts over time, and guide the effective design of advanced therapies. Here, we discuss the progress in these areas and highlight how harmony among these will accelerate therapeutic progress toward vein graft disease. SIGNIFICANCE STATEMENT: Coronary or peripheral artery bypass surgery using saphenous vein grafts are among the most commonly performed cardiovascular surgeries for advanced vascular occlusions. However, both suffer from poor long-term graft patency. The continued development of next-generation multiomics technologies and advanced therapies are illuminating new therapeutic targets that offer hope toward novel precision medicines for peripheral and coronary artery bypass graft failure.
Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, with elevated low-density lipoprotein cholesterol (LDL-C) recognized as a causal factor and the primary target for the prevention of atherosclerotic cardiovascular disease (ASCVD). Currently available lipid-lowering agents, including statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type 9 inhibitors, can significantly reduce the risk of cardiovascular events across a broad range of patient populations. New oral therapies with novel mechanisms of action and potentially lower costs compared with biologics (including oral proprotein convertase subtilisin/kexin type 9 inhibitors and a new cholesteryl ester transfer protein inhibitor) are under investigation to expand the armamentarium of lipid-lowering drugs and increase the number of patients who can be treated if they prove clinically beneficial. To fully understand the potential health benefits of lipid-lowering therapies, it is essential to consider the concept of cumulative LDL-C exposure and its lifelong impact on ASCVD risk. Genetic studies, Mendelian randomization, and clinical trials consistently demonstrate the cardiovascular benefits of early reduction in LDL-C. However, despite this evidence, treatment gaps, inadequate prescribing, and suboptimal treatment adherence are widespread. The cost-benefit ratio and public health impact emphasize the potential of LDL-C lowering to prevent cardiovascular events and reduce the health care burden. In addition to LDL-C, other risk factors such as lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein B must be considered, whereas nonlipid-based mechanisms of atheroprotection, such as inflammation modulation and thrombogenic risk reduction, are also being explored. The future of lipid-lowering and ASCVD prevention requires a more individualized lipid management strategy to optimize cardiovascular outcomes across the lifespan. SIGNIFICANCE STATEMENT: Early and sustained low-density lipoprotein cholesterol reduction dramatically reduces lifelong cardiovascular risk; however, the adoption of lipid-lowering strategies in clinical practice remains suboptimal. Bridging this gap by understanding the true potential of lipid-lowering therapies could significantly reduce the global burden of atherosclerotic disease.
Despite advances in the treatment of certain malignancies, it is anticipated that there will be 626,140 cancer deaths in the United States in 2026. Thus, there remains a great need to develop new antineoplastic drugs with unique mechanisms of action distinct from those of existing drugs. Also relevant is revisiting agents that showed promise in early research. Some of these agents struggled to advance for reasons including an incomplete understanding of their molecular targets and insufficient commitment to pursuing their development. Gallium compounds initially gained attention as radiogallium 67Ga complexes for tumor imaging in cancer patients, but were later found in clinical trials of nonradioactive gallium nitrate to have antineoplastic activity against lymphoma and urothelial malignancies. Coincident with this, tris(8-quinolinolato)gallium(III) has been shown to be active against solid tumors and has now re-emerged in clinical trials as oral AP-002. Subsequent investigations showed that gallium exerts its antineoplastic activity by disrupting iron-dependent processes essential to cancer development and growth. Recent preclinical studies of oral gallium maltolate demonstrated its activity against glioblastoma, an aggressive brain tumor, leading to a Food and Drug Administration-approved phase 1 clinical trial for patients with relapsed glioblastoma. This review will focus on the evolution of gallium compounds in malignancy; advances in our knowledge of their mechanisms of action and tumor resistance; their interactions with cellular iron homeostasis and other targets; the past and present preclinical and clinical experience with gallium compounds; and the development of promising gallium-based agents on the horizon. SIGNIFICANCE STATEMENT: Gallium compounds showed anticancer activity in early clinical studies; however, an incomplete understanding of their mechanisms of action and resistance hindered the selection of patients most likely to benefit from treatment. Herein, we review the development of gallium compounds from early preclinical research to clinical trials for cancer. Recent insights into gallium's molecular targets have advanced the translation of gallium from the laboratory to a clinical trial of oral gallium maltolate in glioblastoma. Newer gallium compounds are being developed; their advancement is eagerly anticipated.
Anticoagulants are essential for preventing and treating thromboembolism across a wide range of clinical settings. Yet, they share a narrow therapeutic index that demands a precise understanding of their pharmacodynamic behavior. Thrombin generation provides an integrated measure of anticoagulant effects by capturing the timing, velocity, and total amount of thrombin formed over time. We reviewed the literature to establish a unified theoretical framework, grounded in mechanistic rationale and supported by experimentation, to better define the pharmacodynamics of anticoagulation therapy using thrombin generation as a common language to compare anticoagulant effects across drug classes.Unfractionated and low-molecular-weight heparins and vitamin K antagonists exert broad, multitargeted inhibition that profoundly suppresses peak thrombin and the endogenous thrombin potential. Direct factor Xa inhibitors primarily blunt propagation, direct thrombin inhibitors delay initiation while preserving overall thrombin output, and factor XIa inhibitors act mainly under low tissue factor conditions. Agents that engage multiple components of the coagulation cascade (prothrombinase formation, thrombin feedback activation, or zymogen depletion) produce deeper, cumulative suppression of thrombin generation and maintain efficacy under highly prothrombotic conditions, as seen with mechanical heart valves, antiphospholipid antibody syndrome, and catheter-associated thrombosis. In contrast, selective inhibitors achieve pharmacodynamic predictability but may lose responsiveness in the face of extreme coagulation activation.From a pharmacodynamic perspective, not all anticoagulants are the same. Divergent mechanisms map to unique, reproducible, and informative pharmacodynamic signatures that are characterized using thrombin generation. These signatures help explain why some patients experience breakthrough thrombosis or bleeding despite “on-target” drug levels. Embedding thrombin generation within clinical research allows anticoagulant effects to be interpreted through a mechanistic lens that bridges molecular pharmacology with patient-level variability. This synthesis provides a common language for comparing anticoagulants and lays the foundation for an individualized, pharmacologically informed approach to anticoagulation therapy.
