Pharmacological Reviews最新文献

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.

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.

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.

The intricate interplay between the gut microbiome and bile acid metabolism via the gut-liver axis is fundamental to hepatic homeostasis. Perturbations in this axis are increasingly implicated in the pathogenesis of diverse liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. This review integrates current understanding of hepatic bile acid synthesis, enterohepatic circulation, and gut microbial bile acid transformations, detailing how bile acids function as signaling molecules through nuclear receptors including farnesoid X receptor, pregnane X receptor, vitamin D receptor, constitutive androstane receptor, and G-protein-coupled receptors; G protein-coupled bile acid receptor 1 (also known as Takeda G protein-coupled receptor 5), and sphingosine-1-phosphate receptor 2. We explore disease-specific alterations in gut microbiota composition and bile acid profiles in metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and liver cancers, focusing on mechanisms linking gut dysbiosis, impaired intestinal barrier function, altered bile acid signaling, inflammation, and immune modulation to liver injury and progression. Furthermore, we discuss the clinical implications, highlighting the potential of microbiome signatures and bile acid profiles as diagnostic and prognostic biomarkers. Therapeutic strategies targeting the gut-liver axis, including probiotics, fecal microbiota transplantation, farnesoid X receptor agonists, and fibroblast growth factor 19 analogs, are reviewed. Finally, we address current challenges and future directions, emphasizing the need for multiomics integration, functional studies, and personalized medicine approaches to leverage the gut-liver axis for improved liver disease management. SIGNIFICANCE STATEMENT: Disruption of the gut microbiome-bile acid-liver axis is now recognized as a unifying mechanism driving multiple liver diseases, including metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, cholestatic liver diseases, and hepatocellular carcinoma. Unraveling the molecular and microbial interactions within this axis offers fundamental insights into disease pathogenesis and reveals novel therapeutic opportunities. Integrating multiomics technologies with artificial intelligence-based analytics will accelerate the discovery of predictive biomarkers and personalized interventions, advancing the field toward precision-based liver disease treatment protocols.

Glycosphingolipids (GSLs) play major roles in viral infections by mediating viral entry and egress from cells in lipid rafts; however, GSLs are also important in neurodegenerative diseases. The role of GSLs in acute COVID-19 infection is critical but remains less-studied in the sequelae of long COVID (post-COVID condition); because the same enzymes that regulate GSL metabolism are critical for viral entry and exit, neuromuscular junctions, neurological function, and cellular metabolism, it is important to determine whether long COVID may increase the risk of subsequent neurodegeneration. SARS-CoV-2 infection alters lipid metabolism and oxygen use and can bind to and modify the expression of neurotrophic GSLs such as GM1 ganglioside. GM1 (N-acetylneuraminic acid) is human-specific and probably evolved as a result of a pandemic 3-2.5 million years ago that drove its selection. GM1 functions as a coreceptor with angiotensin-converting enzyme 2 for SARS-CoV-2 while also being a neurotrophin. Viral multiplication takes place in the endoplasmic reticulum/Golgi apparatus, where GSLs are synthesized. This review defines the complex interaction between viruses, GSLs, and neurodegeneration, which provides new perspectives on the interlinked metabolic changes. A European working group has been set up to assess the risks of neurodegeneration with long COVID, based on potential GSL-mediated mechanisms. SIGNIFICANCE STATEMENT: The SARS-CoV-2 pandemic has resulted in a large number of subjects living with long-term consequences (long COVID). Glycosphingolipids and gangliosides are involved in both viral infections and neurodegeneration; hence, it is important to evaluate whether long COVID may increase the risk of neurodegeneration via this route. This study is the result of a European consortium formed to evaluate this possibility.

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.

Stimulant use disorders represent a significant public health challenge, with no U.S. Food and Drug Administration (FDA) pharmacotherapies currently available. A growing concern is that stimulant use rarely occurs in isolation. Instead, it often involves sequential or simultaneous use of multiple substances. This review explores the mechanistic, epidemiological, clinical, and preclinical dimensions of polysubstance use involving stimulants, particularly cocaine and methamphetamine. Key gaps in the existing literature are identified to underscore the critical need for polysubstance use research across epidemiological, clinical, and preclinical domains. Additionally, the review highlights the importance of fostering interdisciplinary collaborations across these domains to inform the development of more effective interventions for stimulant use disorders and to mitigate the widespread harm caused by substance use globally. SIGNIFICANCE STATEMENT: Stimulant use rarely occurs in isolation and is frequently accompanied by polysubstance use, which increases health risks and complicates prevention and treatment strategies. This review highlights critical gaps in research examining polysubstance use involving stimulants and emphasizes the urgent need for the study of the co-use of drugs and interdisciplinary collaboration. Addressing these gaps is essential to inform the development of effective interventions for stimulant use disorders.

Our understanding of the solute carrier (SLC) family of transporters has greatly increased in recent years, especially in oncology, and a wealth of information is now available, indicating that certain SLC family members contribute to the cellular accumulation of small-molecule cancer drugs at sites of injury and to unwanted toxicity in normal tissues. The present review aimed to provide an overview of the toxic effects of commonly used chemotherapy drugs that are associated with SLC-mediated transport, how these associations have been derived, what ensuing intervention strategies have been explored, and how the investigation of these phenomena might change in the near future with the availability of increasingly sophisticated and innovative models and techniques. It is expected that this rapidly emerging field continues to contribute to filling our gaps in knowledge and will aid in the development of interventions aimed at preventing debilitating side effects of cancer drugs and improving the quality of life. SIGNIFICANCE STATEMENT: Toxicities associated with small-molecule chemotherapeutics can be debilitating or even life-threatening and pose a burden on the healthcare system. Improving our understanding of the initiating transporter-mediated mechanisms of these side effects is crucial to the development of preventative or treatment strategies.