Solute carrier transporters (SLCs) are integral membrane proteins that play pivotal roles in maintaining cellular homeostasis by mediating the transport of a diverse range of substrates across cell membranes. With their involvement in fundamental physiological processes such as nutrient uptake, neurotransmitter signaling, and drug transport, SLCs have emerged as crucial players in health and disease. Dysregulation of SLC function has been implicated in a spectrum of disorders, including metabolic diseases, cancer, and neurological afflictions. Despite their significance, SLCs remain relatively understudied compared to other protein classes, resulting in a gap in understanding their molecular mechanisms of action and potential as therapeutic targets. This review aims to address this gap by providing a comprehensive overview of the diverse array of small-molecule probes utilized in the study of SLCs. Various types of functionalized probes, amongst which fluorescent probes, bivalent probes, covalent inhibitors, affinity-based probes, photoswitchable inhibitors and proteolysis targeting chimeras (PROTACs), have been designed to investigate transporter function, substrate specificity, and regulatory mechanisms. In this review, we describe the principles underlying the design and synthesis of these probes, highlights key examples of their application in elucidating transporter function and regulation, and discuss insights gained from such studies. Furthermore, we examine current challenges and future directions in the development and utilization of small-molecule probes for SLC transporter research. By shedding light on the intricate mechanisms involved in transporter function and regulation, this review not only enhances the understanding of SLCs but also highlights their potential as therapeutic targets in drug discovery and thereby may facilitate systematic implementation of these innovative research approaches and the refinement of existing methodologies.

Neurodegenerative disorders, including Alzheimer's disease (AD), impose a significant burden on society due to their progressive nature and the associated healthcare costs. Autophagy, a vital cellular degradation process, has emerged as a promising therapeutic target in these disorders. This review aims to provide a comprehensive overview of autophagy's role in neurodegenerative diseases, focusing on AD. The pathogenesis of AD involves the accumulation of misfolded proteins, such as beta-amyloid (Aβ) and tau, leading to neuronal dysfunction and cognitive impairment. Autophagy can be crucial in clearing these protein aggregates and maintaining cellular homeostasis. Nevertheless, autophagic dysregulation and mitochondrial dysfunction contribute to further progression of neurodegeneration. Furthermore, recent studies have demonstrated the therapeutic potential of several plant-based phytoconstituents and repurposed molecules that modulate autophagy. These compounds target both mTOR-dependent and independent pathways, highlighting their potential to alleviate disease pathology. This review aims to pave the way for future research and development in this field.

Targeted radioligand therapy has emerged as a promising treatment option for eradicating advanced cancer forms. α-Emitters are considered particularly promising as they can obliterate (micro)-metastases. The α-emitter astatine-211 (At) has experienced increased interest due to its favorable decay properties. As a result, various At-astatination strategies have been developed to address challenges associated with working with this "halogenic metalloid." This review summarizes efforts to produce and scale At, describes its physicochemical properties, discusses the advantages and disadvantages of using a radionuclide with a half-life of 7.2 h and outlines procedures for astatinating radiopharmaceuticals. Moreover, a key focus of this review is to rationalize strategies aimed at minimizing in vivo deastatination. A brief overview of on-going (pre)clinical development with At-labeled radiopharmaceuticals is provided. Astatinated radiopharmaceuticals will play a pivotal role in cancer management in the near future when challenges related to scalability and in vivo stability have been addressed and clinical studies have shown the benefit of At compared to longer-lived therapeutic radionuclides.

The burgeoning field of CBMs represents a significant stride in the evolution of targeted therapeutics. This class of compounds, characterized by their ability to form stable covalent bonds with specific proteins of interest (POIs) or biological effectors, has emerged as a promising avenue for addressing complex pathological conditions such as drug-resistant diseases, undruggable targets, and chronic disorders requiring sustained target modulation. The integration of covalent chemistry in molecular design allows for the creation of highly specific and potent agents capable of modulating protein function with unprecedented precision. Herein, we meticulously classify CBMs according to the object of covalent bond formation and provide a discussion of the progress of CBMs since 2001, covering the design principles, molecular composition, covalent properties, and their reaction efficiencies, which not only reveals the potential of CBMs in drug discovery, but also emphasizes the importance of achieving innovations and breakthroughs in this field.

Catalyzing the conversion of diacylglycerol (DAG) in phosphatidic acid (PA), diacylglycerol kinases (DGKs) play a pivotal role in all the physiological processes modulated by these two bioactive lipids, such as lipid metabolism and immune regulation. Consequently, abnormalities due to a dysregulation of DGK's activity are involved in several pathological contexts, from cancer to autoimmune diseases. Interestingly, ten DGK isoforms with specific structure and expression pattern are present in humans, suggesting nonredundant roles. Despite their potential as therapeutic targets, the possibility of selective DGK pharmacological modulation remains limited to two isoforms. However, the research for DGK isoform-specific modulators is growing, as well as the interest in the structure and functioning of all DGK family members. This review aims to present all the information on DGK modulators, from the literature to patents' databases, starting from what we know about DGK's structure, the key physiological and pathological processes where they are involved and, above all, to understand which are nowadays the possibilities for DGK activation/inhibition. Our aim is to inspire future investigations which could accelerate the discovery of new DGK-targeting compounds.

Pulmonary arterial hypertension (PAH) is a rare and life-threatening pulmonary vascular disease distinguished by vasoconstriction and remodeling of the pulmonary artery, leading to sustained elevated pulmonary artery pressure, right ventricular failure, and even death. Receptor tyrosine kinases (RTKs) are critical in PAH pathogenesis, and targeted therapies against RTKs are becoming a research hotspot due to their potential to inhibit cell proliferation and right ventricular hypertrophy. Abnormal activation of RTKs induces downstream signaling cascades, including metabolic reprogramming through multiple regulatory crosstalk, to meet high energy requirements during cell proliferation. However, the crucial connection between metabolic reprogramming and RTKs in PAH remains largely unexplored. In this review, we focus on four key RTKs: Platelet-Derived Growth Factor Receptor (PDGFR), Epidermal Growth Factor Receptor (EGFR), Fibroblast Growth Factor Receptor (FGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR) in the metabolic reprogramming of PAH and explore hypotheses that require further validation. The aim is to highlight how these mechanisms can be applied to develop better therapeutic strategies.

Alzheimer's disease (AD) and Parkinson's disease (PD), which are characterized by the accumulation of misfolded protein aggregates and cognitive/motor dysfunction, are the most prevalent neurodegenerative diseases (NDDs). Despite strategic investigations aimed at augmenting the pharmaceutical pipeline, available drugs for AD and PD merely slow disease progression without curing or treating the underlying pathology. Recent technological advances have given rise to digital therapeutics (DTx): software systems that aim to prevent, cure, and manage specific diseases, including NDDs. For AD and PD, the majority of DTx focus on enhancing cognitive/executive function and motor-related functions, respectively. In this review, we describe the status of therapeutic development for AD and PD, as well as the characteristics and status of DTx targeting these NDDs. In addition, we address the limitations and challenges of DTx and their implications for the treatment of AD and PD. Ultimately, this review provides insights into the potential of DTx as a therapeutic modality and future directions for the development of DTx targeting AD and PD.

CD73, a membrane-bound ecto-5'-nucleotidase, catalyzes the extracellular conversion of adenosine monophosphate into immunosuppressive adenosine. Functioning as an emerging immune checkpoint, CD73 is frequently upregulated across numerous tumor types, contributing to the accumulation of adenosine within the tumor microenvironment and promoting immune evasion. Intensive efforts have led to the discovery of diverse CD73 inhibitors, which show strong potential in cancer immunotherapy. To date, around eighteen candidates targeting CD73 have entered clinical evaluation, many exhibiting encouraging efficacy in combination regimens for solid tumors. This review provides an overview of the biological functions of CD73 in tumor-induced immunosuppression and highlights the medicinal chemistry strategies employed in the development of small-molecule CD73 inhibitors since 2018. Additionally, the challenges in drug design and future directions are also discussed to enhance the clinical applicability of CD73-targeted therapies in cancer treatment. We believe that this review will offer valuable insights to guide the rational design of next-generation CD73 inhibitors for cancer immunotherapy.

Respiratory syncytial virus (RSV) is a common virus that causes respiratory infections, posing a serious threat, particularly to infants, the elderly, and individuals with compromised immune systems. As the leading cause of lower respiratory tract infections (LRTIs) in infants, RSV is responsible for millions of cases worldwide each year. Its incidence rises significantly during the winter influenza season. Despite decades of research, no effective vaccine exists, and antiviral treatment options remain limited, presenting a major challenge to global public health. With the advancement of emerging technologies, researchers have made significant progress in understanding the pathological and biological characteristics of RSV, the mechanisms of immune response, and its long-term health impacts. This review aims to provide a comprehensive overview of the basic biological characteristics, epidemiology, clinical manifestations, and diagnostic and therapeutic strategies of RSV and to explore preventive measures and future research directions, offering the latest scientific evidence for RSV prevention and control.

Cancer is the second leading cause of death globally, with an estimated worldwide incidence of 19.3 million cases in 2020, and is expected to increase by 47% in the next 20 years. Painful symptoms of tumors and anticancer treatment negatively impact the quality of life of patients with cancer. Cancer pain can occur during all disease periods, being more debilitating and hardest to treat, mainly when tumors metastasize to the bone. Common tumors such as breast, lung, and prostate often metastasize to the bones and cause severe pain in patients. Anticancer therapy with some chemotherapy and hormonal drugs also induces painful symptoms, compromising antineoplastic treatment. Among the analgesics recommended to treat cancer pain, NSAIDs and paracetamol seem to have predominantly antiproliferative activity. However, opioids, mainly morphine, present conflicting effects in reducing and promoting tumor progression. Kinins and their B and B receptors contribute to the development of numerous painful symptoms,including those induced by tumors and anticancer therapy. In addition, kinins stimulate the proliferation of various tumors (breast, lung, prostate and others) while having controversial effects in melanoma. Thus, kinin B and B receptors could be a promising pharmacological target to treat the pain caused by the tumor and its therapy while reducing tumor proliferation. However, it is essential to review the effects of kinins in each specific type of cancer to investigate their involvement in pain. This assessment is also valid and prudent for new analgesic candidates against cancer pain and their therapy, especially to rule out a possible pro-tumor activity of this analgesic.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation of the joint synovium, which can lead to bone destruction. Prolonged inadequate treatment can result in joint disability and an increased risk of mortality. Currently, there are considerable limitations in the availability of effective therapeutic agents for RA. The IL-23/IL-17/NF-κB signaling pathway has emerged as a central pathogenic mechanism underlying the multistage development of RA. This pathway initiates the initial inflammatory response, driving excessive proliferation of the synovial tissue, ultimately leading to late-stage bone and cartilage destruction. A comprehensive understanding of the role of the IL-23/IL-17/NF-κB pathway in the pathogenesis of RA can facilitate the refinement of scientific understanding of RA pathogenesis and assist in developing new therapeutic regimens. A comprehensive literature review and data search were conducted in several scientific databases, including Web of Science, PubMed, Google Scholar, Embase, TCMSP, PubChem, Swiss ADME, and Swiss Target Prediction. The literature review was conducted from 2013 to 2025. The search terms employed included RA, IL-23, IL-17, NF-κB, molecular mechanisms, and therapeutic agents. Following a rigorous screening process, irrelevant data were excluded, resulting in a focused analysis and comprehensive review of the key role of the IL-23/IL-17/NF-κB signaling axis in the multifaceted pathogenesis of RA and the key active ingredients and possible targets of action of related drugs. This comprehensive literature review aims to provide novel mechanistic insights and valuable references to guide the development of more effective therapeutic strategies for this debilitating autoimmune disease.

Since 2013, a rapidly expanding portfolio of U.S. Food and Drug Administration (FDA)-approved drugs has highlighted pyrimidine as one of the most versatile and therapeutically valuable heteroaromatic scaffolds. Building on more than six decades of medicinal chemistry, these recent approvals underscore the pivotal role of pyrimidines in modern drug discovery across oncology, anti-infectives, immunology, immuno-oncology, neurological disorders, chronic pain, and metabolic diseases. This review systematically surveys pyrimidine-containing drugs approved from 2013 to the present, detailing their synthetic strategies, key biological targets, and disease-specific mechanisms of action. This review demonstrates the enduring value of pyrimidine as a privileged chemotype and bioisostere for phenyl and other aromatic π-systems, offering insights to guide the design of next-generation therapeutics for conditions once considered intractable.

Benzodiazepine drugs (BZDs) have been central to neuropsychopharmacology since the 1960s, acting as positive allosteric modulators of γ-aminobutyric acid type A (GABA) receptors to enhance inhibitory neurotransmission. Despite their clinical efficacy, long-term use is limited by tolerance, dependence, and cognitive side effects. This review summarizes the structural evolution of BZD modulators, with a focus on subtype-selective interactions with GABA receptor isoforms. Advances in cryo-electron microscopy and AI-driven modeling have clarified the architecture and pharmacological roles of distinct receptor subunits, enabling the design of ligands that dissociate therapeutic effects from adverse outcomes. We also highlight the development of nonclassical scaffolds-such as imidazopyridines, triazolopyridazines, and cinnolines-which improve metabolic stability and subtype specificity. In addition, emerging formulation technologies and novel indications, including chronic pain, asthma, and neurodegenerative disorders, broaden the therapeutic scope of BZD-related compounds. Collectively, these advances underscore a shift toward rational, structure-based design of next-generation BZD receptor modulators with improved efficacy, safety, and clinical precision.

Arginine is critical in biosynthesis, energy generation, cell proliferation, and immune regulation. In the tumor microenvironment (TME), due to limited supply and high consumption, the competition for arginine is extremely fierce. It always ends up with the victory of tumor cells and immunosuppressive cells, which leads to the arginine deficiency for anti-tumor immune cells, resulting in immune tolerance of tumors. Therapies based on arginine metabolism have been extensively studied. An arginine deprivation therapy has been developed as the tumor progression relies on arginine support. To reverse the arginine shortage of anti-tumor immune cells in TME, supplying arginine to enhance immune therapy has been proposed. Achieving the optimal antitumor effects of these two opposed therapies requires a better understanding of arginine metabolism in TME. In this review, we compared the transport, synthesis, and metabolism of arginine in tumor cells and various immune cells, and proposed key processes that may serve as potential therapeutic targets. In addition, for the two therapies for arginine, deprivation and supplementation, the recent research of them was discussed, and the relevant clinical trials were collected and summarized, which might provide reliable references for the further study and application of arginine-based therapies.

The active sites of numerous metalloproteins feature two metal ion cofactors-either identical or distinct-that are positioned in close proximity, typically around 3.8 Å apart. This two-metal-ion catalytic mechanism (TCM) endows these enzymes with a remarkable catalytic efficiency. Enzymes employing TCM play vital biological roles in both humans and pathogenic organisms, with some identified as validated therapeutic targets. Various rational drug design approaches, including nucleoside analogs, prodrugs, metal-binding group design, bioisosteres, pharmacophore modeling, scaffold hopping, tautomerism, and structure-based drug design, have been successfully applied to several enzymes with TCMs, thus yielding the development and approval of many small-molecule drugs for the treatment of several diseases, including certain catastrophic illnesses, such as hepatitis C infection, coronavirus disease 2019, and acquired immune deficiency syndrome. Additionally, drug repurposing has proven to be a critical strategy in the development of therapeutics targeting TCM enzymes. This article reviews the significant achievements in design and development of small-molecule drugs targeting several enzymes with TCMs, including RNA-dependent RNA polymerase, HIV-1 integrase, influenza virus cap-dependent endonuclease, and phosphodiesterase, hoping to offer valuable insights and guidance to facilitate future drug discovery efforts focused on these enzymes and related molecular targets.

Jellyfish are vital components of marine ecosystems and significantly impact human life and industry. Globally, jellyfish populations are increasing annually, but their applications are currently limited primarily to food processing. Jellyfish contain various peptides and proteins that humans can utilize because of their unique biological structures and compositions. In particular, jellyfish are rich in bioactive peptides that intrigue researchers. Jellyfish bioactive peptides can be categorized functionally into toxin peptides, neuropeptides, antioxidant peptides, angiotensin-converting enzyme (ACE) inhibitory peptides, and antimicrobial peptides (AMPs), each with distinct physiological roles, such as inflammation, apoptosis, ion pathway, reproduction, and vision. They are demonstrated to have valuable pharmacological potential against various diseases, including neurodegenerative disorders, wound healing, osteoarthritis and cancer, and are candidate for nutraceuticals. This review primarily summarizes the reported bioactive peptides from jellyfish, improving our understanding of their potential pharmacological effects and nutraceutical activities, which may promote the further utilization and development of bioactive peptides from jellyfish.

Antimicrobial peptides (AMPs), essential components of the body's innate defense system, are expected to exert and enhance their potential antimicrobials, immunomodation and other bio-activities that combine with traditional antimicrobial agents and vaccines efficiently against multi-drug-resistant (MDR) bacteria. They are multi-source (animal, plant, microbial, etc.) and multi-functional (antimicrobial, immunomodulatory, anticancer, antiviral, antioxidant, etc.), and have been clearly categorized according to source, function, and structure in several AMP databases. However, there is insufficient evidence to support recognizing, developing, and utilizing the source-function relationship of AMPs, as their first function is usually unknown or unclear; in addition, they are usually accompanied by some shortcomings such as weak stability, high toxicity, and production cost. These have seriously hindered their development for clinical application. Therefore, it is necessary to clarify the relationship between the AMP source and function, and establish a complete system to distinguish the first function, so that more AMP candidates can enter the pipeline of new drugs as early as possible. At the same time, the key fundamental elements, scaffold and bottom logistics were proposed for the R & D pipeline of AMPs as new antimicrobial agents, including the following key points: high yielding, stability, and safety of AMPs using heterologous expression, modification, encapsulation, and coadministration toward their final successful application.

High Mobility Group Box 1 (HMGB1) is a nuclear protein crucial for nucleosome stability, gene regulation, DNA repair, cell differentiation, and development. Extracellularly, HMGB1 functions as a cytokine, significantly impacting inflammation, immune response, and the pathogenesis of various diseases, including cancer and inflammatory disorders. Research highlights HMGB1's complex role in cancer, where it promotes tumorigenesis through chronic inflammation and immune suppression while enhancing chemotherapy and genome stability. It also influences cell proliferation, angiogenesis, metastasis, and chemotherapy resistance. In inflammatory diseases, HMGB1 has a dual role: it can promote inflammation in conditions like ischemia-reperfusion injury and sepsis but also induces immune tolerance and suppression. This review provides a comprehensive overview of HMGB1's structure, functions, and regulatory mechanisms, discussing recent advances in understanding its roles in cancer and inflammatory diseases. We emphasize the evolving therapeutic strategies targeting HMGB1, underscoring its potential as a promising target for treating both cancer and inflammatory disorders.

A plethora of cellular signaling pathways are dysregulated in cancer cells, promoting carcinogenesis and migration. Cholesterol has recently been linked to cancer by several subcellular mechanisms, especially by its involvement in the formation of lipid rafts, which promote oncogenic signaling and cancer cell invasion. Squalene synthase (SQS), a pivotal enzyme in the cholesterol biosynthetic pathway downstream of the molecular target of statins, has drawn attention as a potential therapeutic target in cancer. Being the first enzyme in the pathway solely responsible for sterol formation, SQS presents an appealing approach for studying the explicit role of cholesterol in cancer. In recent years, research has re-focused on SQS inhibitors, which modulate cellular cholesterol levels, ultimately regulating crucial processes for cancer progression. However, the mechanisms through which they exert anticancer activity have not been fully elucidated to date. In this review, we examine the roles of cholesterol, lipid rafts, and SQS in cancer and metastasis, and the potential therapeutic implications of SQS inhibitors.

β-Adrenoceptors are important G protein-coupled receptors involved in cardiovascular, metabolic, and neurological regulation. To study their function with high precision, light-based molecular tools have been developed offering precise spatiotemporal control. Fluorescence and bioluminescence techniques allow real-time monitoring of receptor activation and organization, while photopharmacology and optogenetics enable precise external modulation of their activity. A particularly valuable approach involves photoswitchable ligands, which can be switched on and off by specific wavelengths and provide reversible control over receptor activity. In general, the combination of optical biosensing and photopharmacology enhances our ability to analyze GPCR signaling dynamics and function with minimal perturbation. In particular, these approaches open new avenues for targeted research and therapeutic interventions, offering a powerful framework for understanding β-adrenoceptors-related diseases.

Cyclophilins are a family of enzymes with peptidyl-prolyl isomerase activity found in all cells of all organisms. To date, 17 cyclophilin isoforms have been identified in the human body, participating in diverse biological processes. Consequently, cyclophilins have emerged as promising targets for drug development to address a wide array of human diseases. This review describes the structural characteristics of individual cyclophilin isoforms and explores the roles that they play in human health and diseases, such as in viral infections, Alzheimer's disease, Parkinson's disease, cardiovascular diseases, or cancer. Additionally, the review addresses inhibition of cyclophilins, particularly focusing on the development of selective small-molecule inhibitors of individual cyclophilins, which possess a significant potential as novel therapeutics.