Targets, Volume 4, Issue 3 (September 2026) – 10 articles

Microglia are key regulators of central nervous system homeostasis and neuroinflammation, and cannabinoid type 2 receptors (CB₂Rs) have emerged as important modulators of microglial function. Although the pharmacology of CB₂Rs has been extensively characterised in heterologous expression systems and activated microglia, comparatively little is known about the behaviour of CB₂R ligands in non-stimulated microglia. The present study therefore aimed to characterise the pharmacological properties of a panel of CB₂R ligands in non-stimulated BV-2 microglial cells and to determine whether constitutive receptor activity and ligand-dependent signalling bias could be detected under basal conditions. Classical CB₂R agonists (CP 55,940, WIN 55,212-2, JWH 133 and JWH 015), putative protean agonists ((R)-AM 1241 and GW 405833), and inverse agonists (SR 144528, AM 630 and JTE 907) were evaluated using [³⁵S]GTPγS binding and forskolin-stimulated cAMP assays. In the [³⁵S]GTPγS assay, WIN 55,212-2 displayed the highest intrinsic activity, whereas (R)-AM 1241 and GW 405833 behaved as partial agonists. Inverse agonists reduced basal signalling, indicating constitutive CB₂R activity in resting BV-2 cells. In contrast, cAMP measurements revealed greater signal amplification, with (R)-AM 1241 and GW 405833 exhibiting full agonist behaviour and SR 144528 producing pronounced inverse agonism. Marked differences in ligand efficacy and rank order between assays highlighted the influence of downstream signalling mechanisms and ligand-dependent signalling bias. Notably, GW 405833 displayed a strongly biased signalling profile, whereas SR 144528 consistently exhibited the greatest inverse agonist activity. These findings demonstrate that CB₂Rs are functionally active in non-stimulated microglia and that constitutive receptor activity and signalling bias contribute significantly to their pharmacological profile under basal conditions. By focusing on non-stimulated microglia, this study provides new insights into CB₂R signalling in a homeostatic cellular environment and establishes a framework for understanding how CB₂R pharmacology may be altered during neuroinflammatory and neurodegenerative disease states. Full article

Small extracellular vesicles (sEVs) are pivotal mediators of intercellular epigenetic communication in cancer. Following MISEV2023, we use the size- and isolation-based term sEV throughout, because most primary studies cited here cannot resolve which biogenetic route generated the vesicles they analyzed. By selectively packaging and transferring noncoding RNAs (ncRNAs), DNA fragments, chromatin-modifying enzymes, and metabolic effectors, sEVs reprogram recipient-cell chromatin architecture without altering the underlying DNA sequence. Tumor-derived sEVs engage stromal, immune, and vascular compartments to drive malignant progression through mechanisms that include miRNA-directed suppression of DNA methyltransferases (DNMTs), lncRNA-scaffolded Polycomb Repressive Complex 2 (PRC2) recruitment, depositing H3K27me3, and oncometabolite-mediated inhibition of TET dioxygenases. This narrative review synthesizes mechanistic, preclinical, and translational evidence on sEV-driven epigenetic regulation in cancer, applies a four-level evidence hierarchy to calibrate mechanistic claims, and critically evaluates how distinct cargo classes–microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), DNMTs, and histone-modifying enzymes–contribute to chromatin remodeling, aberrant DNA methylation, acquired therapy resistance, and immune evasion in recipient cells. We further examine sEV cargo signatures as minimally invasive liquid biopsy biomarkers and appraise engineered sEV platforms for the precision delivery of miRNA mimics, siRNAs, and small-molecule epigenetic inhibitors. Key methodological challenges, EV isolation standardization, MISEV2023 compliance, cargo stoichiometry at physiological concentrations, in vivo biodistribution, and the transition from post-transcriptional regulation to durable chromatin-state change are critically evaluated, and a translational roadmap is proposed to guide reproducible clinical implementation of sEV-mediated epigenetic cancer therapeutics. Full article

Metal-graphitic nanocapsules are an emerging class of metal-graphitic hybrid nanomaterials, typically consisting of a metal core confined within a single- or few-layer graphitic shell. This unique core–shell architecture integrates the tunable physicochemical properties of metal nanomaterials with the chemical stability, Raman activity, fluorescence-quenching capability, and surface functionalization capacity of graphitic materials. In particular, the metal core can provide plasmonic enhancement as well as magnetic or catalytic auxiliary functions, while the chemically protective graphitic shell protects the core from harsh environments and provides intrinsic Raman bands that can serve as internal standards under well-controlled conditions. These features make metal-graphitic nanocapsules highly attractive as robust nanoprobes for molecular spectroscopy-based chemical analysis, biosensing, and targeted diagnosis. In this review, we first summarize the synthesis strategies, formation mechanisms, and key properties of representative metal-graphitic nanocapsules. We then discuss recent advances in their use across representative analytical and biomedical scenarios, with emphasis on the integration of spectroscopic readouts with targeted recognition strategies. Particular attention is given to how the metal core and graphitic shell cooperatively enhance signal generation, molecular enrichment, selective recognition, environmental stability, internal calibration, and reliable in situ diagnosis in real samples and living systems. Finally, we discuss current challenges and future perspectives for developing metal-graphitic nanocapsules as versatile platforms for molecular spectroscopy-based analysis and diagnosis. Full article

Acute myeloid leukemia (AML) harboring KMT2A rearrangements (KMT2A-r) accounts for approximately 5–10% of newly diagnosed cases and represents a high-risk AML subtype associated with poor clinical outcomes despite intensive treatment strategies, including allogeneic hematopoietic stem cell transplantation (HSCT). KMT2A-r AML is also characterized by a higher incidence of extramedullary disease compared with other AML subtypes. Therapeutic options for patients with relapsed/refractory (R/R) disease, particularly after post-HSCT relapse, remain extremely limited. In recent years, menin inhibitors have emerged as a promising targeted therapeutic class for KMT2A-r and NPM1-mutated AML by disrupting the aberrant HOX/MEIS1 transcriptional program. Revumenib, a first-in-class menin inhibitor, has shown encouraging efficacy in early-phase clinical trials. Other menin inhibitors, including ziftomenib, bleximenib, and enzomenib, have also demonstrated clinical activity, with distinct pharmacokinetic, pharmacodynamic, and safety profiles. We report the case of a 36-year-old patient with KMT2A-r AML who relapsed after HSCT with both bone marrow and hepatic involvement. Compassionate-use treatment with revumenib (160 mg twice daily on days 1–28 of each 28-day cycle) induced, after two treatment cycles, complete hematologic remission with no detectable abnormal myeloid blast population by multiparameter flow cytometry (MFC) and complete radiological resolution of hepatic lesions. However, despite prior intrathecal CNS-directed therapy and sustained systemic disease control, the patient subsequently developed an isolated central nervous system (CNS) relapse. This case highlights a potential discordance between systemic and CNS disease control during menin inhibitor therapy and emphasizes the need for further investigation into CNS surveillance and disease management in patients achieving deep systemic responses. Full article

Foam cell formation of macrophages is a core pathological event in the progression of atherosclerosis. Investigating the changes in active molecules during macrophage foaming is critical for the early warning and mechanistic research of atherosclerosis. Superoxide anion (O₂^•−) and nitric oxide (NO) are two typical representatives of these active species; evaluating the fluctuations of O₂^•− and NO during macrophage foaming is vital for understanding the early diagnosis and pathological mechanisms of atherosclerosis. Herein, we report a fluorescent probe for the detection of O₂^•− and NO concentration changes based on the quenching effect of the urea bond and trifluoromethanesulfonate group on the fluorophore. MB-ROS features favorable sensitivity, selectivity and biocompatibility, enabling imaging of O₂^•− and NO fluctuations in macrophages. It was further validated in ox-LDL-stimulated foam cell models to visually track abnormal ROS/RNS changes during foam formation. This work offers a reliable chemical imaging tool to uncover redox imbalance underlying early atherosclerotic macrophage foaming. Full article

Circadian rhythms determine biological clocks that manage daily biological functions, including the sleep–wake rhythm, hormone release, and immune function. This can affect immune-mediated chronic inflammation in rheumatoid arthritis (RA), which leads to joint damage, pain, swelling, and morning stiffness. These clinical manifestations follow a distinct circadian rhythm because of the cyclic pattern of leukocyte movement, secretion of pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α at night, and fluctuations in cortisol and melatonin levels. Despite the increasing amount of evidence showing that insufficient sleep and disruption of the biological clock may play a role in RA development through suppression of the immune response in macrophages and resorption processes in osteoclasts, the cause of this phenomenon is still under investigation. The present-day guidelines continue to endorse DMARDs as the basis of treatment, while studies are exploring the role of chronotherapy as an adjunctive method for alleviating symptoms and enhancing disease outcomes. In this review, we explore current knowledge regarding the links between the molecular basis of circadian biology and the pathogenesis of RA, highlight recent trends in immune and bone remodeling mechanisms, and discuss modern possibilities for using chronotherapy, precision medicine, and advanced drug-delivery methods based on circadian rhythms to create optimal treatment strategies for RA. Full article

Breast cancer is among the most common cancers globally. While several advancements have been made to improve breast cancer management, there is still a need to find innovative ways to deliver drug therapy to improve efficacy and side effects associated with treatment. Among these methods, local and targeted drug delivery is particularly promising. The current review highlights localized polymer-based methods to effectively deliver breast cancer therapy, with a specific focus on the strengths and limitations of these systems. Injectable and surgically implanted scaffolds, microneedles, topical patches, liquid and semisolid topical drug carriers are amongst some of the delivery systems discussed. Highlighted in the discussion is how physiological changes that occur during breast cancer should be considered and utilized when developing drug formulations, by specifically exploiting the tumor microenvironment. Remaining gaps and future areas for drug delivery research are highlighted including personalized medicine and insights into novel drug delivery systems like nanomedicines and three-dimensional drug printing. Full article

The therapeutic potential of pharmacologically targeting kinases involved in regulating the DNA damage response (DDR) has been investigated for over two decades. Inhibitors of ATM, ATR, CHK1, CHK2 and WEE1 have been developed with the aim of subverting cell cycle checkpoint function in cancer cells, promoting cell death. The DNA repair pathway non-homologous end-joining can also be targeted through DNA-PK inhibition. However, despite extensive preclinical and clinical studies, none of the many candidate inhibitors have yet made it through to clinical approval. Emerging evidence for tumour biomarkers associated with enhanced sensitivity to DDR kinase inhibition may provide a way through this impasse. Clinical testing in appropriately stratified cohorts is now becoming increasingly common, with some promising results. Building on results obtained with small-molecule inhibitors, targeted protein degradation (TPD) utilising proteolysis-targeting chimaeras (PROTACs) or molecular glues for degradation of DDR kinases is a rapidly developing strategy. This review discusses the current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours, as well as the potential benefits of using TPD technology over small-molecule inhibitors. Established and emerging biomarkers that can be applied to patient selection are also discussed. Full article

Lipoprotein(a) [Lp(a)] has emerged as a major genetically determined cardiovascular risk factor that extends beyond the traditional low-density lipoprotein cholesterol (LDL-C)-centred model of atherosclerotic disease. Despite optimal LDL-C lowering, a substantial proportion of patients continue to experience cardiovascular events, highlighting the clinical relevance of residual cardiovascular risk. This review summarizes current evidence regarding the epidemiology, genetics, pathophysiology and therapeutic implications of Lp(a) in cardiovascular disease. Epidemiological, genetic, and Mendelian randomization studies consistently demonstrate an independent and likely causal association between elevated Lp(a) and atherosclerotic cardiovascular disease, ischemic stroke, calcific aortic valve stenosis, heart failure, and recurrent cardiovascular events, even in patients with well-controlled LDL-C levels. Lp(a) promotes atherosclerosis through proatherogenic, proinflammatory, and prothrombotic mechanisms, largely mediated by oxidized phospholipids and the structural homology of apolipoprotein(a) with plasminogen. Current guidelines increasingly recognize Lp(a) as a risk-enhancing factor capable of refining cardiovascular risk stratification beyond traditional algorithms, thus recommending measuring Lp(a) at least once in a lifetime in all adults. Accurate measurement and standardization of Lp(a) remain essential in clinical practice due to apo(a) isoform size variability; reporting in molar concentrations (nmol/L) is preferred as it better reflects particle number being less affected by isoform size variations and improves the reliability of cardiovascular risk stratification. Collectively, these findings support the integration of Lp(a) into precision-based cardiovascular prevention strategies and suggest a paradigm shift from an exclusively LDL-centric approach toward genetically informed risk assessment and treatment. Full article

Small open reading frames (sORFs) encode micropeptides, which are a promising yet largely untapped resource for creating peptide design templates. Owing to their concise nature and functional efficiency, micropeptides often rely on essential structural elements and brief linear motifs, such as domains for membrane interaction, targeting sequences, and sites for protein–protein interactions, to fulfill their biological functions. This inherent simplicity makes them particularly suitable for a bottom-up design approach aimed at identifying, extracting, and systematically refining functional motifs to develop novel bioactive peptides. This review addresses the critical question of how micropeptides, particularly those involved in tumor regulation, can be explored as emerging therapeutic targets, functional templates for peptide design, and potential future therapeutic agents, by synthesizing current understanding of their mechanisms, functional significance in cancer, and the computational and design strategies for their clinical translation. We examined the current methods for analyzing the sequence and structural characteristics that underpin their functional activity and investigated how these attributes can be leveraged for drug discovery and design. Finally, we underscore the primary challenges and future prospects in converting sORF-encoded micropeptides into clinically relevant molecules with the aim of broadening the current scope of the druggable proteome. Full article