Drugs that reprogram the cellular ubiquitin-proteasome system for removal of disease-causing proteins hold great promise as a new type of pharmacology. Small ubiquitin-related modifier (SUMO)-targeted ubiquitin ligases (StUbLs) are E3 ubiquitin ligases that mediate ubiquitylation of proteins primed by modification with SUMO. The antineoplastic drugs arsenic trioxide and fulvestrant stand out as examples for leveraging a SUMOylation-ubiquitylation cascade to inactivate the oncogenic fusion proteins PML-RARα and estrogen receptor α, respectively. However, approaches harnessing the StUbL system for targeting a broader spectrum of disease-relevant proteins are missing. Recent proof-of-concept studies indicate that proximity-inducing modalities can recruit aggregation-prone proteins to the StUbL machinery, potentially mitigating the formation of neurotoxic inclusions. We review new insights on StUbL-based therapeutics and reflect perspectives of reprogramming SUMO-StUbL signaling for use in oncology and neurology.

A central tenet of research articles is that they should accurately describe the experiments performed. Yet important aspects of experimental design and methods are sometimes omitted, precluding proper interpretation and follow-on studies. To remedy this, we urge researchers to adopt the CLEAR principle (Clarity, Evaluation, Assessment, Rigour) when reporting research.

Transcytosis across the blood–brain barrier (BBB) enables systemically administered large therapeutics to reach the brain parenchyma, but their fate in the parenchyma ultimately governs their therapeutic effect. Recent studies show that brain parenchymal cell uptake, internalization kinetics, reuptake at the BBB, and diffusion in the brain parenchyma shape the distribution and retention of therapeutics. Target engagement further influences their behavior beyond the BBB. These insights have prompted new strategies to enhance their distribution, retention, and target engagement. These include the selection of transport targets with favorable trafficking properties, the use of anchoring proteins, and modeling-based optimization. This opinion highlights emerging understanding of the fate of therapeutics in the brain parenchyma and outlines strategies to optimize this fate.

Metabolic derangements, particularly obesity and post-transplant diabetes mellitus, remain major challenges in solid organ transplantation, contributing to graft dysfunction and increased morbidity. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as promising agents due to their glucose-lowering, weight-reducing, and cardiorenal protective effects. Accumulating evidence supports their efficacy in improving glycemic control, reducing body weight, and potentially enhancing graft and patient survival across diverse transplant populations. Notably, GLP-1RAs exhibit a favorable safety profile, with minimal risk of drug interactions or rejection. Early data also suggest immunomodulatory and anti-inflammatory benefits. Moreover, newer dual and triple incretin agonists offer enhanced metabolic efficacy, potentially extending these benefits further. While long-term outcomes remain under investigation, GLP-1RAs represent a compelling therapeutic option that may reshape metabolic management paradigms in both pre- and post-transplant care.

Adjuvants are substances used in vaccines to boost antigen-specific immune responses. Aluminum salts (alum) were the first adjuvant approved for human use. Unfortunately, they mainly induce antibody responses and are ineffective at eliciting strong T cell immunity, limiting their use in cancer vaccines. Recent advances reveal the mechanisms of various metal ions in modulating immune signaling. By integrating the synergistic immunomodulation of metal ion pairings with nanotechnology, bimetallic nanoadjuvants (BMNAs) are revolutionizing cancer vaccine. This approach overcomes the limitation of conventional single metal adjuvants by enabling multiplexed immune activation, leading to robust T cell responses for tumor control. This review highlights the immunological mechanisms of metal ions, the rationale behind their pairing in BMNAs, and current challenges for clinical translation.

Viruses are likely to cause future pandemics due to their inherent ability to evolve and spread rapidly, with limited treatment options. Engineered multivalent decoy receptors (EMDRs) offer a broad-spectrum alternative treatment option. We propose and evaluate EMDRs and their delivery methods to guide future efforts toward pandemic preparedness.

Psilocybin, a serotonergic psychedelic, is gaining attention for its rapid and sustained therapeutic effects in depression and other hard-to-treat neuropsychiatric conditions, potentially through its capacity to enhance neuronal plasticity. While its neuroplastic and therapeutic effects are commonly attributed to serotonin 2A (5-HT2A) receptor activation, emerging evidence reveals a more nuanced pharmacological profile involving multiple serotonin receptor subtypes and nonserotonergic targets such as TrkB. This review integrates current findings on the molecular interactome of psilocin (psilocybin active metabolite), emphasizing receptor selectivity, biased agonism, and intracellular receptor localization. Together, these insights offer a refined framework for understanding psilocybin’s enduring effects and guiding the development of next-generation neuroplastogens with improved specificity and safety.

The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway, a crucial component of host innate immunity, detects aberrant DNA during viral infection. It is well established that cGAS-STING signaling activation during viral infections is often insufficient for complete viral clearance, indicating that numerous viruses have evolved countermeasures against this major pathway. However, the precise mechanisms by which viruses antagonize the cGAS-STING pathway to ensure intracellular survival remain incompletely understood. This review synthesizes recent progress in elucidating how diverse RNA and DNA viruses disrupt various stages of cGAS-STING pathway activation. These mechanistic insights into viral evasion have significant implications for the development of targeted therapeutic interventions. Specifically, the precise delivery of small-molecule or peptide-based drugs designed to counteract viral evasion proteins represents a promising direction for future antiviral therapy.

B7-H3 (CD276), an orphan member of the B7 family, is an immune checkpoint ligand and a tumor-associated antigen. Recent developments regarding dimerization, glycosylation, expression regulation, and effects on cell metabolism are emerging, along with a newfound role as a regulator of obesity. As a therapeutic target, ongoing clinical trials with antibody–drug conjugates (ADCs) and chimeric antigen receptor (CAR) immune cells targeting B7-H3 have proved to be safe and effective across different human cancer types. Multiple new preclinical studies have also provided novel treatments targeting B7-H3, including TMIGD2 optimized potent/persistent (TOP) CAR cells, bispecific ADCs, CAR-natural killer (NK) cells, and T cell engagers. In this review we highlight the diverse emerging functions of B7-H3 in both physiological and pathological conditions, and discuss new therapies targeting this molecule.

Regulatory T cells (Tregs) play a pivotal role in maintaining immune tolerance and sustaining immunological homeostasis. Emerging evidence indicates that Treg characteristics and functional alterations can significantly contribute to the pathogenesis of autoimmune diseases including type 1 diabetes mellitus (T1DM). Notably, recent studies have established a positive correlation between diminished numbers of Tregs and the onset of T1DM. Although targeting Tregs has emerged as an attractive therapeutic strategy for T1DM, the heterogeneity and mechanistic complexities of Tregs remain largely unexplored and limit clinical success. We explore the dynamic alterations of Treg frequencies and phenotypes, and discuss their regulatory mechanisms throughout T1DM progression. Furthermore, we provide an overview of preclinical studies and clinical trials targeting Tregs in T1DM. By addressing translational challenges and current limitations in clinical efficacy, the ultimate aim is to develop innovative immunotherapeutic interventions for T1DM.

The escalating threat of antimicrobial resistance demands innovative therapeutic strategies beyond classical targets. Recent insights into the mechanisms of bacterial iron acquisition – ranging from siderophores and heme uptake to ferrous iron transport – have enabled new approaches to impair pathogen growth and virulence. These pathways are increasingly being harnessed for therapeutic gain. Emerging strategies include next-generation iron chelators with improved specificity and reduced toxicity, gallium-based iron mimics that disrupt redox metabolism, and siderophore–drug conjugates that hijack bacterial uptake systems for targeted delivery. In parallel, antivirulence agents such as hemolysin inhibitors are promising resistance-sparing alternatives by targeting iron-driven pathogenesis. In this review we highlight these advances and emphasize the potential of host-mediated iron sequestration and bio-inspired nanotechnologies to strengthen nutritional immunity and guide future antimicrobial strategies.

Chronic pain remains inadequately managed, partly because of insufficient consideration of neuroimmune interactions in therapeutic design and a continued reliance on single-target strategies ill-suited to its complexity. Multitarget-directed ligands that modulate the non-neuronal microenvironment of neuronal pain pathways show promise, supported by encouraging preclinical data and initial clinical findings.

There is growing interest in developing psychedelic-inspired drugs for treating psychiatric disorders. However, identifying next-generation psychedelic analogs with ideal receptor selectivity and true therapeutic efficacy remains a major challenge. Recent progress has been driven by advances in determining agonist-induced biased signal transduction, high-content behavioral phenotyping via automated video analysis, drug-evoked structural neural remodeling, and activity-dependent gene expression. In this review, we outline a framework for evaluating psychedelics and non-hallucinogenic serotonin 2A (5-HT2A) receptor agonists. We critically examine current methods for assessing (A) agonism, (B) behavior, and (C) cellular plasticity. We highlight emerging techniques that may improve translation to humans. We contend that an effective discovery pipeline must align with specific experimental goals and incorporate multiple approaches to be successful for psychedelic drug development.

Cardiac fibrosis is a hallmark of cardiovascular and systemic diseases that arises in diverse pathological contexts such as inflammation, metabolic stress, and mechanical overload. Despite its clinical relevance, no FDA-approved therapies directly target cardiac fibrotic remodeling, highlighting persistent challenges in disease organization, model fidelity, and translational strategy. Recent advances in human induced pluripotent stem cell (iPSC)-derived models, engineered heart tissues, and in vivo systems have uncovered new fibrotic drivers, including immune–stroma crosstalk, metabolic reprogramming, and mechanotransduction, that are reshaping therapeutic development. This review synthesizes emerging molecular mechanisms, experimental models, and preclinical and clinical investigations of antifibrotic agents. Distinct from previous reviews, we emphasize cross-contextual alignment to support the development of precision antifibrotic therapy for cardiac fibrosis.

Historically, the clinical application of cell-free RNA (cfRNA) liquid biopsies has been limited by background noise. In a recent study, Nesselbush et al. developed a method for denoising cfRNA analysis, resulting in RARE-seq, a versatile liquid biopsy platform that enables transcriptomic profiling, and cancer detection and monitoring, unlocking the potential of this exciting analyte.

GlycoRNAs are glycosylated noncoding RNAs displayed on the cell surface. Emerging studies reveal their roles in intercellular communication and their dysregulation in inflammation and cancer, highlighting therapeutic potential. This review summarizes disease-related insights into glycoRNAs and outlines current strategies and challenges in developing glycoRNA-targeted interventions.

Diabetic retinopathy (DR) and nephropathy (DN) are leading microvascular complications of diabetes, yet current therapies remain inadequate. Fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist approved for dyslipidemia, has gained attention for its protective effects on the retina and kidney that extend beyond lipid modulation. Emerging preclinical and clinical evidence highlights the pleiotropic actions of fenofibrate (anti-inflammatory, antioxidative, neuroprotective, and antifibrotic), mediated through both PPAR-α-dependent and -independent pathways. These properties support its potential benefits in DR and DN, even in normolipidemic individuals. In this review, we integrate mechanistic insights with clinical outcomes, critically evaluate landmark trials, and explore emerging molecular targets of fenofibrate. We highlight the multifunctional actions of fenofibrate and propose strategies to advance its clinical utility in diabetic microvascular complications.

Allosteric potentiation of G protein-coupled receptor (GPCR) signaling provides new opportunities for therapeutic discovery. Recently, the laboratory of Peter Chidiac has reported strong allosteric potentiation of numerous GPCRs by extracellular ATP, with the minimal pharmacophore represented by sugar monophosphates. This discovery potentially aids the development of novel allosteric modulators for numerous therapeutically attractive GPCRs.

Glycans are complex sugar modifications found on cell surfaces that play crucial roles in biological processes. Glycosylation patterns are aberrantly altered in the tumor microenvironment (TME), which helps cancer cells escape immune surveillance by creating a tumor-specific 'glyco-code' that weakens immune responses and reduces immunotherapy effectiveness. Recent studies have illustrated the potential to improve antitumor immune responses by manipulating glycosylation in the TME. We review the effects of aberrant glycosylation on the regulation of tumor immunity and the corresponding strategies for manipulating glycosylation to enhance antitumor immunity. These strategies include inhibiting glycan–receptor interactions, engineering cell-surface glycans, and remodeling the extracellular matrix. This Review highlights the importance of glycosylation in designing effective and personalized cancer treatments.

STRUCTURE: Danicopan is a small-molecule drug that features a 2-(3-acetyl-1H-indazol-1-yl)acetyl core, connected to a 6-bromopyridin-2-amine group through a (2S,4R)-fluoroproline linker via amide bonds. The indazole ring is further functionalized at position 5 with a 2-methylpyrimidin-5-yl group. The molecular formula is C26H23BrFN7O3 and its molecular weight is 580.4 g/mol.