Deubiquitinases regulate key oncogenic and immune pathways but have proven challenging to exploit therapeutically. Among them, ubiquitin-specific protease 22 (USP22) has emerged as a molecule of interest due to its involvement in both tumor-intrinsic programs and tumor-immune interactions. In this review, we synthesize current evidence describing how USP22 modulates oncogenic transcriptional states and immune evasion. Tumor-intrinsically, USP22 has been implicated in stabilizing select oncogenic factors and shaping chromatin accessibility in ways that can reinforce proliferation, survival, stem-like properties, and metastatic potential. In parallel, USP22 influences antitumor immunity by modulating MHC-I-mediated antigen presentation, immune checkpoint expression, and the fitness of intratumoral regulatory T cells. We discuss emerging pharmacological approaches to target USP22, the limitations of current inhibitor strategies, and the importance of distinguishing direct enzymatic functions from indirect transcriptional consequences. Together, these insights suggest that USP22 inhibition may offer a therapeutic strategy with dual effects on tumor biology and antitumor immunity.
Platelet-derived biotherapies are emerging as innovative approaches for complex neurological disorders requiring multimodal interventions. Platelet-derived products, including lysates, platelet concentrate supernatants, secretome, extracellular vesicles, and fractionated components, represent a scalable and clinically accessible biotechnology platform for precision neuromedicine. Platelets provide a reservoir of trophic factors, cytokines, chemokines, lipids, antioxidants, and noncoding RNAs with demonstrated neuroprotective, anti-inflammatory, and antiferroptotic effects in models of neurodegeneration, trauma, and aging. Preclinical and patient-derived omics and neuroimaging data can help characterize mechanisms of action, identify biomarkers, and refine platelet secretome preparations toward indication-specific formulations. Combined with virus inactivation and purification technologies adapted from plasma protein manufacturing, these advances position platelet-derived biotherapies as a rational and versatile path toward future acellular therapeutics for brain disorders.
Tumor progression depends on coordinated adaptation of cancer cells and the tumor microenvironment to immune pressure, metabolic limitations, genomic instability, and biomechanical stress. While these adaptive responses have often been investigated through distinct experimental and conceptual frameworks, increasing evidence indicates that they converge on shared regulatory pathways. Calcium signaling is a fundamental regulator of cellular adaptation; however, its role in integrating tumor stress responses remains unclear. This review synthesizes emerging evidence identifying calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2) as a key regulator linking calcium signaling to coordinated tumor and microenvironmental adaptation across mechanical, metabolic, replication, and immune stress responses. We discuss how CaMKK2 supports tumor ecosystem fitness through convergent tumor-intrinsic and microenvironmental programs and consider the therapeutic implications of targeting CaMKK2 and its signaling network, emphasizing context dependence, rational combination strategies, and biomarker-guided clinical translation.
Gene therapy is evolving from gene addition to precise genome editing, enabling the direct correction of disease-causing mutations. Breakthrough technologies, such as clustered regularly interspaced short palindromic repeats-CRISPR-associated protein (CRISPR-Cas) nucleases, base editors, prime editors, and CRISPR-associated transposases are reshaping the therapeutic landscape. This review covers the progression of precision editing technologies and their clinical applications, spanning from ex vivo therapies to in vivo treatments targeting vital organs. The rise of personalized medicine, highlighted by therapies, such as carbamoyl phosphate synthetase 1 editing, underscores the shift toward N-of-1 medicine for rare diseases. Clinical trial progress, delivery and accessibility challenges, and the role of AI in optimizing editing tools and predicting outcomes are also discussed. These innovations are transforming genetic medicine, offering the promise of safer, more durable, and personalized cures.
Aging affects virtually all organs and biological processes, and age-related diseases remain the leading causes of death worldwide. Genetic factors play a central role in modulating lifespan, and discoveries in the genetic manipulation of the aging process in animal models have transformed our perception of aging. However, translating these findings into clinical therapies remains challenging. Recent breakthroughs demonstrate that gene therapies can directly target aging mechanisms. Single-gene therapies have ameliorated multiple age-related pathologies, such as pediatric Parkinson disease. In this review, we discuss recent advances and prospects for developing gene therapies for aging and age-related diseases, highlighting potential targets, delivery strategies, cellular rejuvenation, and lessons from long-lived species. Despite remaining challenges, longevity gene therapy offers a promising avenue to reprogram aging and delay age-related decline.
[Formula: see text] Dr. Tayade earned a Doctor of Veterinary Medicine, Masters, and PhD in Immunology from the Indian Veterinary Research Institute. He then completed a postdoctoral fellowship at the University of Guelph. He joined Queen's University in 2009 as an Assistant Professor and is currently working as a Vice Dean, and the Director of MD PhD Program in the Faculty of Health Sciences. The central theme of Dr. Tayade's research focusses on how immune dysfunction contributes to endometriosis pathophysiology, and identifying immune-based markers for diagnostic and therapeutic interventions. Dr. Tayade has published over 100 peer-reviewed articles in journals such as JCI Insight, Journal of Immunology, American Journal of Pathology, American Journal of Obstetrics and Gynecology, and Trends in Molecular Medicine. He has received competitive funding from the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Endometriosis Foundation of America; and industrial funding from Bayer, Aurinia Pharmaceutical, and AbbVie. For his outstanding contributions to research, Dr. Tayade has received numerous special recognitions. In 2012, he won both the Early Researcher Award from the Ministry of Research and Innovation, as well as the Christian J Herr Award for Outstanding Contributions in Reproductive Immunology from the American Society for Reproductive Immunology. In 2014, he earned the Mihran and Mary Basmajian Award for Research Excellence from the Queen's Faculty of Health Sciences.
Tumor-infiltrating lymphocytes (TILs) are recognized as a key component of anticancer immunity and serve as an important prognostic factor in cancer progression. In this review, the latest updates and perspectives on the diverse populations of TILs and their roles in cancer immunity are discussed. The presence and balance between anti-tumorigenic and pro-tumorigenic immune cells in the tumor microenvironment (TME) largely determine tumor progression and fate. Thus, the properties of TILs were reviewed to provide a better insight into the roles of these immune cells within the TME. Additionally, the different factors influencing immune cell infiltration in solid tumors are also described to suggest novel immunotherapeutic approaches for improved TIL infiltration. These recent approaches are then summarised as recommendations to improve infiltration and potentially achieve better clinical outcomes. Overall, this review highlights the critical role of TILs, factors governing immune cell homing and infiltration, and strategic approaches to improve TIL infiltration.
Mechanical forces regulate development, homeostasis, and repair in the skin, lung, and cornea-external barrier organs that are exposed to stretch, shear, and stiffness. Dysregulated mechanotransduction drives fibrosis, inflammation, and impaired repair via conserved pathways [Piezo1 (Piezo-type mechanosensitive ion channel 1), TRPV4 (transient receptor potential vanilloid 4), and integrin-YAP (Yes-associated protein)]. Targeting these circuits with small molecules, biologics, or stiffness-tuned biomaterials offers a novel category of cross-organ therapies. As mechanosensitive pathways and mechanically informed biomaterials advance toward clinical testing, an integrated cross-organ perspective is urgently needed to address unmet therapeutic needs in chronic barrier diseases. This review unifies disparate insights into biophysics, molecular biology, and clinical practice to reveal how shared mechanisms underpin barrier pathologies and enable breakthrough mechanomedicine treatments.
Ferroptosis has emerged as a critical contributor to secondary brain injury in cerebrovascular diseases (CVDs). However, the clinical translation of antiferroptotic therapies remains stalled because current strategies often treat CVDs as a uniform entity, neglecting profound pathophysiological heterogeneity. In this review, we propose a pathology-guided framework mapping distinct ferroptotic cascades across CVDs. We delineate how ischemic stroke hinges on endogenous iron retention and the collapse of nuclear factor erythroid 2-related factor 2 antioxidant defenses, whereas hemorrhagic stroke is triggered by acute exogenous heme influx. Furthermore, chronic hypoperfusion in vascular dementia lowers the threshold for oligodendrocyte ferroptosis. By deconstructing these subtype-specific mechanisms-from iron overload modes to lipid vulnerability-we emphasize a paradigm shift for CVD: advancing precision medicine requires mechanism-stratified, context-dependent interventions rather than uniform ferroptosis inhibition.
The central nervous system (CNS) orchestrates homeostatic responses and organismal behaviors by integrating cues from the whole body. Like other peripheral tissues, skeletal muscle can signal to the brain, and this occurs via muscle-secreted signaling factors (myokines/myometabolites). In this review article, we examine exercise-induced myokines and myometabolites that improve cognitive capacity and impede neurodegeneration and, conversely, detrimental myokines secreted by diseased muscles that negatively impact brain function. Cellular processes modulated by myokines in the CNS include proteostasis, angiogenesis, neurogenesis, synaptic plasticity, cell senescence, and neuroinflammation, resulting in the modulation of diverse behaviors, such as motor control, memory, foraging, and sleep. Collectively, muscle-to-brain signaling emerges as an important influencer of CNS function and aging, with the prospect of utilizing myokine-/myometabolite-based therapies for treating neurodegeneration.
TANGO2 deficiency disorder (TDD) is an ultrarare, autosomal recessive disease characterized by neuromuscular impairment, intellectual disability, and recurrent metabolic crises leading to life-threatening ventricular arrhythmias. Intrafamilial phenotypic variability and overlapping manifestations with other metabolic diseases complicate timely and accurate diagnosis. This review summarizes the clinical spectrum and emerging molecular mechanisms of TDD, integrating insights from structural biology and experimental disease models. Evidence suggests that high-dose vitamin B complex supplementation can reduce the frequency of metabolic crises and improve neurocognitive outcomes, underscoring the importance of early diagnosis and intervention. By integrating recent advances, this review aims to provide a thorough understanding of TANGO2 deficiency, identify key unmet needs, and define future research priorities.
Circadian rhythms play a central role in how bone tissue is formed, resorbed, and remodelled during the 24-h cycle. Bone cells express core clock proteins, which coordinate the timing of these processes, each contributing differently to the balance between bone formation and resorption. These intrinsic bone-cell clocks are further influenced by external temporal cues, including hormonal effects and mechanical forces such as exercise. Taken together, these features indicate that skeletal bone tissue is significantly influenced by the peripheral clock. In this review, we summarise recent advances on how intrinsic and extrinsic timing cues interact to regulate skeletal physiology, and we discuss how emerging insights into bone circadian biology might inform therapeutic and regenerative strategies aimed at improving skeletal health.
Most solid tumors remain immunologically 'cold' and refractory to therapy, making immunogenic cell death (ICD) induction a central therapeutic goal. Z-DNA binding protein 1 (ZBP1) acts as a sensor, converting intrinsic nucleic acid stress into ICD programs. This review establishes ZBP1 as a convergence point linking distinct nucleic acid stress signals, including DNA damage response, telomere crisis, replication stress, dysregulated RNA splicing, endogenous retroelement re-expression, and mitochondrial stress response, to PANoptosis. We highlight recent therapeutic strategies, ranging from biological inducers and direct agonists to Z-DNA proteolysis targeting chimeras and pharmacological stressors, that harness nucleic acid stress responses to engage ZBP1. Finally, we propose a translational roadmap emphasizing combination strategies and biomarker-guided patient selection to engage the ZBP1 signaling axis and promote durable antitumor immunity.
Myelination is increasingly recognized as a dynamic and adaptive process regulated by oligodendrocytes throughout life. Beyond providing electrical insulation, myelin supports axonal metabolism and may serve as an energy reservoir under metabolic stress, highlighting the importance of physiological myelin turnover. Dysregulation of myelin dynamics contributes to a wide spectrum of neurological disorders, including demyelinating, neurodegenerative, and neuropsychiatric diseases. Growing evidence indicates that neurotransmitter signaling through G protein-coupled receptors (GPCRs) expressed by oligodendrocyte lineage cells regulates myelin formation, remodeling, and repair. In this review, we discuss how neurotransmitter-activated GPCRs control oligodendrocyte function and myelin plasticity, and we explore their potential as targets to promote myelin regeneration and restore neural circuit function.
Hepatocellular carcinoma (HCC) remains lethal due to its high refractoriness to standard treatment, which is contributed to by factors including adaptive metabolic reprogramming of HCC cells and pre-existing liver diseases that compromise liver function. Abnormal tumor vasculature creates a nutrient-deprived microenvironment, intensifying competition between HCC cells and immune cells and impairing antitumor immunity. Among the complex metabolic network, amino acid (AA) metabolism emerges as a critical player and an attractive therapeutic target. This review first examines how dysregulated AA metabolism supports HCC hallmarks, including metabolic reprogramming and immune evasion. We discuss the translational potential of therapies targeting AA metabolism in HCC, ranging from pharmacologic inhibition to dietary AA intervention, which can be further integrated with existing HCC treatments to improve clinical outcomes.
The Lifestyle for Brain Health (LIBRA) index evaluates modifiable dementia risk, mainly in midlife and older adults. We examined the frequency of LIBRA factors and their individual and combined associations with cognitive functioning across adulthood (20-75 years), considering age, sex, and socioeconomic status (SES). Data came from the population-based German National Cohort (NAKO baseline; n = 149,948). We calculated proportions for LIBRA factors, tested frequency trends, and analyzed cross-sectional associations with cognitive functioning using cluster-adjusted regression controlling for confounders. Behavioral and psychosocial risks (smoking, physical inactivity, depression) were more common in younger adults, while cardiovascular risks (hypertension, coronary heart disease, hypercholesterolemia) predominated in older age. Men had higher LIBRA scores. Higher scores were consistently linked to lower cognitive functioning and lower SES across age groups. Dementia risk factors were frequent and already associated with poorer cognition in younger adults, underscoring the need for early, targeted, and equity-oriented prevention.
Peripheral nerve regeneration declines with aging and prolonged denervation, yet the underlying mechanisms have remained elusive. Recent studies identify senescent Schwann cells (senSCs) as a key contributor. Following injury, repair Schwann cells (SCs) enter a senescent state marked by p16INK4a/p21CIP1 upregulation and secretion of a senescence-associated secretory phenotype (SASP) that impairs axonal regrowth. Clearing senSCs in preclinical models restores regeneration, suggesting that failed repair results from active inhibition rather than diminished capacity. Moreover, SASP-like signatures emerge across neuropathies of diverse etiology, suggesting broader relevance. In this review, we synthesize emerging evidence linking SC senescence to impaired regeneration and chronic neuropathies and outline therapeutic strategies targeting senescence. We also examine translational challenges and explore how these approaches could advance nerve repair and neuropathy treatment.
Hepatocellular carcinoma (HCC) remains a major global health challenge, with rising incidence, frequent development of drug resistance, and limited long-term survival despite advances in systemic therapies. Within the tumor microenvironment, the interaction between hyaluronic acid (HA) and cluster of differentiation 44 (CD44) is linked to tumor progression and therapeutic failure. Accordingly, targeting the HA-CD44 signaling axis represents a promising strategy to overcome resistance. This review highlights potential approaches, including inhibition of HA synthesis, enzymatic HA degradation, CD44 blockade, and HA-based nanocarriers for selective drug delivery, alone or combined with existing therapies. Leveraging HA-CD44 biology may help refine profiling and support the development of more personalized treatments, ultimately enhancing outcomes for HCC patients.
Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a key mechanism in disease pathogenesis and treatment. As essential biomedical models, mice have played an instrumental role in uncovering the relationship between ferroptosis and disease. However, a systematic synthesis of phenotypic outcomes and mechanistic insights derived from these studies remains lacking. This review outlines the important molecular pathways of ferroptosis, including dysregulated iron metabolism, lipid peroxidation, and antiferroptotic defense systems, and highlights key genes involved in its regulation. We further integrate functional evidence from gene-edited mouse models to provide deeper insights into the pathophysiological relevance of ferroptosis across different disease contexts. Finally, promising yet underexplored areas are discussed to facilitate the clinical translation of ferroptosis research.
Cartilage is susceptible to degeneration from injury, overuse, or age-related wear. Articular cartilage, the smooth hyaline cartilage covering the ends of bones in synovial joints, has limited intrinsic repair capacity because its avascular, aneural, and alymphatic matrix contains sparse, low-proliferative chondrocytes, allowing matrix damage to persist and drive joint dysfunction and osteoarthritis. Most therapies relieve symptoms without reliably restoring durable cartilage architecture. Recent advances in cell-based therapy, matrix-associated chondrocyte implantation, engineered scaffolds, controlled-release biologics, and quantitative clinical endpoints have shifted the field toward mechanism-based cartilage regeneration. In this feature review, we assess emerging clinical evidence across cell-based strategies, biomaterial- and scaffold-assisted repair, biologics, and combination approaches. We emphasize integrated, multimodal approaches and standardized outcome measures as essential for achieving durable cartilage repair and true disease modification.