Gorgun C, Lordan R, Kennedy OD
… +2 more, Hoey DA, Curtis AM
Trends Mol Med
· 2026 May · PMID 42115084
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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 contributin...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.
Trends Mol Med
· 2026 May · PMID 42091394
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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...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.
Trends Mol Med
· 2026 May · PMID 42086409
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Long COVID may reflect a failure of coordinated physiological recovery rather than persistent infection. Emerging evidence identifies inflammation-driven disruption of erythropoiesis and hormonal balance as central mecha...Long COVID may reflect a failure of coordinated physiological recovery rather than persistent infection. Emerging evidence identifies inflammation-driven disruption of erythropoiesis and hormonal balance as central mechanisms linking immune dysregulation, metabolic stress, and persistent symptoms. This framework positions erythroid-endocrine pathways as key determinants of recovery and promising therapeutic targets.
Ibrahim M, Hossain MS, Ooi L
… +6 more, Hasan MM, Ahsan S, Salem AK, Piazza GA, Feng X, Ahsan F
Trends Mol Med
· 2026 May · PMID 42086408
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Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, a...Amyotrophic lateral sclerosis (ALS) remains a fatal neurodegenerative disease with few effective therapies. Emerging evidence indicates that oxidative DNA damage, defective base excision and single-strand break repair, and progressive NAD depletion contribute to motor neuron degeneration. The NAD-PARP1-XRCC1 axis sits at the intersection of genome maintenance and metabolic control, linking DNA damage signaling to cellular bioenergetics. When dysregulated, this pathway may drive persistent PARP1 activation, failed repair, and energetic collapse. In this review, we integrate mechanistic and translational evidence supporting this axis as a therapeutic target in ALS. We propose a staged translational framework that prioritizes repurposable low-trapping PARP1 inhibitors combined with NAD support, followed by central nervous system-directed RNA-lipid nanoparticle delivery of repair factors, with poly(ADP-ribose) and NAD metabolites as pharmacodynamic biomarkers.
Mitochondria are central regulators of cerebrovascular health through their control of energy metabolism, Ca homeostasis, and redox signaling, and their dysfunction represents a convergent pathogenic mechanism across cer...Mitochondria are central regulators of cerebrovascular health through their control of energy metabolism, Ca homeostasis, and redox signaling, and their dysfunction represents a convergent pathogenic mechanism across cerebrovascular diseases. In ischemic stroke, mitochondrial failure exacerbates neuronal injury via permeability transition pore opening, oxidative stress, and bioenergetic collapse, while altered mitochondrial dynamics and the release of mitochondrial damage-associated molecular patterns amplify neuroinflammation during reperfusion. Beyond stroke, mitochondrial dysfunction contributes to intracranial aneurysms, atherosclerotic stenosis, and vascular malformations, where oxidative stress, mitochondrial DNA instability, and cell type-specific metabolic reprogramming drive vascular remodeling and lesion progression. In this review, we integrate recent evidence highlighting context- and stage-dependent roles of mitochondria in cerebrovascular pathology and discuss implications for biomarker discovery, therapeutic targeting, and translational strategies.
Previous epidemiological studies have associated viral pneumonia with an increased risk of lung cancer. Recently, Qian et al. revealed that epigenetic reprogramming following respiratory viral infections accelerates tumo...Previous epidemiological studies have associated viral pneumonia with an increased risk of lung cancer. Recently, Qian et al. revealed that epigenetic reprogramming following respiratory viral infections accelerates tumorigenesis by orchestrating a protumor microenvironment, providing mechanistic insights and potential therapeutic strategies for intercepting lung cancer progression after viral pneumonia.
Neurodegenerative dementias are debilitating diseases that include Alzheimer's disease (AD) and AD-related dementias (ADRDs). Creutzfeldt-Jakob disease (CJD) is a rapidly progressive dementia caused by the accumulation o...Neurodegenerative dementias are debilitating diseases that include Alzheimer's disease (AD) and AD-related dementias (ADRDs). Creutzfeldt-Jakob disease (CJD) is a rapidly progressive dementia caused by the accumulation of prions in the brain. Despite the many similarities between CJD and the ADRDs, CJD is currently not included in the ADRD group. In this opinion article, we discuss the significant impact of prion research on our understanding of the molecular pathogenesis of ADRDs as well as on the development of diagnostic tests and therapeutic strategies. We argue that CJD should be included in the group of ADRDs to enhance research cooperation and accelerate understanding of underlying disease mechanisms toward the goal of developing effective therapies to slow neurodegeneration.
In a recent study in Cell, Liu et al. identify β-hydroxybutyrate as a practical metabolic adjuvant for CAR-T cells. By fueling the TCA cycle and reshaping transcriptional and epigenetic programs, this ketone body enhance...In a recent study in Cell, Liu et al. identify β-hydroxybutyrate as a practical metabolic adjuvant for CAR-T cells. By fueling the TCA cycle and reshaping transcriptional and epigenetic programs, this ketone body enhances proliferation, persistence, and tumor control, suggesting that metabolic supplementation may offer a simple route to more effective adoptive immunotherapy.
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 tu...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.
The function of the thymus, essential for T cell development, declines sharply with age. Genetic defects that disrupt thymic organogenesis or function lead to profound immunodeficiency and autoimmunity. Allogeneic thymus...The function of the thymus, essential for T cell development, declines sharply with age. Genetic defects that disrupt thymic organogenesis or function lead to profound immunodeficiency and autoimmunity. Allogeneic thymus transplantation for congenital athymia, the only existing thymus replacement therapy, provides proof of concept for T cell reconstitution but remains constrained by donor availability and Human Leukocyte Antigen (HLA) mismatch. Advances in single-cell biology and stem cell engineering now make scalable thymus regeneration an attainable goal. In particular, induced pluripotent stem cell-derived thymic epithelial cells could restore endogenous T cell development and immune tolerance in an HLA-compatible manner. We propose that the thymus is uniquely suited for stem cell-based regeneration, with the potential to transform the treatment of immune deficiency, transplantation, cancer, autoimmunity, and aging itself.
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 u...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.
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 i...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 p16/p21 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.
The incidence of esophageal adenocarcinoma is rising in Western countries. Despite advances in chemotherapy and immunotherapy, the prognosis remains poor, with an overall 5-year survival rate below 15%. A major challenge...The incidence of esophageal adenocarcinoma is rising in Western countries. Despite advances in chemotherapy and immunotherapy, the prognosis remains poor, with an overall 5-year survival rate below 15%. A major challenge is the cancer's poor and often unpredictable response to current treatments. Animal venoms represent a promising yet underexplored source of therapeutic agents, offering millions of structurally diverse and highly potent bioactive peptides that can modulate a wide array of molecular targets. However, only a small fraction of these peptides has been pharmacologically characterized. This review presents the therapeutic potential of venom-derived peptides in cancer treatment, summarizes the role of ion channels in esophageal adenocarcinoma (EAC), and discusses peptides targeting ion channels that may offer new opportunities for future EAC treatment.
Trends Mol Med
· 2026 May · PMID 41933994
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Yuan et al. present a novel method for expanding adult human hepatocytes and assembling them with cholangiocytes and portal fibroblasts into patient-specific periportal liver assembloids. This system recapitulates liver...Yuan et al. present a novel method for expanding adult human hepatocytes and assembling them with cholangiocytes and portal fibroblasts into patient-specific periportal liver assembloids. This system recapitulates liver architecture and function, enabling personalized disease modeling, including liver fibrosis, and offering new possibilities for precision hepatology and regenerative medicine.
Trends Mol Med
· 2026 May · PMID 41933993
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Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via c...Satellite glial cells transfer mitochondria to sensory neurons via myosin 10-dependent tunneling nanotubes. Ji et al. show that this transfer is impaired in diabetic neuropathy, causing energy failure. Restoring it via cell or mitochondrial transplantation alleviates pain and promotes nerve regeneration, revealing a new therapeutic strategy for peripheral neuropathy.
Trends Mol Med
· 2026 Jun · PMID 41925421
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Invasive candidiasis is a severe fungal infection with management challenges due to a lack of biomarker-guided patient stratification and limited availability of antifungal drugs. Liu et al. identified the cytokine Meteo...Invasive candidiasis is a severe fungal infection with management challenges due to a lack of biomarker-guided patient stratification and limited availability of antifungal drugs. Liu et al. identified the cytokine Meteorin-like as a key regulator and potential theranostic target, offering new hope for better diagnosis and treatment of these life-threatening infections.
Trends Mol Med
· 2026 Mar · PMID 41925420
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Interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), have dismal prognoses, with a median survival of 3-5 years, owing to a lack of early biomarkers or effective treatments. This review highlight...Interstitial lung diseases, particularly idiopathic pulmonary fibrosis (IPF), have dismal prognoses, with a median survival of 3-5 years, owing to a lack of early biomarkers or effective treatments. This review highlights the lung microbiome as a key biological factor in IPF pathogenesis and a promising therapeutic target. Elevated burdens of pathogenic bacteria, including Streptococcus and Staphylococcus, in bronchoalveolar lavage fluid correlate with accelerated progression and higher mortality. These bacteria release toxins and activate Th17-driven inflammation, providing mechanistic links to alveolar injury and fibrosis. Host genetics and systemic factors, including oral-gut-lung interactions, further shape disease progression. Although antibiotic trials have been unsuccessful, embracing the microbiome as an active participant in IPF may open unprecedented opportunities for personalized interventions.
Trends Mol Med
· 2026 Mar · PMID 41925419
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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 occur...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.
Chou ML, Blum D, Cognasse F
… +3 more, Kuchcinski G, Devos D, Burnouf T
Trends Mol Med
· 2026 Mar · PMID 41904071
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Platelet-derived biotherapies are emerging as innovative approaches for complex neurological disorders requiring multimodal interventions. Platelet-derived products, including lysates, platelet concentrate supernatants,...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.