Classic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), have emerged as potent modulators of neuroplasticity and metaplasticity in the adult brain, offering novel therapeutic strategies for neuropsychiatric disorders. Recent findings reveal that beyond their transient psychotropic effects, these compounds activate serotonin 5-HT2A receptors and downstream signaling cascades-including CaMKII (calcium/calmodulin-dependent protein kinase II), ERK (extracellular signal-regulated kinase), mTOR (mechanistic target of rapamycin), and BDNF (brain-derived neurotrophic factor) pathways-thereby inducing synaptogenesis, dendritic spine remodeling, and transcription of the immediate early genes. Critically, the brain's extracellular matrix (ECM), particularly perineuronal nets (PNNs), has been identified as a central regulator of synaptic stability and a key target of psychedelic action. Psychedelics transiently disrupt ECM integrity by loosening PNNs and reorganizing pericellular scaffolds, a process that reopens developmentally restricted critical periods of plasticity and restores circuit-level flexibility. These ECM-mediated metaplastic effects appear essential to the sustained therapeutic outcomes observed in the clinical studies of psychedelic-assisted therapy for depression, posttraumatic stress disorder, addiction, and potentially neurodegenerative diseases. This article synthesizes current cellular, molecular, and translational evidence highlighting the ECM as a dynamic and permissive substrate through which classic psychedelics exert long-lasting structural and functional brain changes, underscoring its potential as a target for precision interventions in neuropsychiatric care.

Classic psychedelics such as lysergic acid diethylamide (LSD), psilocybin, N,N-dimethyltryptamine (DMT), and mescaline induce lasting changes in neuroplasticity and behavior that extend far beyond their acute pharmacological effects. Emerging evidence highlights that these enduring therapeutic benefits in neuropsychiatric conditions may be significantly mediated through complex epigenetic reprogramming mechanisms, although direct causal evidence remains limited. This review synthesizes current knowledge on how classical psychedelics and the rapid-acting antidepressant ketamine (an NMDA receptor antagonist) influence epigenetic regulation at multiple molecular levels, encompassing DNA methylation and hydroxymethylation, histone post-translational modifications (acetylation, methylation, phosphorylation), nucleosome positioning and higher-order chromatin restructuring, non-coding RNA (ncRNA) dynamics, and RNA epitranscriptomic modifications. Moreover, psychedelics appear to alter metabolic and mitochondrial pathways, thereby modulating the availability and nuclear transport of key epigenetic cofactors, such as acetyl-CoA, S-adenosylmethionine (SAM), and α-ketoglutarate. By integrating these pathways, we propose a unified model wherein psychedelic-induced signaling cascades may intersect with metabolic and epigenetic networks, potentially contributing to persistent transcriptional alterations and enhanced synaptic connectivity. Understanding these intricate mechanisms provides crucial insights into how transient exposure to psychedelics translates into sustained therapeutic outcomes, informing the development of novel neuroepigenetic interventions in molecular psychiatry.

Elucidating the relationships among in vivo activity, brain-wide projection, and gene expression is critical for understanding neuronal functions, but characterizing these modalities for the same neuron remains technically challenging. Here, we developed a trimodal platform combining in vivo Ca2+ imaging, morphological reconstruction of single neurons in cleared whole brains, and post hoc imaging-based in situ transcriptomic profiling in thick brain sections. We applied this platform to the mouse primary visual cortex (VISp) and obtained trimodal profiles for 141 intratelencephalic (IT) and pyramidal tract (PT) neurons. We found that regional axonal arborization, soma location, transcriptomic signatures, and subcellular RNA localization emerged as informative predictors for distinguishing neurons preferentially responsive to different visual stimuli. Importantly, morphological and transcriptomic features are complementary and, when integrated, can better predict neuronal function. Thus, this trimodal platform enables a comprehensive understanding of the relationships among gene expression, morphological diversity, and functional properties of single neurons.

Cognition-enhancing drugs (CEDs) are pharmacological agents aimed at improving memory, attention, and executive function. This review explores both established and emerging CEDs that target neurotransmitter systems, neuroinflammation, and neuroplasticity. It discusses innovative design strategies, such as multi-target agents and prodrugs, and examines clinical challenges in Alzheimer’s disease and other conditions. We address ethical, societal, and regulatory concerns, especially those relating to non-medical use, highlighting the importance of responsible development and precision-based approaches in cognitive therapeutics.

Toll-like receptor 13 (TLR13) is a critical innate immune sensor that recognizes a conserved RNA sequence, RNA15 (2054-2068, ACG GAA AGA CCC CGU), within bacterial 23S rRNA, thereby initiating a pro-inflammatory response. While the alarmin high mobility group box 1 (HMGB1) is known to modulate various TLR pathways, its influence on TLR13 signaling has remained unexplored. Here, we reveal that HMGB1 directly binds RNA15 with high affinity and profoundly disrupts its hairpin structure, which is essential for TLR13 recognition. Using a combination of fluorescence anisotropy, FRET assays, NMR spectroscopy, and enhanced-sampling molecular dynamics simulations, we demonstrate that HMGB1 binding remodels RNA15 into a stem-open conformation, making it thermodynamically unfavorable for receptor activation. Functionally, HMGB1 significantly inhibits RNA15-induced TLR13 activation, leading to a dose-dependent reduction in inflammatory mediators. These findings uncover a novel “ligand remodeling” mechanism, whereby HMGB1 acts as a negative regulator of TLR13 signaling by structurally altering the RNA ligand rather than directly blocking the receptor. This work provides new insights into host-pathogen interactions and suggests important implications for the design and immunogenicity of RNA-based therapeutics and vaccines.

Sleep is a near-universal, evolutionarily conserved behavior across animals, yet its core function remains debated. Classical theories emphasize synaptic homeostasis, memory consolidation, and metabolic waste clearance, but emerging perspectives from systems neuroscience and network science suggest a more integrative role: sleep as a mechanism that maintains the robustness of the brain as a complex, dynamic network. In this Perspective, evidence from neuroimaging, electrophysiology, and computational modeling is synthesized to argue that sleep supports system-level resilience by stabilizing large-scale dynamics, limiting maladaptive over-specialization, and preserving efficient information flow. Sleep-dependent processes, including synaptic renormalization, neural replay, and glymphatic clearance, are discussed as coordinated components that reorganize connectivity and restore functional capacity after waking perturbations. Parallels with artificial neural networks (ANNs) further highlight how structured offline phases can improve the stability–plasticity trade-off and mitigate catastrophic forgetting during continual learning. Clinically, framing sleep as a resilience mechanism provides a mechanistic lens for disorders marked by network fragility, suggesting how disrupted sleep architecture in conditions such as insomnia or neurodegeneration may impair recoverability and contribute to persistent cognitive and affective symptoms. Overall, this network-level account positions sleep not merely as rest, but as an active, stage-structured strategy for sustaining resilient computation in both biological and artificial systems.

Natural hallucinogenic compounds have arisen independently across plants, fungi, and animals, evolving into a diverse chemical arsenal that includes phenethylamines, indolealkylamines, and terpenoid scaffolds. Beyond clinical and cultural frameworks, their ecological origins and evolutionary trajectories may help explain why such potent modulators of perception, emotion, and cognition persist in nature. Here, integrating chemical ecology, comparative genomics, biosynthetic logic, and evolutionary biology, we propose that these molecules may function as defensive agents or symbiosis-associated manipulators of herbivore and pollinator behavior. A "building-block" biosynthetic logic links primary metabolism to convergent psychotropic scaffolds via a recurrent set of tailoring reactions, including decarboxylations and methylations. Recent advances illuminate mescaline biosynthesis in cacti, horizontal gene transfer of psilocybin clusters in fungi, and symbiont-derived alkaloids in grasses. We also assess the debate surrounding endogenous mammalian tryptamines, arguing that the leading hypothesis points toward sigma-1 receptor-mediated cytoprotection and stress responses, supported by convergent pharmacological and cellular evidence, rather than inherent hallucinogenic functions. Across kingdoms, natural hallucinogens appear to converge on conserved neural targets, including serotonergic and other neuromodulatory systems that are shared across phyla. From this perspective, human psychoactivity is likely an evolutionary by-product of molecules selected for ecological interactions with animals possessing deeply conserved receptor architectures. Framing hallucinogens through chemical ecology not only clarifies their origins but also highlights translational opportunities in target discovery, pathway engineering, and sustainable production, while emphasizing the need to integrate conservation, ethical sourcing, and benefit-sharing into the current hallucinogenic renaissance.

Methamphetamine (METH) addiction represents a severe global public health crisis with currently limited therapeutic options, highlighting an urgent need for innovative approaches. Emerging evidence indicates that neuroinflammation, particularly microglial activation and subsequent cytokine release, significantly contributes to the neuropathology associated with METH use. Cannabidiol (CBD), a phytocannabinoid with promising anti-inflammatory and neuroprotective properties, has demonstrated therapeutic potential in mitigating METH-related neuroimmune responses. However, its clinical translation is severely restricted due to low bioavailability, rapid hepatic metabolism, and limited blood-brain barrier (BBB) penetration. To address these challenges, we developed a novel therapeutic platform utilizing exosomes derived from hypoxia-preconditioned human umbilical vein endothelial cells. These exosomes were loaded with CBD and surface-functionalized with the transcriptional activator protein (TAT) peptide, generating HP-Exo-CBD-TAT, to enhance brain targeting. Intranasal administration of HP-Exo-CBD-TAT significantly improved BBB penetration and brain accumulation compared to unmodified CBD-loaded exosomes (HPExo-CBD). In mouse models of METH addiction, treatment with HP-Exo-CBD-TAT markedly attenuated behavioral sensitization and conditioned place preference (CPP), two key indicators of addiction-like behaviors. The observed therapeutic effects correlated strongly with reductions in microglial activation and pro-inflammatory cytokine expression (interleukin-1 8 (IL-1 8), IL-6, tumor necrosis factor- alpha (TNF- alpha)) in critical addiction-associated brain regions, such as the medial prefrontal cortex and ventral tegmental area. Importantly, even the carrier alone (HP-Exo-TAT) exhibited intrinsic immunomodulatory effects, underscoring the dual therapeutic action of this delivery system. Our findings highlight HP-Exo-CBD-TAT as a highly efficient, biocompatible, and non-invasive strategy that effectively targets neuroinflammation and addictive behaviors. This intranasal exosomal platform demonstrates significant translational promise for the clinical management of METH addiction. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Classic serotonergic psychedelics-such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT)-hold remarkable promise for treating neuropsychiatric disorders, yet their clinical translation is severely constrained by first-pass metabolism, erratic pharmacokinetics, unsuitable action profiles, and off-target peripheral serotonin effects. To overcome these barriers, advanced delivery systemssuch as transdermal and microneedle patches, intranasal sprays, sublingual films, and injectable formulationshave been developed, alongside molecular strategies including prodrugs, "off-switch" 5-HT receptor antagonists for session control, selective receptor bias, and adjunctive pharmacological approaches. These innovations help bypass hepatic metabolism, enable precise control over onset and duration of action, and minimize peripheral receptor activation. Preclinical and early clinical evidence shows gains in bioavailability, half-life extension, and conversion of fleeting psychedelic effects into manageable windows. These platforms offer a path to safer, patient-centered therapies. Despite regulatory and trial-design challenges, delivery innovations provide the essential pharmacokinetic toolkit to advance the field and clinical adoption.

Ionizing radiation inflicts lethal double-strand DNA breaks and oxidative stress that underlie acute radiation syndrome, secondary malignancies, and dose-limiting toxicity in radiotherapy; yet the conventional armamentarium of radioprotectants—aminothiols, broad-spectrum antioxidants, cytokines, and superoxide-dismutase mimetics—yields only modest benefit because of narrow therapeutic windows, systemic toxicity, and inadequate protection of radiosensitive tissues. In striking contrast, tardigrades (phylum Tardigrada) routinely endure exposures beyond 5 kGy by deploying a multifaceted defense repertoire that includes genome-shielding proteins such as damage suppressor (Dsup) and Tardigrade DNA-Repair protein 1 (TDR1), families of intrinsically disordered proteins that vitrify cytoplasm and scavenge radicals, antioxidant pigments acquired via horizontal gene transfer, and exceptionally efficient DNA-repair and redox networks. Viewing radioprotection through a translational pharmacology lens reveals a pipeline of emerging modalities—including recombinant or cell-penetrating proteins, mRNA therapeutics, peptidomimetics, and biomimetic nanomaterials—while also spotlighting critical hurdles of scalable bioprocessing, macromolecule stability, immunogenicity, and targeted delivery. By integrating insights from extremophile biology with cutting-edge drug-discovery platforms, tardigrade-inspired interventions promise to safeguard healthy tissue during cancer treatment, reduce casualties in nuclear accidents, and shield astronauts on deep-space missions, thereby redefining the future landscape of radioprotection and transforming an evolutionary curiosity into a potent arsenal of medical countermeasures.

Glycosylation and RNA modifications are fundamental processes in cellular biology.Glycosylation has been a subject of inter-est since the early 20th century,begin-ning with studies on ovalbumin,which eventually led to the discovery of N-glycosylation.The term"glycobiology"was first coined in the late 1980s to reflect the growing understanding of the cell and molecular biology of glycans,particularly their conjugates with pro-teins and lipids.In parallel,RNA mod-ifications began to be elucidated,with pseudouridine being discovered in 1951,shortly after the structure of RNA was understood(Cohn and Volkin,1951).

Despite the long history of Traditional Chinese Medicine (TCM) in disease treatment, the underlying "Jun-Chen-Zuo-Shi" principle remains largely unexplored. To address this gap, it is essential to elucidate the interactions between active substances in TCM through quantitative molecular and cellular pharmacology. The Chou-Talalay method is particularly effective for investigating drug combinations, making it highly relevant for TCM formulas. This study employed the Chou-Talalay method to explore the drug-drug interactions in Xuebijing (XBJ), a TCM formula used for treating sepsis. The aim was to elucidate the "Jun-Chen-Zuo-Shi" principle by investigating the interactions of the main active substances in XBJ: danshensu and salvianolic acid B (from Radix Salviae Miltiorrhizae), senkyunolide A (from Rhizoma Chuanxiong), ligustilide (from Radix Angelicae Sinensis), safflower yellow and hydroxysafflor yellow A (from Flos Carthami), and paeoniflorin (from Radix Paeoniae Rubra). We quantitatively analyzed their TLR4 antagonistic activities and used the combination index (CI) to quantify their interactions, revealing synergism (CI < 1), additive effects (CI = 1), and antagonism (CI > 1). The results show these agents inhibit nitric oxide (NO) production, with some combinations demonstrating synergistic effects at certain concentrations, while others present antagonistic effects. Understanding these interactions provides a scientific foundation for optimizing TCM formulations, enhancing quality control, efficacy, and safety.

Anorexia nervosa (AN) is a severe psychiatric disorder characterized by extreme food restriction, an intense fear of weight gain, and a distorted body image, leading to significant morbidity and mortality. Conventional treatments such as cognitive-behavioral therapy (CBT) and pharmacotherapy often prove inadequate, especially in severe cases, highlighting the need for novel therapeutic approaches. Recent research into psychedelics, such as psilocybin and 3,4-methylenedioxymethamphetamine (MDMA), offers promising avenues for treating anorexia nervosa by targeting its neurobiological and psychological underpinnings. These psychedelics disrupt maladaptive neural circuits, enhance cognitive flexibility, and facilitate emotional processing, offering potential relief for patients unresponsive to traditional therapies. Early studies have shown positive outcomes with psychedelics, including reductions in anorexia nervosa symptoms and improvements in psychological well-being. However, further research is needed to establish their long-term safety, efficacy, and integration into clinical practice. Addressing the legal, ethical, and safety challenges will be crucial in determining whether psychedelics can transform the treatment landscape for anorexia nervosa and other eating disorders.

Membrane curvature is a fundamental biophysical property that regulates the spatial organization, conformation and function of membrane-associated proteins, playing a crucial part in cellular signaling, material transport and membrane remodeling. Recent advances in imaging and computational technologies have deepened our understanding of the mechanisms driving membrane curvature and its influence on membrane protein function. In this review, we explore the key determinants of membrane curvature, its influence on the structure, function, localization, aggregation and dissociation of membrane proteins, and the experimental and computational strategies employed to investigate these interactions. Additionally, we discuss the therapeutic potential of targeting membrane curvature for disease treatment and outline current challenges and future research directions.

Psychedelics including psilocybin, dimethyltryptamine, and lysergic acid diethylamide are known to disrupt the normal flow of time perception, for example, producing time dilation, compression, and loss of time. These temporal anomalies provide interesting clues about how the brain processes time, what consciousness is, and what produces the sense of self. This opinion article discusses the neural mechanisms of time perception altered by psychedelics by integrating emerging research findings in cognitive neuroscience and subjective effects. We suggest that the psychedelic-induced time warp can offer a new approach to studying brain correlates of the perception of the passage of time and conscious perception of time, and may have potential therapeutic value in psychiatric disorders in which altered perception of time is core, such as posttraumatic stress disorder, depression, and anxiety. Through examining these time changes, we discuss the potential of psychedelics in shaping transformative cognitive-affective states and their relevance for clinical applications.

Classic psychedelics and the gut microbiome interact bidirectionally through mechanisms involving 5-HT2A receptor signaling, neuroplasticity, and microbial metabolism. This viewpoint highlights how psychedelics may reshape microbiota and how microbes influence psychedelic efficacy, proposing microbiome-informed strategies─such as probiotics or dietary interventions─to personalize and enhance psychedelic-based mental health therapies.

Toll-like receptors (TLRs) are important players in the innate immune system. Binding of pathogen-related molecules to the extracellular domains of TLRs initiates signalosome assembly, a key event in signal transduction. Despite extensive research on individual receptor domains, the mechanism of signalosome assembly remains unclear. Recent evidence suggests that the intracellular TIR domain of TLR1 binds zinc ions, with cysteines playing a pivotal role in binding and receptor activation. This study explores the zinc-binding ability of the TLR2 TIR domain (TLR2TIR). We found that TLR2TIR binds zinc with nanomolar affinity through its cysteine residues. Two of them, C673 and C713, are essential for receptor activation. These results suggest that zinc may be involved in the initiation of signalosome assembly.

Cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, is renowned for its nonpsychoactive properties and therapeutic potential. However, its clinical application is limited by nonselective cytotoxicity, affecting microglia, oligodendrocytes, and other cells. To address this, subcellular organelle-targeting strategies were explored to minimize off-target effects and enhance CBD's therapeutic index. Three organelle-specific conjugates targeting mitochondria, endoplasmic reticulum, and lysosomes were synthesized. Among these, the mitochondria-targeting triphenylphosphonium (TPP)-modified CBD conjugates demonstrated reduced cytotoxicity and enhanced anti-inflammatory activity. Further optimization identified a four-carbon ether chain linker (CBD-TPP-C4) that increased antineuroinflammatory activity by 3-fold and reduced cytotoxicity by 1.6-fold, compared to unmodified CBD. CBD-TPP-C4 also elevated mitochondrial ATP levels in vitro, improved mitochondrial morphology and locomotor function in Caenorhabditis elegans, and potentiated morphine analgesia in mice. These findings highlight subcellular targeting as a promising strategy to enhance CBD's safety and efficacy, paving the way for improved therapeutic applications.

Cannabidiol (CBD), a non-psychoactive cannabinoid, shows great promise in treating methamphetamine (METH) addiction. Nonetheless, the molecular target and the mechanism through which CBD treats METH addiction remain unexplored. Herein, CBD was shown to counteract METH-induced locomotor sensitization and conditioned place preference. Additionally, CBD mitigated the adverse effects of METH, such as cristae loss, a decline in ATP content, and a reduction in membrane potential. Employing an activity-based protein profiling approach, a target fishing strategy was used to uncover CBD's direct target. ATP5A1, a subunit of ATP synthase, was identified and validated as a CBD target. Moreover, CBD demonstrated the ability to ameliorate METH-induced ubiquitination of ATP5A1 via the D376 residue, thereby reversing the METH-induced reduction of ATP5A1 and promoting the assembly of ATP synthase. Pharmacological inhibition of the ATP efflux channel pannexin 1, blockade of ATP hydrolysis by a CD39 inhibitor, and blocking the adenosine A1 receptor (A1R) all attenuated the therapeutic benefits of CBD in mitigating METH-induced behavioral sensitization and CPP. Moreover, the RNA interference of ATP5A1 in the ventral tegmental area resulted in the reversal of CBD's therapeutic efficacy against METH addiction. Collectively, these data show that ATP5A1 is a target for CBD to inhibit METH-induced addiction behaviors through the ADO-A1R signaling pathway.