Pancreatic ductal adenocarcinoma (PDAC) remains a formidable malignancy characterized by late diagnosis, high recurrence rates, and pronounced chemoresistance. While nanoparticle-based drug delivery systems (NDDS) offer theoretical advantages over conventional therapies, their clinical translation in PDAC has been severely limited. The dense desmoplastic stroma, elevated interstitial fluid pressure, and hypovascularity effectively neutralize the enhanced permeability and retention (EPR) effect, restricting passive nanoparticle penetration. Consequently, the therapeutic paradigm is shifting from indiscriminate stromal depletion-which paradoxically accelerates metastasis-to stromal normalization and immune microenvironment reprogramming. This review comprehensively evaluates advanced NDDS platforms, highlighting transcytosis-triggering active targeting, stimuli-responsive carriers, and multimodal theranostic systems designed to bypass physical barriers and convert immunologically "cold" tumors to "hot." Furthermore, we analyze the expanding role of artificial intelligence (AI) and machine learning in predicting synergistic drug combinations and optimizing nanoparticle physicochemical properties. Crucially, we critique current epistemic limitations in AI-driven nanomedicine, particularly data sparsity and the reliance on 2D preclinical models, emphasizing the necessity of 3D patient-derived organoid validation. By integrating rational NDDS design with AI and biomarker-driven strategies, this review maps the essential pathways toward personalized nanotherapeutics for PDAC.
Parkinson's disease (PD) is increasingly recognized not merely as a localized proteinopathy, but as a systemic metabolic disorder driven by bioenergetic failure. While mitochondrial dysfunction is a well-established pathological hallmark, the compensatory reprogramming of glycolysis has emerged as a critical, yet double-edged, determinant of neuronal survival. This review critically examines the molecular and spatial architecture of glucose metabolism in the parkinsonian brain. We systematically dissect how upstream genetic regulators, including PTEN and PARK7/DJ-1, alongside downstream rate-limiting enzymes orchestrate the glycolytic shift in response to mitochondrial collapse and α-synuclein proteotoxicity. Moving beyond a neuron-centric view, we highlight cell-specific metabolic compartmentalization, emphasizing the disruption of the astrocyte-neuron lactate shuttle and the divergent glycolytic phenotypes of reactive microglia. Crucially, we evaluate the dual nature of glycolytic metabolites by demonstrating that a moderate flux sustains basal energy requirements and prevents apoptosis, whereas unchecked hyperglycolysis drives secondary pathological cascades through methylglyoxal-induced protein crosslinking and lactate-mediated neuroinflammation. By bridging these mechanistic insights with cross-disease metabolic links to type 2 diabetes and oncology, we evaluate the therapeutic potential of emerging metabolic modulators, including terazosin, cordycepin, and GLP-1 receptor agonists. Finally, we outline the pressing translational bottlenecks, particularly blood-brain barrier penetrance and cell-specific targeting, which must be overcome to successfully harness glycolytic modulation as a disease-modifying strategy for neurodegenerative disorders.
The saturated five-membered pyrrolidine ring is a privileged scaffold in medicinal chemistry. There is great interest in the pyrrolidine skeleton due to several key characteristics of this heterocyclic ring: its sp3 hybridized carbon framework, the contribution of multiple chiral centers, and the inherent planarization of the ring, typically manifested as conformational flexibility or pseudorotation. These characteristics make pyrrolidine-based structures highly attractive in the drug design for various biological targets. The pyrrolidine moiety also enhances drug-like properties such as metabolic stability, water solubility, and modulation of basicity, and can interact favorably with a wide range of biological targets through specific stereochemical interactions. This review surveys the synthesis and clinical applications of FDA-approved pyrrolidine-containing drugs since 2014, with the aim of informing the rational design of next-generation pyrrolidine-based therapeutics.
G-protein-coupled receptors (GPCRs) represent a compelling intersection of structural biology, systems pharmacology, and clinical medicine. They function as essential molecular regulators of cardiovascular physiology, governing processes from the initiation of cardiac rhythm in the sinoatrial node to the regulation of vascular tone. Their widespread expression in cardiac and vascular tissues, combined with their ability to integrate diverse extracellular signals, positions GPCRs as key regulators of heart rate, contractility, vascular tone, inflammation, and metabolic homeostasis. Recent advances in GPCR structural biology, coupled with mechanistic insights into G-protein- and β-arrestin-mediated signaling mechanisms, underscore their central role in both cardiovascular health and disease. Notably, dysregulation of GPCR signaling has emerged as a unifying mechanism across major cardiovascular diseases (CVDs), contributing to pathological remodeling, impaired contractile function, and maladaptive vascular responses. This review uniquely integrates GPCR structural biology, signaling dynamics, and mechanosensitive and biased signaling mechanisms within the cardiovascular system. We discuss the contributions of class A, class B, and other GPCR families to cardiovascular physiology and pathology emphasizing their relevance to the development of targeted interventions for hypertension, heart failure, arrhythmias, atherosclerosis, and related CVDs. Together, these insights establish a contemporary framework for advancing precision GPCR-directed therapies in CVDs. By framing these developments within a mechanistic and translational context, the review offers a timely and clinically significant resource for both basic researchers and clinicians.
The rise of antimicrobial resistance (AMR) poses a critical threat to global health, mostly due to the proliferation of β-lactamases, a class of enzymes responsible for the inactivation of β-lactam antibiotics. Among the most promising strategies to restore β-lactam efficacy is the use of β-lactamase inhibitors (BLIs), with boronic acid derivatives emerging as a pivotal and chemically versatile class. These compounds act as transition-state analogs, forming reversible covalent bonds with the catalytic serine of serine β-lactamases (SBLs), effectively mimicking the tetrahedral intermediate of β-lactam hydrolysis. Their electron-deficient boron atom, combined with a tunable scaffold, allows fine modulation of potency, selectivity, and pharmacokinetic properties. This review traces the evolution of boronic acid-based BLIs from early phenylboronic acids to next-generation acyclic and cyclic derivatives, highlighting key structure-activity relationships, binding mechanisms, and microbiological profiles. Clinically approved agents such as vaborbactam, as well as investigational compounds including taniborbactam, xeruborbactam, and benzoxaboroles, are discussed in the context of their therapeutic relevance and spectrum of activity. Particular attention is given to their ability to inhibit class A and C enzymes, with ongoing efforts aimed at extending coverage to class D and metallo-β-lactamases. Additionally, the review explores innovative approaches such as kinetic target-guided synthesis and fragment-based design to expand the chemical space of boronic acid pharmacophores. Together, these advances underscore the potential of boronic acid-based BLIs as powerful tools in overcoming β-lactamase-mediated resistance and developing next-generation antimicrobial therapies.
Natural products (NPs) have historically yielded numerous therapeutic agents, yet their integration into modern drug discovery has been constrained by chemical complexity, low abundance, laborious dereplication, and limited target annotation. Convergence of multi-omics technologies with high-resolution structural and biological data has created unprecedented opportunities for artificial intelligence (AI) to accelerate NP-based therapeutics development. This review provides an operational, end-to-end workflow that explicitly connects computational predictions to medicinal chemistry decision points, addressing a critical gap between computational prediction and clinical translation. We trace the complete discovery pipeline: computational mining of biosynthetic gene clusters (BGCs) and metabolomes, deep learning (DL)-assisted structural elucidation and dereplication, network-based target identification using protein-ligand prediction, and generative molecular design inspired by NP scaffolds (including large language models, diffusion models, and genetic algorithms). Critical evaluation of current limitations (data scarcity, lack of standardized ontologies, model interpretability) is complemented by discussion of emergent strategies (foundation models trained on multi-modal data, graph neural networks, autonomous closed-loop laboratories). Representative case studies, including the synthetic AI-designed clinical benchmark rentosertib, illustrate the current evidence spectrum from discovery-level validation to early clinical benchmarking, while also highlighting that most AI-enabled NP discovery workflows remain at the preclinical or proof-of-concept stage, with limited quantitative evidence of improved clinical productivity. We conclude with an Outlook proposing feasible developments for 2025-2030: self-driving laboratories with reported acceleration in specific experimental contexts, foundation models enabling hypothesis-free chemical space exploration, and sustainability-aware AI frameworks embedding biodiversity impact assessments. This operational focus fills a critical gap between algorithmic capability and clinically actionable NP-derived leads. Importantly, while AI has demonstrably accelerated several early discovery steps, quantitative comparisons with classical NP workflows remain limited, and most reported advances are supported by preclinical or proof-of-concept studies rather than systematic evidence of improved time-to-lead, cost reduction, or clinical success rates.
Glycogen synthase kinase-3 (GSK-3) is a central regulator of numerous cellular signaling pathways, with critical roles in metabolism, proliferation, differentiation, and tissue regeneration. This review explores the multifaceted effects of pharmacological GSK-3 inhibition across multiple body districts, focusing on its highly context-dependent impact. It has been proven that blocking GSK-3 promotes embryonic stem cell self-renewal, neuronal differentiation, osteogenesis, and dentinogenesis, while it has an inhibitory effect on adipogenesis. GSK-3 inhibition effects on muscle, heart, liver, and skin are more complex and often contradictory, influenced by critical factors, such as dosage, timing of administration, cellular microenvironment, and isoform specificity (GSK-3α vs. GSK-3β). A dual role also emerges in fibrosis and epithelial-mesenchymal transition processes, where GSK-3 inhibition can either have a suppressive or promoting role. Despite its promising therapeutic potential in regenerative medicine, clinical translation is still hindered by its contradictory effects in some tissues, the need for fine-tuned treatment regimens, and the lack of isoform-specific inhibitors. Selective targeting approaches and robust preclinical studies are thus essential to fully harness the therapeutic potential of GSK-3 modulation.
The global burden of multidrug-resistant tuberculosis (MDR-TB) and the rising incidence of nontuberculous mycobacterial (NTM) infections highlight the urgent need for innovative therapeutic strategies. Current treatments are prolonged, toxic, and increasingly compromised by resistance and limited diagnostic capacity. This review focuses on emerging therapeutic strategies against Mycobacterium tuberculosis (Mtb) and highlights evidence relevant to NTM whenever available. Specifically, it explores direct anti-mycobacterial small molecules, including the optimization of drug classes, such as hydrazide-hydrazones, isoniazid derivatives, nitrofurans, multicomponent forms, and metal complexes, as well as emerging chemical entities in early-stage development. These compounds target essential bacterial enzymes such as decaprenylphosphoryl-β-d-ribose oxidase (DprE1), enoyl acyl carrier protein reductase (InhA), and deoxyribonucleic acid (DNA) gyrase inhibitors, offering promising avenues for overcoming resistance. The review also examines natural products and phytochemicals, including siderophore inhibitors, plant-derived compounds, and essential oils. Non-classical strategies such as antimicrobial peptides (AMPs) and phage therapy are also discussed. Finally, we discuss the expanding field of host-directed therapies (HDTs), which aim to modulate the host immune response to enhance mycobacterial clearance and reduce tissue damage. Ultimately, advancing mycobacterial treatment will require integrated, mechanism-based regimens that combine new compounds with HDTs and improved delivery systems. Although therapeutic innovation for NTM has lagged, adapting promising TB-focused compounds and implementing NTM-specific screening and validation frameworks are essential. Collaborative efforts across academia, industry, and the public health sector will be key to translating these advances into shorter, safer, and more effective therapies that address the complexity of mycobacterial disease and the rise of antimicrobial resistance.
Immune checkpoint inhibitors and adoptive cell therapies have revolutionized cancer treatment, yet their success is accompanied by immune-related hepatotoxicity that can range from asymptomatic enzyme elevation to life-threatening liver failure. Unlike conventional drug-induced liver injury, immune-mediated hepatotoxicity arises from complex, therapy-specific mechanisms that remain incompletely understood, creating critical knowledge gaps in risk prediction and prevention. This review incorporates current evidence on the clinical presentation, mechanistic pathways, and risk factors underlying hepatotoxicity across major immune and cell therapy platforms, with emphasis on translating mechanistic insights into actionable management strategies. We systematically examine hepatotoxicity patterns for immune checkpoint inhibitors, CAR-T cell therapies, bispecific T-cell engagers, and tumor-infiltrating lymphocyte therapy, integrating clinical trial data, real-world evidence, and mechanistic studies. Our analysis shows distinct injury mechanisms: T-cell-mediated hepatocyte destruction following checkpoint blockade, cytokine-driven bystander injury during cytokine release syndrome, and emerging on-target/off-tumor toxicity from engineered lymphocytes. Critical risk modifiers include pre-existing liver disease, concomitant hepatotoxic medications, gut microbiome dysbiosis from antibiotic exposure, and host pharmacogenomic variation. We propose three priority research directions: development of predictive biomarkers enabling pretreatment risk stratification, microbiome-directed interventions to preserve hepatic immune tolerance, and implementation of Safety-by-Design engineering strategies that integrate hepatotoxicity prevention into therapeutic design. This review provides a mechanistic framework for transitioning from reactive toxicity management to predictive, personalized prevention, essential for maximizing the therapeutic potential of immune and cell therapies while protecting patient safety in this rapidly expanding treatment landscape.
Hydrogels have been widely used in tissue engineering due to their high-water content and biocompatibility, yet their densely cross-linked microstructure inherently limits cell infiltration, mass transport, and mechanical support. Cryogels, formed through partial freezing and crosslinking under subzero conditions, provide unique 3D macroporous networks with excellent permeability, elasticity, and shape-memory behavior. These structural and mechanical advantages facilitate cell migration and angiogenesis, while enabling minimally invasive delivery via syringe injection and highlighting strong translational potential. In musculoskeletal tissues such as bone, cartilage, and skeletal muscle, which have distinct biomechanical requirements, cryogels allow precise control over pore size, anisotropy, hierarchical architecture, and stiffness to better emulate native functionalities. Furthermore, tunable chemical composition and surface cues enable enhanced cell-matrix interactions and biological responsiveness. In addition, recent advances that incorporate growth factors, cells, nanomaterials, and conductive or immunomodulatory elements have established cryogels as therapeutic platforms that actively contribute to regeneration. These advancements further reinforce their clinical applicability and impact. This review summarizes the principles of cryogelation, crosslinking mechanisms, and structure-property relationships and examines recent cryogel-based strategies for musculoskeletal regeneration. By comparing fabrication parameters and their regenerative outcomes, we provide engineering insights for tissue-specific scaffold design and future optimization of cryogel-based musculoskeletal repair platforms.
ABSTRACT Cysteine‐aspartic protease‐1 (Caspase‐1), the terminal effector of canonical inflammasome signaling, represents a validated yet pharmacologically underexploited target at the convergence of inflammatory pathology and pyroptotic cell death. Although three peptide‐based inhibitors—Ac‐YVAD‐CMK, Z‐YVAD‐FMK, and Ac‐YVAD‐CHO—have long served as prototypical experimental standards, their structural determinants, structure‐activity relationships, and developmental liabilities have not been systematically reassessed from a medicinal chemistry perspective. Integrating evidence from 144 studies (2015–2025), this review rigorously interrogates these archetypal scaffolds as both pharmacological probes and foundational templates for inhibitor design. We delineate how C‐terminal warhead chemistry (chloromethyl ketone, fluoromethyl ketone, and aldehyde) dictates covalency, reversibility, and kinetic selectivity, while N‐terminal capping strategies modulate membrane permeability, metabolic stability, and systemic exposure. By correlating chemical architecture with caspase selectivity, off‐target engagement, and context‐dependent efficacy across inflammatory, infectious, autoimmune, and oncologic models, we define structure‐kinetics‐pharmacology relationships that govern selectivity, durability, and in vivo predictability. Persistent barriers—including inadequate pharmacokinetic characterization, metabolic fragility, broad caspase cross‐reactivity, and limited scaffold diversification—are identified as principal impediments to the clinical translation of all three prototypical inhibitors. By repositioning these legacy peptide inhibitors as foundational chemical templates for translational optimization, this synthesis establishes design principles centered on kinetic selectivity, rational warhead refinement, and context‐guided optimization, and outlines strategic pathways for the development of selective, clinically viable Caspase‐1‐targeted therapeutics.
ABSTRACT The extracellular signal‐regulated kinases 1 and 2 (ERK1/2) play central roles in the mitogen‐activated protein kinase (MAPK) pathway and have emerged as critical regulators of tumorigenesis. Aberrant ERK1/2 signaling is frequently observed in cancers such as melanoma, pancreatic cancer, and colorectal cancer. This review outlines the historical milestones in ERK1/2 research, from their discovery and structural characterization to their identification as oncogenic drivers and therapeutic targets. We detail the ERK1/2 signaling network, highlighting key upstream regulators, including rat sarcoma (RAS), rapidly accelerated fibrosarcoma (RAF), and mitogen‐activated protein kinase kinase (MEK), along with downstream substrates that mediate diverse oncogenic processes. Therapeutic approaches aimed at ERK1/2 currently fall into two main classes: small‐molecule inhibitors with single‐target specificity and those designed to simultaneously act on dual targets, along with combination therapies designed to overcome resistance and improve efficacy. Furthermore, we explore innovative approaches, including proteolysis‐targeting chimeras (PROTACs), autophagy‐targeting chimeras (AUTACs), and antibody‐drug conjugates (ADCs), which offer promising avenues for selectively modulating ERK1/2 activity. By integrating mechanistic insights with clinical development trends, this review underscores the potential of ERK1/2‐targeted therapies in precision oncology.
Monoacylglycerol lipase (MAGL), a member of the endocannabinoid system (ECS), plays a crucial role in physiological processes such as regulating the signal transduction of the ECS and the eicosanoid system. In recent years, MAGL has been validated as a potential therapeutic target for several human diseases. Small-molecule MAGL inhibitors have shown considerable promise for the treatment of neurodegenerative diseases, depression, and cancer, with several candidates having advanced to clinical trials. This review briefly outlines the structural features and physiological functions of MAGL, highlights the associations between MAGL and human diseases, and systematically discusses small-molecule MAGL inhibitors developed for different disorders, with the goal of providing a reference for the discovery of more potent MAGL inhibitors.
Diabetic glaucoma, a severe microvascular and neurodegenerative complication of diabetes, involves complex pathological mechanisms including chronic hyperglycemia‑induced oxidative stress, inflammatory responses, microcirculatory disturbances, and retinal ganglion cell (RGC) apoptosis. While conventional Western medicine has achieved significant success in intraocular pressure (IOP) control, it faces challenges in providing long‑term neuroprotection and delaying disease progression. Traditional Chinese Medicine (TCM), guided by its holistic concept and treatment based on syndrome differentiation, demonstrates unique advantages through multi-component, multi‑target, and multi‑pathway synergistic regulation. This review systematically elucidates the TCM pathogenesis evolution pattern of "deficiency leading to stasis, ocular collateral damage" in diabetic glaucoma and establishes correlation networks between TCM syndrome types and modern pathological mechanisms. Integrating epidemiological evidence, we analyze the core mechanisms of representative Chinese herbs and formulas-including Ginkgo biloba extract, indirubin‑related components, and the Si‑Hua formula-in exerting antioxidant, anti‑inflammatory, microcirculation‑improving, and direct neuroprotective effects through regulation of key signaling pathways such as PI3K/AKT, Nrf2, and NF‑κB. Importantly, this article employs network pharmacology methods to visually present the synergistic "component‑target‑pathway" interaction network of the Si‑Hua formula, and introduces a quantitative comparison of the regulatory intensity of key herbal components on signaling pathways. We also discuss the chemical structures of major secondary metabolites from these herbs and the principles of reverse pharmacology that connect TCM to modern drug discovery. By quantitatively evaluating the regulatory intensity of key herbal components on signaling pathways and exploring the interventional potential of TCM in emerging mechanisms like ferroptosis (Figure 9), this review aims to establish a comprehensive scientific framework for TCM prevention and treatment of diabetic glaucoma, providing solid academic support for the modernization and internationalization of TCM.
Influenza A virus (IAV) continues to be one of the most serious health burdens causing widespread illness and mortality. Limited efficacy and reduced susceptibility of available drugs and vaccines to the emergence of resistant strains have spurred the pursuit of alternative treatment strategies. Hemagglutinin (HA), essential for viral attachment and membrane fusion in the first step of the virus infection cycle, has emerged as an attractive target. Over the past few decades, HA has garnered considerable attention, and significant progress has been achieved in the discovery of HA modulators, even though no anti-IAV drugs targeting HA have been approved by the FDA. This article provides a comprehensive overview of the current landscape of HA inhibitors and degraders, mainly focusing on the systematic structure-activity relationship (SAR) exploration of both synthetic and natural product (NP)-derived small molecules endowed with abundant structural frameworks, together with a brief introduction of different binding modes based on cocrystal structures of IAV HAs and HA inhibitors. We anticipate that this review will serve as practical guidance for the development of urgently needed, more effective, and structurally innovative HA-targeting drugs capable of addressing the escalating challenge of drug resistance.
The Nav1.5 channel, a major isoform of voltage-gated sodium ion channel, is mainly found in ventricular cardiomyocytes, playing a key role in generating essential cardiac action potentials for normal heart rhythms. Mutations in Nav1.5 have been associated with severe heart conditions such as long QT syndrome, Brugada syndrome, cardiac conduction disorders, atrial fibrillation, and dilated cardiomyopathy. Recent research has linked Nav1.5 to cardiac fibrosis and proposed its role in non-cardiac illnesses, including specific neurological disorders and cancers, subjects that will be reviewed in this paper. On the other hand, sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially designed to manage diabetes by facilitating glucose excretion through urine, have demonstrated unexpected and encouraging cardioprotective benefits in clinical trials. This review compares the important SGLT2 inhibitors empagliflozin, dapagliflozin, and canagliflozin in terms of their interactions with Nav1.5 and their therapeutic effects on the heart. We also investigate new medications and compounds being developed to regulate Nav1.5 function, providing a preview of potential future treatments. Past attempts to develop late INa inhibitors and difficulties in transitioning from the research phase to clinical trials have raised doubts about the optimal design of such trials. In addition, we cover the applications of molecular dynamics simulations in understanding the mechanism of action of these drugs within the Nav1.5 channel computationally. We hope that this review identifies new opportunities to generate more effective inhibitors using novel methods and advanced multiscale molecular modelling techniques.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the pathological misfolding and aggregation of α-synuclein (α-syn), which leads to dopaminergic neuronal loss and multisystem dysfunction. Conventional clinical diagnosis is often delayed until after substantial neuronal degeneration has occurred. Recent advances in α-syn seed amplification assays (α-syn SAAs), including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have revolutionized PD biomarker research. These assays exploit the prion-like seeding and propagation properties of pathological α-syn to amplify trace aggregates in biological samples with exceptional sensitivity and specificity. Here, we summarize the mechanistic principles and biophysical underpinnings of α-syn SAAs, compare their diagnostic performance across biospecimens such as cerebrospinal fluid, skin, blood, and saliva, and evaluate their potential for differential diagnosis among synucleinopathies. We further discuss the integration of SAAs with other biomarkers including α-syn oligomer ELISAs, neurofilament light chain assays, and dopaminergic PET/SPECT imaging. Emerging developments, such as same-day RT-QuIC, quantitative kinetic readouts, and peripheral blood-based assays, are accelerating clinical translation. Despite challenges in assay standardization, strain discrimination, and regulatory validation, α-syn SAAs hold transformative potential for early diagnosis, patient stratification, and monitoring of therapeutic efficacy in PD. Their convergence with artificial intelligence, organoid modeling, and multimodal biomarker frameworks promises to redefine precision medicine in PD and other synucleinopathies.
Chitinase-3-like-1 (CHI3L1, also known as YKL-40) has been recognized as a biomarker of inflammation and tissue remodeling and has now emerged as a pseudoenzymatic immune checkpoint. Recent structural, immunological, and translational studies redefine it as an active regulator of immune suppression rather than a passive disease marker. Despite lacking catalytic activity, CHI3L1's conserved chitinase fold and glycan-decorated surface acts as a modular scaffold linking cytokine, metabolic, and stress signals to immune suppression and fibrotic remodeling. Through its chitinase-like structure it engages with receptor triad complex, including IL-13Rα2, TMEM219, and Galectin-3, activating signaling pathways such as MAPK, PI3K/AKT, and TGF-β/Smad. Through these interactions, CHI3L1 has been reported to promote fibroblast activation, angiogenesis, and immune suppression, creating environments where immune cells are excluded or silenced. These checkpoint-like effects are not limited to cancer; they also appear in fibrosis, infection, and neuroinflammatory diseases, linking CHI3L1 to a broad spectrum of immune-resistant conditions. This review integrates structural glycobiology, receptor pharmacology, and immunometabolic mechanisms to reveal CHI3L1 as a unifying regulator of stromal-immune crosstalk. It further highlights preclinical and clinical evidence demonstrating that antibody, RNA-based, and small-molecule inhibitors of CHI3L1 restore immune surveillance and limit pathological remodeling. Targeting this pseudoenzymatic checkpoint alongside canonical PD-1 and CTLA-4 blockade represents a promising strategy to overcome immune resistance and normalize pathogenic tissue remodeling across diverse diseases.
Synthetic cannabinoids (SCBs) represent a rapidly expanding and chemically diverse class of new psychoactive substances, deliberately designed to mimic the effects of natural cannabis. However, their high potency and full agonism at cannabinoid receptors lead to severe public health risks. The primary mechanism of SCBs' action involves the robust activation of CB1 and CB2 receptors, which in turn trigger a cascade of downstream events. This includes the profound dysregulation of key neurotransmitter systems, critical ion channel functions, and essential intracellular signaling pathways, culminating in widespread cellular dysfunction and damage. This comprehensive review delves into the multifaceted pathogenesis through which SCBs induce systemic harm. It systematically examines the clinical evidence and molecular mechanisms that connect SCB exposure to a spectrum of adverse outcomes, including life-threatening cardiovascular toxicities, significant neurological and psychiatric disorders, respiratory system diseases, digestive system diseases, and nephrotoxicity, and so forth. The point of this review, elucidating the intricate mechanisms underlying SCB toxicity, will be crucial, as this knowledge is the key to unlocking targeted therapies and effectively mitigating the severe health consequences of their abuse.
