Abstract The heterodimeric amino acid transporter L-type amino acid transporter 1 (LAT1)-4F2hc (SLC7A5-SLC3A2) is a key regulator of large neutral amino acid exchange, linking extracellular nutrient availability to intracellular growth signaling. It is physiologically enriched at the blood-brain barrier (BBB) and in proliferative tissues but is broadly upregulated in cancer, where it supports metabolic reprogramming and mechanistic target of rapamycin complex 1 (mTORC1)-driven oncogenic growth. These properties make LAT1-4F2hc both a metabolic vulnerability in tumors and a promising gateway for central nervous system (CNS) drug delivery. Recent cryo-electron microscopy (cryo-EM) structures have resolved LAT1-4F2hc in multiple conformational states, defining its alternating-access mechanism, substrate recognition determinants, and allosteric gating network. These insights have enabled structure-guided, conformation-selective drug design, yielding substrate-mimetic inhibitors and state-stabilizing compounds such as JPH203 (nanvuranlat), now in clinical evaluation. Conversely, the same transport cycle can be exploited at the BBB to enhance brain delivery of LAT1-utilizing prodrugs, including l -dihydroxyphenylalanine (L-DOPA) and emerging therapeutic conjugates. Here, we integrate structural biology, nutrient sensing, and pharmacology to highlight conformational targeting strategies for both anticancer therapy and CNS drug delivery, and discuss key translational challenges such as metabolic compensation, selectivity, and pharmacokinetics.
Traditional disease screening methods often rely on protein biomarkers or imaging, which are somewhat constrained by their sensitivity, invasiveness, and limitation in detecting diseases at earlier stages. To achieve both noninvasive and early warning of diseases or physiology change, monitoring gaseous biomarkers such as volatile organic compounds (VOCs) and nitric oxide (NO) in exhaled breath is a promising solution. It has been demonstrated that these biomarkers as a group change rapidly in response to alterations in human physiology, which allows rapid noninvasive earlier screenings of asthma, lung cancer, coronavirus disease 2019 (COVID-19) and other diseases. Interestingly, this has also been demonstrated for real-time monitoring of air toxicity by resolving rats' breath-borne biomarkers. Here, we propose the use of artificial intelligence (AI) and breath-borne gaseous biomarkers to construct the "fingerprint pattern" of a specific disease or certain environmental hazards for early warning.
The tumor invasive front is a critical interface for tumor-host interactions that impacts patient prognosis. Although the tumor-node-metastasis (TNM) staging system and single-parameter assessments such as tumor budding, T-cell density, tertiary lymphoid structures (TLS), and stromal features provide important prognostic information, they capture only partial aspects of this spatially organized tumor-host interface. Inspired by the traditional Chinese medicine concept of "Huchang", used here as a metaphorical descriptor of host-protective organization at the tumor boundary, and informed by recent advances in spatial immunology, we propose the Huchang-Barrier (HB) framework. HB conceptualizes the invasive front as a dynamic tumor-host interface whose biological state is determined by the balance between tumor invasive burden and host physical/tissue and spatial immune barriers. Unlike fixed single-marker scores or tumor-type-specific microenvironmental indices, HB integrates three conserved functional elements while allowing cancer-adapted readouts, thereby providing a modular framework for evaluating the invasion-barrier balance at the invasive front. To improve operability, we outline a two-tier assessment strategy and provide a minimal executable HB-Standard example in resected non-small cell lung cancer (NSCLC). The HB framework is proposed as a hypothesis-generating spatial pathology model that requires retrospective calibration, independent validation, and prospective testing before clinical implementation.
Malignant tumors have long been viewed as uncontrolled cell proliferation driven by somatic mutations. However, emerging multi-omics and microenvironment evidence challenges this paradigm. Advanced tumors transcend cellular abnormality to form a "neoorgan" - a complex tissue ecosystem with multicellular coordination, functional autonomy, metabolic symbiosis, neural integration, and evolutionary potential. Genomic instability generates lineage-specific karyotypes; tumors reactivate ancient gene modules from primitive multicellular organisms; they actively remodel immune function via mitochondrial transfer; and they establish functional connections with the nervous system. Based on this evolutionary trajectory, we propose testable predictions: tumors may progress from a parasitic neoorgan toward an independent species, as exemplified by naturally occurring transmissible tumors and the "tumor-derived animal" hypothesis. Recognizing cancer as an evolutionary entity striving for independence - rather than a mere genetic malfunction - demands a fundamental shift in therapeutic strategy. Instead of solely cytotoxic "killing", rational approaches may aim to reintegrate the tumor into host regulatory networks or guide its evolution toward self-destruction. This framework expands tumor biology and challenges conventional boundaries between disease, life, and species.
Abstract The vast majority of environmental microorganisms remain recalcitrant to culture under standard laboratory conditions, posing a long-standing and bottleneck in exploring microbial biodiversity and harnessing their metabolic potential for biotechnological and clinical applications. This review synthesizes state-of-the-art breakthroughs in combining advanced cell sorting platforms – including fluorescence-activated cell sorting (FACS), droplet microfluidics, polymerase chain reaction (PCR)-activated sorting, magnetic-activated systems, and novel label-free artificial intelligence (AI)-driven sorting technologies – with innovative in situ culture approaches such as diffusion chambers, isolation chips (iChip), and droplet-based microfluidic culture, and 3D bioprinting-assisted niche simulation. By coupling high-resolution, viability-preserving sorting strategies with culture devices that faithfully replicate the native ecological niches (including physicochemical gradients, symbiotic interactions, and nutrient dynamics), these integrated workflows dramatically enhance the recovery of previously uncultured microbes that constitute the so-called microbial “dark matter”. Besides, emerging trends such as machine learning-guided medium optimization, automated high-throughput culture pipelines, and single-cell culture-transfer methods and spatial omics-integrated culture monitoring are highlighted as transformative tools for next-generation microbiology. In conclusion, the combination of microbial cell sorting and cultivation technologies is a great significance for accelerating the discovery of novel antibiotics and engineered strains, as well as exploring the interaction mechanisms between microorganisms and hosts.
Bone marrow transplantation (BMT) has traditionally been viewed as a curative strategy for hematologic malignancies through replacement of the diseased hematopoietic system. However, accumulating evidence indicates that BMT represents a far more profound biological process: an enforced collapse and subsequent reconstruction of the hematopoietic and immune system. This process provides a unique human model to investigate how immune homeostasis can be reprogrammed beyond physiological conditions. Importantly, post-transplant immunity does not revert to a pre-existing state but instead converges on a newly defined equilibrium shaped by conditioning-induced injury, donor-recipient immune interactions, stromal regeneration, and therapeutic interventions. In this review, we conceptualize BMT as an immune reset and synthesize emerging insights into the mechanisms that govern tolerance reinstallation and immune stability after transplantation. By reframing BMT as a model of immune reset rather than simple immune reconstitution, we highlight general principles of immune homeostasis restoration that extend beyond transplantation and may inform therapeutic strategies for autoimmunity, immune aging, and immune-mediated diseases.
Abstract Chimeric antigen receptor (CAR) T cells have revolutionized oncology, delivering unprecedented clinical responses in patients with refractory B-cell malignancies. However, the traditional autologous paradigm – encompassing patient-specific leukapheresis, genetic modification, and extensive ex vivo expansion – imposes severe constraints on manufacturing timelines, costs, and global scalability. Allogeneic universal CAR-T (uCAR-T) reimagines this therapeutic unit as an “off-the-shelf” cellular medicine, utilizing healthy donor-derived cells produced in standardized batches to overcome the bottlenecks of individualized therapy. Over the past decade, the field has transitioned from foundational proof-of-concept studies in murine models to sophisticated early-phase human clinical trials. This review delineates the core biological and engineering principles of uCAR-T, specifically focusing on the genomic strategies employed to mitigate graft-versus-host disease (GvHD) and host-versus-graft disease (HvGD). We synthesize pivotal preclinical and clinical data alongside a comprehensive overview of the current clinical landscape. Furthermore, we highlight the primary translational hurdles remaining: ensuring durable CAR-T persistence and navigating the complexities of innate and adaptive immune rejection. We explore the potential for combination immunotherapies and specialized CAR architectures designed to penetrate solid tumors. Ultimately, uCAR-T is poised to democratize cellular immunotherapy, offering a scalable and transformative therapeutic perspective across diverse disease indications.
While maintaining absorption and physiological exchange, the gut mucosal barrier prevents microorganisms and their products from freely entering tissues and blood vessels. Therefore, its functional state can affect signals transmitted to distal organs. This review defines the gut-X axis as bidirectional communication between the intestine and extraintestinal systems, and points the intestinal barrier as a selective gatekeeper that regulates thresholds and amplifies gut-derived information flow. We summarize barrier organization, the renewal and repair mechanism to maintain the epithelial integrity under persistent exposure. We then integrate factors shaping barrier steady state, including diet, microbial metabolites, host factors and drugs. Next, we explained how barrier-regulated signal outputs disseminate through immune inflammatory mediators, neural pathways and endocrine metabolic signals, and analyzed how reverse regulation by the brain, liver, lungs and systemic metabolic state reshapes barrier responses. In neuropsychiatric, hepatic, pulmonary, and endocrine metabolic diseases, we focus on the positive feedback cycle, heterogeneity, and the ambiguity in causal direction, and evaluate treatment strategies, covering dietary intervention, microbiota-directed therapies including fecal microbiota transplantation (FMT), and pharmacologic or immunologic methods. Progress will rely on standardized intestinal barrier indicators longitudinal research design to clarify temporal relationship, and hierarchical intervention tests to verify barrier-centered causal hypotheses.
Fibrotic interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF), are characterized by an irreversible decline in lung function and high mortality. While two approved antifibrotic therapies, nintedanib and pirfenidone, have been shown to alter the disease trajectory by slowing its progression, the disease remains incurable. This review summarizes current pharmacological treatments for fibrotic interstitial lung disease (f-ILD), mainly IPF and PPF; highlights novel antifibrotic targets such as the lysophosphatidic acid (LPA) receptor; outlines the therapeutic development pipeline; and discusses emerging strategies, including personalized medicine and early intervention.
Abstract Radiotherapy (RT) has long been regarded as a local treatment modality designed to eradicate tumor cells through targeted deoxyribonucleic acid (DNA) damage and, more recently, as an in situ vaccine capable of triggering the abscopal effect. However, increasing evidence now defines RT as a systemic immune modulatory intervention that elicits both antitumor and tumor growth-promoting effects. The recently described “badscopal effect”, the paradoxical progression or growth acceleration of non-irradiated disease associated with systemic immunosuppressive and growth-factor programs initiated by the irradiated lesion, highlights that RT may, under certain inflammatory and cellular contexts, foster immune tolerance or accelerate distant disease progression. Central to this duality is the host’s capacity to integrate and balance antitumor and pro-tumor responses following RT. Unlike the relatively binary activation states often attributed to T cells, myeloid cells exhibit high plasticity, integrating signals of DNA damage, hypoxia, and tissue repair to direct the inflammatory responses that inhibit or promote tumor growth. In this review, we examine how RT induces dual inflammatory programs, as a partial explanation as to why classical abscopal models incompletely capture clinical practice and how myeloid plasticity emerges as a central determinant of systemic responses to RT, with important implications for the rational design of combination therapies.
G protein-coupled receptors (GPCRs) actively participate in crucial cellular processes such as cell proliferation, differentiation, and communication. GPCRs play a pivotal role in the initiation and progression of tumors. In this review, focusing on non-small-cell lung cancer (NSCLC), one of the most prevalent cancers, we highlight the roles of GPCRs including understudied receptors in cancer oncogenesis and progression. We summarize current knowledge on GPCR functions in NSCLC, detailing their contributions to tumor development, progression, and therapy resistance. Furthermore, we evaluate the therapeutic potential of agents targeting GPCR-driven tumorigenic signaling in lung cancer. Critical knowledge gaps in understanding GPCR involvement in NSCLC biology are identified, and we address the limitations and challenges of targeting GPCRs for NSCLC treatment. This review provides insights into the current landscape, recent progress, and persisting challenges in developing GPCR-targeted anticancer therapies.
Aging and metabolic diseases are intricately linked through bidirectional molecular mechanisms that foster a harmful cycle of physiological decline. This cycle is driven by several key factors, including altered nutrient sensing, mitochondrial dysfunction, cellular senescence, chronic inflammation, epigenetic modifications, circadian rhythm disruptions, and imbalances in the gut microbiota. Emerging interventions targeting this aging-metabolism axis hold significant promise for extending healthspan. These approaches include the use of pharmacological mimetics, senolytics, multi-omics strategies, and microbiome modulation, all of which aim to restore metabolic homeostasis and mitigate age-related pathologies. However, several challenges remain in translating these strategies into clinical practice. These include the need for tissue-specific targeting, ensuring the long-term safety of interventions, and addressing socioeconomic disparities in healthcare access. Future research efforts are focusing on integrating multi-omic technologies, organoid and human cellular models, and developing equitable precision medicine frameworks. These initiatives aim to extend healthspan and reduce the global impact of aging-related metabolic diseases.
N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate the majority of excitatory synaptic transmission in central nervous system. Dysfunction of these receptors may result in various diseases, including epilepsy. In recent years, a growing number of studies have targeted NMDARs and AMPARs to screen for antiepileptic agents that are both efficacious and well-tolerated. This review summarizes compounds, herbal extracts, and herbal complexes of traditional Chinese medicine (TCM) that have demonstrated antiepileptic effects through their modulation of NMDARs and AMPARs over the past 25 years. Furthermore, this review also systematically synthesizes the molecular mechanisms underlying these drugs, with the aim of facilitating the rational design and translational development of future antiepileptic therapeutic agents.
Modern biomedical sensing increasingly demands technologies capable of capturing structural, functional, and molecular information simultaneously. Photoacoustic (PA) and electrochemical (EC) sensing individually address these needs but exhibit inherent limitations when used alone. PA imaging offers deep-tissue, label-free visualization with high spatiotemporal resolution, yet lacks molecular specificity. Conversely, EC sensing provides quantitative, chemically specific information through electrode functionalization, but struggles with spatial mapping and noninvasive detection. Integrating these complementary modalities establishes a unified framework—Photoacoustic–Electrochemical Synergy (PAECS)—that fuses PA’s noninvasive, flow-resolved optical contrast with EC’s molecular selectivity and quantitative accuracy. PAECS enables multimodal sensing across scales, improving rare-event detection, dynamic monitoring of metabolic and hemodynamic processes, and mechanistic studies of disease and drug response. Applications include coupling PA flow cytometry with EC microfluidics for circulating tumor cell and biomarker analysis, as well as integrating PA imaging with EC metabolite monitoring for real-time tissue profiling. To realize PAECS, future efforts must address system co-registration, signal decoupling, and biomarker-driven design. By bridging optical, acoustic, and electrochemical information, PAECS represents a transformative step toward comprehensive, multiscale biomedical diagnostics and personalized health monitoring.
Artificial Intelligence (AI) is bringing an unprecedented evolution in human history. As it develops, the utilization of AI in clinical practice becomes one of the hot topics that attracts the attention of the medical field as well as the public. While we know that AI will be heavily involved in the medical system, a critical question is what we expect for the future AI medical doctor. To answer this question, it is important to understand that the developing patterns of any other discovery and industrialization do not fit the pattern of AI development, because it acts more like a human instead of simply being a machine or tool. Thus, AI doctors function like human doctors to provide patient-centered reasoning, intellectual judgment, and ethical decision-making rather than just mechanical data processing. Here we present such a likely development process, including current AI status, expected AI doctors, challenges, and future directions.
Gastrointestinal (GI) complications are prevalent and severe clinical challenges encountered in critically ill patients. They are closely linked to disease progression, increased morbidity and mortality, and escalating healthcare expenses. This comprehensive review summarizes the epidemiology of GI complications in critically ill patients, elucidating the underlying pathophysiological mechanisms including hemodynamic alterations, inflammatory cascades, neuro-endocrine dysregulation, and gut microbiota imbalance. It confers distinctive clinical manifestations and effective diagnostic approaches. Therapeutic strategies, encompassing nutritional support, pharmacological management, and surgical or interventional procedures will be discussed. The review also briefly introduces the concept of the "gut-organ axis," emphasizing how intestinal barrier disruption and dysbiosis can disseminate inflammatory and metabolic signals to distant organs such as the lungs, liver, kidneys, and brain, thereby underscoring the need for clinicians to recognize systemic effects. In essence, prompt identification and multimodal intervention are pivotal for optimizing outcomes in critically ill patients; judiciously addressing GI complications in clinical decision-making can mitigate morbidity and enhance both short-term and long-term prognosis.
N-lactoyl-phenylalanine (Lac-Phe), an exercise-induced metabolite that suppresses appetite, has quickly emerged as a key molecule in metabolic signaling networks. Lac-Phe, following its CNDP2-mediated synthesis, mediates key appetite- and weight-modulating effects of metformin, which acts primarily by mitochondrial inhibition in gut epithelial cells. Both Lac-Phe and related N-lactoyl-amino acids serve as potent biomarkers of mitochondrial dysfunction. Elevated levels of these metabolites are found in genetic mitochondrial diseases, offering potentially superior prognostic value compared to lactate in conditions alike. Despite uncertainties regarding its specific receptor(s) and signaling mechanisms, the expanding roles of Lac-Phe underscore its critical position at the intersection of exercise physiology, pharmacology, energy metabolism, and disease pathology, suggesting significant potential for future diagnostics and therapeutics in mitochondrial and metabolic disorders.
Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that form in non-lymphoid organs, frequently observed in conditions such as cancer, autoimmune diseases, transplant rejection, and chronic inflammation. Growing evidence suggests that TLSs are beneficial for patients' prognosis with higher TLS density generally correlating with improved therapeutic response and survival outcomes across malignancies and might serve as a novel therapeutic target for cancer immunotherapy. However, the correlation between TLSs and tumor development is still ambiguous. The exact timing of TLS formation during tumorigenesis and their dynamic evolution throughout tumor progression remain under investigation. Recent studies have identified potential strategies for inducing TLSs, but there remains a considerable distance from clinical application. More advanced techniques such as high-resolution spatial multi-omics technologies combined with big data analysis will benefit understanding the complex interactions within TLSs and developing novel immunotherapies.
Extrachromosomal DNA (ecDNA) drives the evolution of cancer cells. Its widespread presence in tumors and strong association with poor clinical outcomes make ecDNA a promising and broadly applicable therapeutic target. Recent studies have begun to unravel the mechanisms by which ecDNA promotes tumorigenesis and maintains its presence in cancer cells. These discoveries have paved the way for developing ecDNA-targeted therapies. In this Perspective, we summarize the latest advances in our understanding of the mechanism underlying both the ecDNA-induced cancer phenotype and ecDNA maintenance. We also explore potential strategies for targeting ecDNA in cancer treatment.
Increased transcript diversity, which is caused in part by alternative splicing and cryptic transcription, is an underappreciated aspect of age-associated transcriptome remodeling. Recent work has revealed that structurally novel transcripts increase during aging in many tissues. Genes with cryptic and alternatively spliced transcripts with age are enriched for functional categories relevant to tissue function and aging, and have been implicated in cognitive decline, decreased muscle strength, reduced oocyte quality, immune aging, altered stem cell properties, and senescence. Indeed, there is emerging evidence that alternatively spliced transcripts and elevated cryptic transcription directly contribute to aging phenotypes in multiple tissues. The full impact of the increased transcript diversity on the aging process has yet to be explored. The increased transcript diversity engendered by alternative splicing and cryptic transcription is emerging as a potent driver of aging and aging phenotypes, adding another layer to our understanding of the transcriptional regulation of aging.
