Heavy metals (HMs), such as chromium, arsenic, cadmium, mercury, and lead, constitute a class of environmental pollutants with significant toxicity that pose a serious threat to human health. This review provides a comprehensive overview of the biochemical properties of HMs, and their effects at the cellular, molecular, and genetic levels. HMs exert their toxic effects by interfering with various intracellular biochemical processes, including enzyme activity, protein synthesis, and energy metabolism. Furthermore, they can disrupt the integrity of cell membranes and affect cellular signaling, leading to cellular dysfunction and death. At the molecular and genetic levels, HMs can cause DNA damage and induce gene mutations, thereby affecting genetic transmission and expression. Then, the effects of HMs on the nervous system, kidneys, cardiovascular system, reproduction, and cancer risk are discussed. Therapeutic strategies, such as chelation therapy, antioxidants and free radical scavengers, supportive therapy, and prevention and reduction of exposure, have been shown to mitigate the toxic effects of HMs. Last, based on the current findings on the mechanisms of HMs, future research directions are prospected. Through multidisciplinary cooperation and integrated interventions, it is expected that the health risks posed by HMs can be alleviated. Future research needs to further elucidate the mechanisms of HMs toxicity, develop more effective treatments, and strengthen preventive and control measures.

Lung metastasis is the most common site of extrahepatic spread in hepatocellular carcinoma (HCC) and is associated with significantly poorer outcomes. Current guidelines classify these patients as Barcelona Clinic Liver Cancer (BCLC) stage C, recommending systemic therapy alone. However, this one-size-fits-all approach may overlook potential benefits in selected patients. In this multicenter cohort study of 1203 HCC patients—including 119 with lung metastases—we evaluated prognostic factors and treatment outcomes. Lung metastasis significantly reduced overall survival, both before and after propensity score matching. However, among patients with early-stage intrahepatic tumors, curative locoregional treatments such as hepatectomy or radiofrequency ablation improved survival and led to outcomes comparable to those without metastasis. Systemic therapies including tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) prolonged survival, and combination regimens yielding the greatest benefit. Interestingly, lung metastases impaired intrahepatic response to systemic monotherapy, but this effect was mitigated by combining TKIs with ICIs. These findings suggest that a subset of HCC patients with lung metastases may benefit from individualized, multimodal treatment strategies, challenging the current staging framework and supporting a more refined, personalized therapeutic approach in this population.

The poly(ADP-ribose) polymerase (PARP) family consists of 17 members of nicotinamide adenine dinucleotide (NAD⁺)-dependent enzymes that regulate key biological processes by catalyzing adenosine diphosphate (ADP)-ribosylation, either poly(ADP-ribosyl)ation (PARylation) or mono(ADP-ribosyl)ation (MARylation). These biological processes encompass DNA repair, metabolism, telomere maintenance, and immune responses. Based on structural and functional features, the PARP family is classified into subcategories, such as DNA-dependent PARPs, Tankyrase, CCCH-type PARPs, MacroPARPs, and atypical PARPs. These enzymes dynamically maintain genome stability through mechanisms, including base excision repair and homologous recombination, while also regulating telomere dynamics and metabolic pathways. Dysregulation of PARP activity is implicated in the pathogenesis of diverse human diseases. Though PARP inhibitors have gained therapeutic interest in oncology, their wider roles in nononcological conditions, such as neurodegenerative diseases, cardiovascular disorders, and viral infections, remain poorly defined. This review elucidates the unique structural features of PARP family members and describes their multiple roles under physiological and pathological conditions, thus providing insights into treatment strategies. Additionally, it summarizes the advances and challenges in PARP-targeted therapies and explores future directions for innovative therapeutic approaches. The findings may serve as a valuable resource for informing both clinical research and drug development.

While circulating tumor DNA (ctDNA) testing has demonstrated utility in identifying muscle-invasive urothelial carcinoma (MIUC) patients likely to benefit from adjuvant immunotherapy, the prognostic value of transcriptome data from surgical specimens remains underexplored. Using transcriptomic and ctDNA data from the IMvigor010 trial, we developed an artificial intelligence (AI)-driven biomarker to predict immunotherapy response in urothelial carcinoma, termed UAIscore. Patients with high UAIscore had significantly better outcomes in the atezolizumab arm versus the observation arm. Notably, the predictive performance of the UAIscore consistently outperformed that of ctDNA, tTMB, and PD-L1, highlighting its value as an independent biomarker. Moreover, combining ctDNA, tTMB, and PD-L1 with the UAIscore further improved predictive accuracy, underscoring the importance of integrating multi-modality biomarkers. Further analysis of molecular subtypes revealed that the luminal subtype tends to be sensitive to adjuvant immunotherapy, as it may exhibit the highest level of immune infiltration and the lowest degree of hypoxia. Remarkably, we elucidated the role of the NF-κB and TNF-α pathways in mediating immunotherapy resistance within the immune-enriched tumor microenvironment. These findings stratify patients likely to respond to adjuvant immunotherapy, concurrently providing a mechanistic rationale for combination therapies to augment immunotherapy efficacy in urothelial carcinoma.

Mitochondria are indispensable for the normal physiological activities and metabolism of living organisms. The proper function of mitochondria in the brain is crucial for maintaining the normal brain function with high energy demands. There are growing evidences that mitochondrial dysfunction plays a critical role in multiple of neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Huntington's disease. In this review, the research progress and future development trajectory of mitochondrial function in NDDs will be comprehensively summarized, which focusing on mitochondrial physiological function, the mechanisms underlying mitochondrial dysfunction in diverse NDDs, research approaches for exploring mitochondrial function, various strategies for targeted mitochondrial therapy, and the challenges and opportunities encountered in the evaluation of mitochondrial-targeted therapeutic drugs. The feasibility of in vivo mitochondrial imaging and the future perspectives of AI for mitochondria-targeted drug screening are deliberated, which will facilitate the advancement of the comprehension of mitochondrial functional mechanisms in NDDs and the development of future clinical therapeutic drugs. This review shall furnish several insights regarding novel research methodologies and drug developments for researchers engaged in the investigation of mitochondrial dysfunction in NDDs.

Pleural mesothelioma (PM) presents significant challenges in clinical management, with current treatment options such as chemotherapy, anti-angiogenic therapies, and immunotherapies only modestly extending progression-free survival (PFS) and overall survival (OS). Another relevant reason is the absence of subsequent-line therapy strategies following progression of PM after approved therapy. Despite extensive research efforts, the development of effective targeted therapies has proven difficult, as most identified mutations in PM tend to be tumor suppressors rather than the driving mutations seen in other cancers. This review aims to provide an in-depth analysis of the biological mechanisms of PM, focusing on genetic alterations, the tumor's immune microenvironment, and dysregulated signaling pathways that contribute to tumorigenesis and resistance to treatment. Additionally, we discuss the growing importance of biomarkers for patient stratification and the development of personalized therapeutic approaches tailored to individual molecular profiles. We also explore promising avenues for novel therapeutic strategies, such as combination therapies and immunotherapeutic interventions. By integrating insights from both basic and clinical research, this review seeks to present a comprehensive framework for understanding PM and advancing its therapeutic management, ultimately aiming to improve patient outcomes through more effective and targeted treatment approaches.

Central nervous system (CNS) diseases, a leading cause of global disability and mortality, encompass a wide range of brain disorders such as stroke, Alzheimer's disease, Parkinson's disease, and so on. These diseases are characterized by dynamic cellular heterogeneity and disrupted intercellular crosstalk, yet their molecular drivers remain incompletely resolved. Single-cell RNA sequencing (scRNA-seq) dissects transcriptional diversity at cellular resolution, while spatial transcriptomics (ST) maps niche-specific interactions within tissue architecture—complementary approaches that have revealed disease-associated subpopulations, neural–glial communication, and microenvironmental remodeling. However, standalone omics layers inadequately capture the genetic, epigenetic, and functional cascades underlying CNS pathologies. Here, we highlight the transformative potential of integrating scRNA-seq and ST with multiomic profiling to delineate spatially orchestrated molecular networks. Such multiomic convergence enables systematic deconstruction of molecular mechanisms and intercellular communication across disease progression. By correlating these signatures with clinical phenotypes, this strategy accelerates biomarker discovery, patient stratification, and therapeutic target identification. We further discuss challenges in data harmonization, subcellular spatial resolution, and computational scalability that must be addressed to realize personalized CNS medicine. This synthesis advocates for interdisciplinary frameworks to translate multiomic insights into mechanistically grounded diagnostics and therapies, ultimately bridging the gap between molecular discovery and precision clinical intervention.

Astrocytes, the most prevalent glial cells in the central nervous system (CNS), play crucial roles in maintaining CNS homeostasis and responding to various pathological stimuli. They play key roles in neural development, neurotransmission, neuroinflammation, metabolic support, and tissue repair. Recent advancements in single-cell sequencing have revealed the remarkable heterogeneity of astrocytes, with distinct subpopulations differentially contributing to disease progression in neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, ischemic stroke, intracerebral hemorrhage, and multiple sclerosis. In addition, they play an important role in various behavioral neuropsychiatric disorders. This review highlights the dual roles of astrocytes in disease progression, driven by their diverse molecular profiles and functions. It outlines the key molecular mechanisms underlying astrocyte heterogeneity and their impact on neuroinflammation, neuronal support, and ionic balance regulation. Additionally, the review discusses potential therapeutic strategies targeting astrocytes to modulate these processes, aiming to improve treatment outcomes in neurological diseases. By elucidating the specific roles of astrocyte subsets in disease, this review seeks to advance the development of precision medicine for astrocyte-related neurological disorders.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that lacks ideal models to comprehensively recapitulate its pathological features. TDP-43 pathology, a hallmark of neurodegenerative diseases, plays a critical role in disease progression. Given the anatomical and physiological similarities between pig and human brains, large animal models offer a unique advantage in more accurately simulating patient-specific disease characteristics. In this study, we rapidly established a TDP-43-induced neurodegenerative disease model in pigs through ear vein injection of the TDP-43^M337V virus. Disease progression was systematically evaluated using behavioral assessments and pathological analyses. This porcine model produced extremely severe motor dysfunction accompanied by significant muscle atrophy and fibrosis. Additionally, characteristic TDP-43 pathological phenotypes were observed, including degeneration of spinal motor neurons and proliferation of glial cells in both the brain and spinal cord. Notably, TDP-43^M337V induction led to a significant upregulation of TMEM106B, SOD1, and APOE4 levels. This TDP-43 porcine model recapitulates multiple key features of ALS and serves as a valuable complement to existing animal models, providing a robust platform for investigating TDP-43-related pathogenic mechanisms of TDP-43 and developing effective therapeutics.

The immune checkpoint molecule B7-H3 is upregulated in many solid tumors, and B7-H3-targeted immunotherapies are in clinical trials. Recently, a growing body of research has highlighted the presence of tumor cell intrinsic while immune cell-independent functions of B7-H3 in tumorigenesis and cancer cell stemness. However, its receptors and mechanisms of action on cancer cells remain poorly understood. Here, we report that c-Met, a canonical oncogenic receptor tyrosine kinase on cancer cells, is identified as a novel binding protein for B7-H3. The binding between c-Met and B7-H3 directly activates the c-Met/STAT3 signaling cascade, promoting cancer cell stemness in both colorectal cancer and glioblastoma-derived tumor cells. More importantly, we evaluated the translational implications of this discovery by screening a high-affinity antibody designed to selectively disrupt the interaction between B7-H3 and c-Met, demonstrating strong anti-tumor activities, surpassing that of the B7-H3-specific antibody lacking the blocking capability. Combination therapy of this newly developed interaction blocking antibody with c-Met inhibitor results in significantly improved therapeutic effects in inhibiting tumor growth. These findings shed light on previously undisclosed interaction of B7-H3 to c-Met on cancer cells, thereby indicating a new mechanism of cancer cell stemness and intervention pathway of molecular targeted therapy.

Radiation therapy is a fundamental component of cancer treatment, benefiting 50%–70% of patients by selectively targeting malignant tissues. However, radioresistance remains a significant challenge, often driven by epithelial–mesenchymal transition (EMT). EMT increases cancer invasiveness and metastasis by upregulating mesenchymal markers, including vimentin and N-cadherin, and downregulating epithelial markers, such as E-cadherin. EMT under radiation involves principal signaling pathways, including TGF-β, Wnt/β-catenin, Notch, and ERK, which regulate EMT through transcription factors such as Snail, Slug, Twist, and Zeb1/2. These alterations drive cytoskeletal reorganization, decrease cell–cell adhesion, and enhance extracellular matrix degradation via integrins, MMP-2, and MMP-9. We also explored how growth hormones, inflammatory cytokines, and hypoxia in the tumor microenvironment affect radiation-induced EMT. Targeting EMT pathways with monoclonal antibodies and small-molecule inhibitors of signaling pathways may help overcome radioresistance. However, due to the dual role of EMT in cancer progression and tissue regeneration, precise treatment strategies are essential. There is a lack of comprehensive multi-omics studies that provide insights into postradiation EMT progression. This review examines how radiation induces EMT and its impact on metastasis and immune responses while also proposing therapeutic approaches. Integrating EMT-targeting strategies with existing cancer treatments could enhance the effectiveness of radiotherapy and improve patient outcomes.

Hematopoietic stem cell transplantation (HSCT) profoundly disrupts the gut microbiome and metabolome, which in turn influence immune-related complications and patient outcomes. To systematically characterize these perturbations, we performed a longitudinal analysis of fecal microbiota composition and metabolite profiles in HSCT recipients at three critical timepoints: pre-transplant (T1), peri-transplant (T2), and post-transplant (T3). We observed that reduced microbial diversity at T1 and T3 was strongly associated with increased incidence of graft-versus-host disease (GVHD), progressive disease (PD), and decreased overall survival (OS). Metabolomic profiling revealed a significant decline in short-chain fatty acids (SCFAs), particularly acetate, from T1 to T2, which correlated with adverse clinical outcomes including GVHD, diarrhea, PD, and lower OS. Elevated levels of uric acid at T2 were predictive of GVHD onset, while decreased 1-phenylethylamine was linked to transplant-associated diarrhea. Furthermore, enrichment of beneficial bacterial taxa such as Lachnospiraceae and Ruminococcaceae was associated with improved survival. Together, these findings highlight the gut microbiome–metabolome axis as a dynamic biomarker for HSCT prognosis. This integrated insight offers potential avenues for microbiota-targeted diagnostics and interventions aimed at mitigating transplant-related complications and improving patient survival.

Atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) therapy is beneficial for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-resistant non-small cell lung cancer (NSCLC); however, the resistance mechanisms are not fully understood. In this study, we conducted a single-cell RNA-sequencing analysis of EGFR-TKI-resistant NSCLC patients grouped into ABCP responders and non-responders. VEGFA was overexpressed in ABCP responders, whereas VEGFC was upregulated in non-responders. VEGFA and VEGFC had exclusive distributions and interactions, suggesting their distinct roles. VEGFA facilitated the proliferation of responder tumor subcluster cells, whereas VEGFC secreted from non-responder tumor cells interacted with tumor microenvironment cells. VEGFC predominantly cooperated with drug resistance pathways such as fibroblast growth factor signaling and YAP-TAZ regulation, whereas VEGFA coordinated several oncogenic signaling pathways. VEGFC expression was the most significant prognostic marker (hazard ratio, 1.8 [95% confidence interval, 1.1–3.0], p = 0.015). Both VEGFA and VEGFC inhibition effectively suppressed tumor growth, suggesting that VEGF signaling complexity hampers the response to ABCP. In conclusion, combinatorial targeting of both ligands (VEGFA and VEGFC) or their receptors (VEGFR2 and KDR) may enhance the clinical benefit of ABCP in EGFR-TKI-resistant NSCLC patients.

Nanomaterials have become promising platforms in the field of drug and gene delivery, offering unique advantages over traditional therapeutic approaches. Their tunable physicochemical properties enable improved pharmacokinetics and therapeutic performance. A wide range of nanocarriers, including lipid-based, polymer-based, and hybrid systems, have been rapidly developed and are attracting increasing attention in both preclinical and clinical research. However, despite promising preclinical outcomes, these systems still encounter critical challenges in achieving precise delivery to specific tissues, cells, and intracellular compartments. This review provides a comprehensive assessment of recent advances in the design and application of nanocarriers for targeted delivery, with emphasis on strategies designed for nuclear targeting. In the context of nuclear targeting, it explores passive approaches involving modulation of particle size, morphology, and surface charge, alongside active targeting strategies incorporating nuclear localization signals and other ligands. In addition to highlighting progress, the review examines the limitations associated with delivery efficiency, off-target effects, and barriers to clinical translation. By addressing both advances and ongoing challenges, this review provides valuable insights into the design and engineering of targeted nanocarriers. These developments are crucial for unlocking the full potential of precision nanomedicine.

Cancer represents a growing cause of death and a threat to public health worldwide; thus, there is an urgent need to understand its pathological mechanism and design effective therapies. The Hippo pathway regulates diverse cellular processes under physiological conditions; however, its dysregulation is associated with several types of cancer, including lung, pancreatic, colorectal, breast, and prostate cancer. Consequently, compounds targeting deregulated Hippo components represent potential treatments for a broad spectrum of cancers. Nonetheless, currently, there is limited information integrating the growing evidence of this potential. Therefore, the review's objective is to provide insight into the potential efficacy of targeting the Hippo/yes-associated protein (YAP) pathway for cancer therapy. First, we describe the molecular mechanisms of the Hippo signaling pathway in physiological conditions and several cancer types. We then provide an overview of natural products and synthetic compounds targeting this pathway, highlighting their potential applications in treating diverse cancers. We also discuss relevant preclinical and clinical studies of compounds targeting the Hippo pathway in cancer. Finally, we summarize our findings and offer recommendations for future research. This review emphasizes the role of the Hippo/YAP pathway in cancer and the potential of natural products and synthetic compounds targeting this pathway for cancer treatment.

Severe liver injury is a life-threatening condition with high mortality and limited therapeutic options. Extensive research on heterochronic parabiosis has highlighted the potent regenerative repair capabilities of young blood in tissue regeneration. However, it remains unclear whether younger blood, specifically umbilical cord blood, can offer similar benefits for tissue repair. In this study, we demonstrate that exosomes derived from umbilical cord blood plasma (CBP-Exos) exhibit significant therapeutic effects in both acute and chronic liver injury models, outperforming exosomes from young peripheral blood plasma. Treatment with CBP-Exos notably reduced liver necrosis, lipid peroxidation, and apoptosis in liver tissues of acute liver injury (ALI) mice. Mechanistically, miR-410-3p, derived from CBP-Exos, directly targets the proapoptotic gene Bim for posttranscriptional degradation. The downregulation of Bim facilitates the activation of mitochondrial-mediated Bcl2-CytoC antiapoptotic signaling, resulting in the restoration of mitochondrial structure and function, thereby inhibiting hepatocyte apoptosis and oxidative stress. Furthermore, overexpression of miR-410-3p significantly improved liver function in ALI mice. These findings identify the therapeutic effects of CBP-Exos are attributed to the miR-410-3p/Bcl2/CytoC axis, laying a foundation for the clinical application of CBP-Exos and miR-410-3p in liver diseases.

Postinfectious subacute cough (PISC) and postinfectious chronic cough (PICC) are triggered by respiratory infections, which induce adaptive immunity. The expression of T-lymphocyte subsets and cytokine signatures remains elusive in these patients. Here, we recruited 40 healthy controls, 64 PICC patients, 65 PISC patients, and 20 recovered individuals with postinfectious subacute cough (R-PISC). As cough and airway inflammation resolved in R-PISC subjects, sputum lymphocytes dropped substantially. Both PICC and PISC patients had an increase in blood activated interferon-γ (IFN-γ)⁺ T-lymphocytes, which were decreased in R-PISC subjects. Elevated cough sensitivity, higher proportions of activated IFN-γ⁺ T-lymphocytes, and CD8⁺/CD4⁺ T-lymphocyte ratios, as well as elevated concentrations of uric acid, IFN-γ, tumor necrosis factor-α (TNF-α), IFN-α, IFN-β, and interleukin-10 in sputa, were observed in PICC and PISC patients but normalized in R-PISC subjects. Correlation analyses and logistic regression models identified activated IFN-γ⁺ T-lymphocytes and these cytokines in sputa as biomarkers for predicting cough risk. PICC patients exhibited greater cough severity, elevated activated IFN-γ⁺ T-lymphocytes, and TNF-α concentrations in sputa compared to PISC patients. Overall, postinfectious cough patients exhibit airway inflammatory signatures characterized by activated IFN-γ⁺ T-lymphocytes and elevated levels of IFN-γ, TNF-α, IFN-α, IFN-β, and interleukin-10, which are valuable for effective treatment options.

RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine, and pseudouridine, serve as pivotal regulators of gene expression with significant implications for human health and disease. These dynamic modifications influence RNA stability, splicing, translation, and interactions, thereby orchestrating critical biological processes such as embryonic development, immune response, and cellular homeostasis. Dysregulation of RNA modifications is closely associated with a variety of pathologies. This review systematically synthesizes recent advances in understanding how dynamic RNA modifications orchestrate health and disease. We critically review the m6A modifications, the most abundant RNA methylation, its association with diseases, and regulations by post translation. We evaluate three interconnected themes: disease mechanisms, where dysregulated m6A drives oncogenesis (e.g., METTL3-mediated hypermethylation in breast cancer) and contributes to neuropsychiatric/cardiovascular disorders; homeostatic functions, spanning embryogenesis (maternal-to-zygotic transition), tissue regeneration (YTHDF1 in muscle), and immune regulation; therapeutic frontiers, including enzyme-targeting strategies (FTO inhibitors, METTL3 stabilizers) and diagnostic approaches. Our analysis reveals that context-dependent RNA modification networks operate as biological “switches” whose dysregulation creates pathogenic cascades. We further propose a novel framework for targeting these networks using multiomics integration. This review establishes RNA modifications as central targets for precision medicine, while highlighting critical challenges in clinical translation that demand interdisciplinary collaboration.

RNA-targeting small molecules represent a transformative frontier in drug discovery, offering novel therapeutic avenues for diseases traditionally deemed undruggable. This review explores the latest advancements in the development of RNA-binding small molecules, focusing on the current obstacles and promising avenues for future research. We highlight innovations in RNA structure determination, including X-ray crystallography, nuclear magnetic resonance spectroscopy, and cryo-electron microscopy, which provide the foundation for rational drug design. The role of computational approaches, such as deep learning and molecular docking, is emphasized for enhancing RNA structure prediction and ligand screening efficiency. Additionally, we discuss the utility of focused libraries, DNA-encoded libraries, and small-molecule microarrays in identifying bioactive ligands, alongside the potential of fragment-based drug discovery for exploring chemical space. Emerging strategies, such as RNA degraders and modulators of RNA–protein interactions, are reviewed for their therapeutic promise. Specifically, we underscore the pivotal role of artificial intelligence and machine learning in accelerating discovery and optimizing RNA-targeted therapeutics. By synthesizing these advancements, this review aims to inspire further research and collaboration, unlocking the full potential of RNA-targeting small molecules to revolutionize treatment paradigms for a wide range of diseases.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition affecting millions of people worldwide. The severity of ARDS is associated with the dysfunction of pulmonary endothelial cells (PECs). Metabolic reprogramming is characterized by enhanced glycolysis and lactate accumulation, which play a critical role in this process. Here, we showed that lactate levels in the lungs of patients with ARDS were associated with disease severity and prognosis. Lactate promoted PEC dysfunction and drove experimental ARDS progression via lysine lactylation (Klac), a recently described posttranslational modification. Suppression of lactate-induced lactylation mitigated the development of ARDS and inhibited the release of chemokines, particularly CXC motif chemokine ligand 12 (CXCL12), from PECs. Through quantitative lactylome analysis, we identified hyperlactylation at K193 of Enolase 1 (Eno1), a glycolytic enzyme with RNA-binding capacity, as a previously unknown mechanism promoting CXCL12 production in PECs. Under homeostatic conditions, Eno1 could bind and inhibit the translation of CXCL12 mRNA, whereas increased glycolysis and accumulated lactate drove K193 hyperlactylation of Eno1 to release CXCL12 mRNA for accelerated translation. In addition, K193 hyperlactylation enhanced Eno1 enzymatic activity, further amplifying glycolysis. These findings establish Klac as a link between glycolytic reprogramming and PEC dysfunction, offering a new therapeutic target for ARDS.

Chronic obstructive pulmonary disease (COPD) is a complex and irreversible respiratory disorder with a poor prognosis and a lack of effective pharmaceutical treatment. Our previous metabolomics study identified phytosphingosine (PHS) as a key differential metabolite in COPD that is positively correlated with lung function. In this study, we investigated the bioactive effects of PHS on experimental COPD and its underlying mechanisms using cigarette smoke (CS)-induced mouse and cell models. We found that administering PHS improved CS-induced lung dysfunction, emphysema, and airway inflammation by reducing cellular senescence and the senescence-associated secretory phenotype in bronchial epithelium. Mechanistically, PHS interacted with the free fatty acid receptor 4 (FFAR4) and upregulated its expression, leading to the modulation of STIP1 homology and U-Box containing protein 1 (STUB1) downstream, which controlled the ubiquitination levels of P53 and mitigated cellular senescence. Moreover, both FFAR4 overexpression through intratracheal injection of adeno-associated virus and the administration of the FFAR4 agonist TUG891 showed therapeutic effects on CS-induced lung damage. Our results highlight the beneficial impacts of PHS in experimental COPD mediated through the FFAR4 receptor, protecting against CS-induced bronchial epithelial cell senescence and suggesting PHS as a promising therapeutic agent for COPD.

Since the United States Food and Drug Administration approved the first immune checkpoint inhibitor ipilimumab for metastatic melanoma in 2011, ICIs have been approved for a range of cancers and significantly improving treatment outcomes. However, the objective response rate of ICI monotherapy remains modest (10–40%), with clinical benefit observed in only 15–20% of patients. The limited efficacy of ICIs in many patients is often attributed to poorly immunogenic (“cold”) tumors. Radiotherapy and chemotherapy exhibit immunomodulatory properties that can enhance tumor immunogenicity. These effects provide a rationale for combining ICIs with conventional therapies. Current research lacks systematic synthesis and consistent clinical evidence on the immunomodulatory effects of radio/chemotherapy, and the optimal selection and sequencing of radio/chemotherapy with immunotherapy remain unclear, limiting the optimization of combination strategies with immunotherapy. This review outlines the current landscape of cancer immunotherapy and elucidates the immunomodulatory effects of radiotherapy and chemotherapy that form the basis for combination strategies. It further summarizes clinical advances in combined modalities and discusses associated toxicities, management approaches, and potential predictive biomarkers. This review provides a comprehensive framework for understanding and optimizing radio/chemo-immunotherapy by integrating mechanistic insights with clinical evidence to guide future personalized cancer treatment strategies.

Ferroptosis, an iron-dependent cell death pathway driven by lipid peroxidation, has emerged as a critical pathophysiological mechanism linking cancer and inflammatory diseases. The seemingly distinct pathologies exhibit shared microenvironmental hallmarks—oxidative stress, immune dysregulation, and metabolic reprogramming—that converge on ferroptosis regulation. This review synthesizes how ferroptosis operates at the intersection of these diseases, acting as both a tumor-suppressive mechanism and a driver of inflammatory tissue damage. In cancer, ferroptosis eliminates therapy-resistant cells but paradoxically facilitates metastasis through lipid peroxidation byproducts that remodel the tumor microenvironment and suppress antitumor immunity. In chronic inflammatory diseases—from atherosclerosis to rheumatoid arthritis—ferroptosis amplifies neuroinflammatory cascades while simultaneously exposing vulnerabilities for therapeutic targeting. Central to this duality are shared regulatory nodes, including nuclear factor kappa B-driven inflammation, NOD-like receptor family pyrin domain-containing 3 inflammasome activation, and GPX4 dysfunction. Therapeutically, ferroptosis induction shows promise against therapy-resistant cancers but risks exacerbating inflammatory damage, underscoring the need for precision modulation. Emerging strategies—nanoparticle-based inducers, immunotherapy combinations, and biomarker-guided patient stratification—aim to balance prodeath efficacy against off-target toxicity. By dissecting the ferroptosis–inflammation–cancer axis, this review provides a unified framework for understanding disease pathogenesis and advancing therapies for conditions resistant to conventional treatments. Future research must prioritize spatial mapping of ferroptosis dynamics, mechanistic crosstalk with immune checkpoints, and combinatorial regimens that exploit ferroptosis vulnerabilities while mitigating its inflammatory consequences.

Diabetic retinopathy (DR), a major cause of vision loss in adults, involves aberrant metabolism and inflammation. This study investigated the interplay between glycolysis, histone lactylation, and PANoptosis in DR using human retinal pigment epithelial (RPE) cells under high glucose and diabetic mouse models. Results demonstrated a positive feedback loop where enhanced glycolysis increased histone lactylation, which in turn further promoted glycolysis. This cycle activated the expression of thioredoxin interacting protein (TXNIP) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), leading to PANoptosome formation and triggering PANoptosis, a coordinated cell death pathway contributing to DR pathology. Crucially, experiments manipulating TXNIP expression (via RNAi or overexpression) confirmed its central role in linking histone lactylation to NLRP3 activation and PANoptosome assembly. Importantly, inhibiting glycolysis or downregulating TXNIP successfully reduced histone lactylation, suppressed PANoptosome formation, and alleviated PANoptosis. These findings establish that the glycolysis-histone lactylation axis, mediated by TXNIP/NLRP3 signaling, drives PANoptosis in RPE cells through PANoptosome formation, playing a critical role in DR development. Targeting this specific pathway presents a promising new therapeutic strategy for diabetic retinopathy.

Effective treatment of ischemic disease requires the reconstruction of blood vessels through the delivery of angiogenic factors, such as chemicals, proteins, and cells. In particular, substantial efforts have focused on enhancing the therapeutic potential of mesenchymal stem cells (MSCs) for treating ischemic diseases. In this study, we investigated the use of electrical stimulation (ES) to potentiate the proangiogenic properties of human adipose-derived MSCs. Electrically potentiated MSCs (epMSCs) were generated by applying optimized ES parameters (0.3 V, 100 Hz). EpMSCs exhibited significantly enhanced angiogenic potential, including upregulated expression of proangiogenic factors (e.g., vascular endothelial growth factor [VEGF]-A and hepatocyte growth factor) and improved endothelial cell migration and tube formation in vitro. Transcriptomic and proteomic analyses revealed activation of key angiogenic pathways, particularly VEGFA–VEGFR2 signaling, which plays a critical role in enhancing the functionality of epMSCs. In vivo studies using a murine hindlimb ischemia model demonstrated that epMSCs enhanced blood flow recovery, induced angiogenesis, and reduced muscle atrophy more effectively than unstimulated MSCs. Overall, these findings suggest that electrical potentiation of MSCs is a promising strategy for effectively enhancing their angiogenic capabilities for treating ischemic diseases.

The emergence of novel and highly transmissible coronavirus (CoVs) highlights the urgent need for broad-spectrum antiviral agents. In our pursuit of effective treatments for coronavirus, we identified tetrandrine, the traditional Chinese medicine, as a pan-coronavirus inhibitor, exhibiting efficacy against HCoV-229E, HCoV-OC43, SARS-CoV-2, and its major variants of concern (VOCs), including alpha, beta, and omicron. Mechanistic investigations revealed that tetrandrine primarily targets the viral entry stage by binding to the Spike protein, disrupting its interaction with the host protease transmembrane serine protease 2 (TMPRSS2), and promoting Spike protein degradation, ultimately blocking the membrane fusion. Drug resistance selection study identified two mutations, G688R and D814Y, at S2 subunit of Spike, which reduced HCoV-229E's sensitivity to tetrandrine, supporting its direct action on the viral fusion machinery. Molecular docking and molecular dynamic (MD) simulation together with co-IP assay also verified the disruption of Spike-TMPRSS2 complex formation by tetrandrine. Importantly, tetrandrine treatment reduced viral load and mitigated neuropathological damage in infected neonatal mice. These findings establish tetrandrine as a broad-spectrum coronavirus entry inhibitor and offer mechanistic insights into its antiviral activity, providing a promising candidate for therapeutic development against current and future coronavirus threats.

Dendritic cells (DC) are known to modulate antiviral immune responses; however, the knowledge about the role of different DC subsets in antiviral T cell priming in human tissues remains uncompleted. In the context of HIV infection, we determined the phenotype and location of plasmacytoid and CD141+ myeloid DCs (pDCs and mDCs) in lymph nodes of people living with HIV (PLWH). We found an interaction between pDCs and CD141+ mDCs with CD8+ T cells, being associated with participants’ viral levels in blood and tissue. Moreover, we demonstrated a higher and more polyfunctional superantigen- and HIV-specific CD8+ T cell response after the coculture with Toll-like receptor (TLR)-primed pDCs and CD141+ mDCs. Last, we showed the potential of programmed cell death-1 (PD-1) blocking using pembrolizumab to further increase antigen-specific CD8+ T cell response along with TLR agonists. Therefore, these results showed a cooperation between pDCs, CD141+ mDCs and CD8+ T cells in lymph nodes of PLWH, which is associated with higher HIV control, highlighting the importance of DC subsets crosstalk to achieve a more potent anti-HIV response and support the use of DC-based immunotherapies for HIV control.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Recent evidence has linked butyrophilin 3A1 (BTN3A1) to immune dysregulation. This study was to elucidate the relationship of BTN3A1 in SLE. Expression of BTN3A1 in plasma and peripheral blood mononuclear cells from SLE patients and healthy controls explored the association between BTN3A1 and SLE. We found that BTN3A1 mRNA, plasma levels, and expression in CD4⁺ T cells were significantly elevated in SLE patients. In BTN3A1 gene knock-in (BTN3A1^KI) mice, inflammation and lupus-like manifestations occurred, including increased proportions of Th1, Th2, and Th17 cells, decreased Treg cells, elevated levels of inflammatory cytokines and anti-dsDNA antibodies, renal injury, and suppressed IL-38 serum levels. Intraperitoneal injection of IL-38 in pristane-treated BTN3A1^KI mice notably alleviated these pathological changes. Mechanistic investigations revealed that CD4⁺ T cells and the ferroptosis pathway were closely associated with the effects mediated by the BTN3A1-IL-38 axis. In vitro experiments showed that IL-38 stimulation reduced proliferation, apoptosis, and decreased the expression of ferroptosis-related proteins, Fe²⁺, glutathione, and malondialdehyde in CD4⁺BTN3A1^+/+ T and BTN3A1^+/+ Jurkat T cells. Overall, BTN3A1 plays a crucial role in SLE pathogenesis by regulating CD4⁺ T cell function.

Cancer remains the most lethal disease globally, despite the significant progress made in early screening, surgery, and therapeutic development in recent decades. Programmed cell death (PCD) is a genetically regulated process essential for eliminating aberrant cells, yet its dysregulation drives tumorigenesis and therapy resistance. In this review, we present a complete discovery timeline of them and comprehensively synthesize the roles and mechanisms of major PCD forms, such as apoptosis, necroptosis, autophagy, pyroptosis, ferroptosis, and cuproptosis, across diverse cancer types. We not only detail the molecular mechanisms, dual functions, and alterations of these PCD modalities in cancers, but also summarize their interconnections and intrinsic crosstalk. Furthermore, we comprehensively discuss how diverse therapies, including chemotherapy, radiotherapy, immunotherapy, targeted agents, and hormone therapy, engage and manipulate specific PCD pathways, revealing the involvement of PCD in cancer treatment mechanisms. This review integrates extensive preclinical and clinical evidence on PCD-targeted therapies with an in-depth focus on ferroptosis, including its regulatory networks and therapeutic relevance. Special emphasis is placed on prostate cancer, highlighting the PCD-based translational opportunities in this common malignancy. Taken together, we provide novel insights into the complex interplay between PCD and cancer biology and offer a framework for developing precision oncology therapies.

Cancer metabolic reprogramming is a fundamental hallmark that enables tumor cells to sustain their malignant behaviors. Beyond its role in supporting growth, invasion, and migration, metabolic rewiring actively contributes to anticancer drug resistance. Cancer cells not only reshape their own metabolism but also engage in aberrant metabolic crosstalk with nonmalignant components within the tumor microenvironment (TME). These metabolic alterations create multiple barriers to the efficacy of drug therapies, including chemotherapy, targeted therapy, and immunotherapy. Despite growing evidence, an integrated understanding of how metabolic reprogramming contributes to the development of drug resistance and how it may be therapeutically targeted to overcome the resistance remains incomplete. This review summarizes recent progresses in tumor-intrinsic and TME-associated metabolic alterations that contribute to drug resistance by sustaining metabolic needs and modulating nonmetabolic processes and explores the upstream regulatory mechanisms driving these changes, focusing particularly on glucose, lipid, and amino acid metabolism. We also discuss the current advances in the integration of small molecule inhibitors targeting cancer metabolism to address drug resistance. By consolidating mechanistic insights and therapeutic opportunities, this review highlights metabolic reprogramming as a promising intervention point to overcome anticancer drug resistance.

The pancreatic islets of Langerhans, which are composed of α, β, δ, ε, and PP cells, orchestrate systemic glucose homeostasis through tightly regulated hormone secretion. Although the precise mechanisms involving β cells in the onset and progression of diabetes have been elucidated and insulin replacement therapy remains the primary treatment modality, the regulatory processes, functions, and specific roles of other pancreatic islet hormones in diabetes continue to be the subject of ongoing investigation. At present, a comprehensive review of the secretion and regulation of pancreatic islet cell hormones as well as the related mechanisms of diabetes is lacking. This review synthesizes current knowledge on the secretion mechanisms of insulin, glucagon, somatostatin, ghrelin, and pancreatic polypeptides, emphasizing their functional crosstalk in diabetes. Emerging advances include CRISPR-based β-cell regeneration, bioengineered islet transplantation, and bioelectronic interventions aimed at restoring pancreatic function. Future research directions highlight artificial intelligence-guided prediction of hormone dynamics, therapeutics targeting the gut microbiome–islet axis, and tissue-engineered artificial islets. By integrating mechanistic insights, physiological roles, and translational innovations, this review outlines precision strategies for targeting islet hormone networks, offering a roadmap toward restoring metabolic equilibrium in diabetes.

Somatic retinoblastoma 1 (RB1) loss is prevalent across different cancer types and is enriched in treatment-refractory tumors, such as castration-resistant prostate cancer (CRPC) and small-cell lung cancer, but cannot be considered as a direct druggable target. In this study, we revealed that the close proximity of nudix hydrolase 15 (NUDT15) and RB1 may result in their common somatic codeletion or epigenomic cosilencing in different cancer types and subsequent significant positive correlations of their expressions at the bulk transcriptional and single-cell levels. With clinical CRPC samples, co-loss of RB1 and NUDT15 were commonly observed (14 out of 21). Due to the contribution of NUDT15 deficiency to thiopurine-induced toxicity, exploiting a vulnerability conferred by RB1–NUDT15 loss raised the possibility of repurposing thiopurine (e.g., mercaptopurine) for precise therapeutics. A positive relationship between RB1/NUDT15 ploidy score and mercaptopurine drug sensitivity was found in 543 cancer cell lines. Experimentally, knocking-down NUDT15 sensitizes the cancer cell lines to mercaptopurine treatment by inhibiting cell cycle progression and increasing apoptosis, but does not induce mercaptopurine-related leucopenia in xenograft model. Our study elucidates the molecular basis for precise mercaptopurine therapy in RB1-deficient tumors and demonstrates how leveraging collateral lethality alongside drug repurposing uncovers targetable vulnerabilities in stratified patient cohorts.

CABP2 modulates presynaptic Ca_V1.3 Ca²⁺ channel function in inner hair cells (IHCs) and is required for indefatigable synaptic sound encoding. Biallelic variants in CABP2 are associated with non-syndromic hearing loss (DFNB93). Otoacoustic emissions have been observed in an Italian family with a homozygous CABP2 variant, indicating preservation of outer hair cell-mediated cochlear amplification. Hence, DFNB93 belongs to the hearing disorders caused by impairment of IHC synapses, termed auditory synaptopathy. DFNB93 mouse models have recapitulated findings and demonstrated that lack of CaBP2 impairs synaptic sound encoding by enhanced steady-state inactivation of Ca_V1.3 Ca²⁺ channels. Furthermore, preclinical studies have demonstrated feasibility of gene therapy. As growing evidence from OTOF clinical trials confirms synaptopathies as promising therapeutic targets for hearing restoration, CABP2 ranks highly among the candidate genes for virus-mediated gene therapy to restore hearing. This perspective summarizes the preclinical gene replacement studies for hereditary hearing loss and outlines the characteristics that make genetic targets ideal for therapy development. It reviews the current literature on human CABP2 studies, pre-clinical therapy development, and introduces a patient registry that aims to support research involvement with the CABP2 patient community. We conclude with a preview of the next steps toward CABP2 gene therapy clinical trials.

Diabetic wound (DW) represent a common complication of diabetes. Despite advances in regenerative repair utilizing endothelial progenitor cells (EPCs), challenges such as low survival and impaired angiogenic function of EPCs remain. Herein, we explored an effective method to induce injury-induced protection for EPCs and improves their function. This was achieved through cell preconditioning under conditions of nutrient deprivation and high glucose (NDHG), combined with sb431542, a transforming growth factor beta (TGF-β) signaling inhibitor. Specifically, after three generations of cell passage during preconditioning, umbilical cord-derived endothelial cells (ECs) exhibited characteristics resembling those of EPCs, with over 80% of the cells expressed CD34, a typical marker of EPCs. Notably, these preconditioned EPC-like cells (pEPCs) showed tolerance to pathological environment, as evidenced by robust cell viability, improved antioxidant capacity, and stable tube-forming ability under NDHG condition. The protective effect of preconditioning in pEPCs is partly achieved by activating the PI3K/AKT pathway to upregulate the expression of Nrf2 and HIF-1α. Importantly, pEPCs exhibited therapeutic potential in two diabetic mouse models-limb ischemia and skin wounds by enhancing blood vessel formation and facilitating tissue repair. Overall, this preconditioning method induced the generation of functionally enhanced pEPCs, providing an alternative source of cells for treating DWs.

Hepatitis B virus (HBV) precore G1896A mutation is closely associated with poor prognosis of liver disease. We previously revealed that the G1896A mutation could enhance HBV replication and promote hepatocellular carcinoma (HCC) cell growth both in vitro and in vivo. However, the in-depth mechanisms by which this mutation promotes the malignancy of HCC still need to be explored. Here, we examined the activation of endoplasmic reticulum (ER) stress and glycolysis in HBV G1896A mutation–associated HCC. Bioinformatics, chromatin immunoprecipitation assay and dual-luciferase assay were performed to give insight into the underlying molecular interaction between ER stress and glycolysis. Here, we observed that HBV G1896A mutation also promoted HCC cell invasion and migration. Furthermore, HBV G1896A mutation induced ER stress, and specifically, PERK-ATF4 pathway was responsible for the HCC cell malignancy. Mechanistically, PERK-ATF4 signaling induced transcriptional activation of PFKFB3, a key gene in the process of glycolysis. Finally, in vitro rescue experiments and in vivo efficacy studies revealed that the ATF4-PFKFB3 axis is necessary for the HCC tumor growth and metastasis. These results highlight that the ER stress and glycolysis are involved in the HCC-promotion function of HBV G1896A mutation, providing new insights into HBV-related HCC.

This study aimed to estimate the prevalence of adverse childhood experiences (ACEs) and explore their associations with mental health among Chinese adults. This population-based, cross-sectional survey was conducted in China in 2023. Data on participants' ACEs, depressive symptoms, anxiety symptoms, suicidal ideation, and other information were collected among participants who were selected using multi-stage stratified quota random sampling. Of 30,054 participants, 26.0% (7809/30,054) reported at least one ACE. The prevalence of major depression symptoms, moderate or severe anxiety symptoms, and suicidal ideation were 19.5%, 12.7%, and 21.7%, respectively. There was a dose‒response relationship between the cumulative number of ACEs and mental health among Chinese adults. Compared to those with no ACEs, the adjusted odds ratios (ORs) and 95% confidence interval for major depression symptoms were 1 ACE: 1.340 (1.226‒1.465), 2 ACEs: 1.769 (1.588‒1.971), 3 ACEs: 2.172 (1.909‒2.472), and ≥4 ACEs: 3.084 (2.712‒3.507). The ORs for anxiety symptoms of 1, 2, 3, and ≥4 ACEs were 1.262 (1.135‒1.403), 1.714 (1.513‒1.942), 2.119 (1.831‒2.452), and 2.890 (2.512‒3.325). The ORs for suicidal ideation were 1.056 (0.966‒1.154), 1.324 (1.188‒1.477), 1.470 (1.287‒1.679), and 3.134 (2.761‒3.557). Sexual abuse survivors were at great risk for mental health problems. Comprehensive measures are needed to support populations affected by ACEs.

The activation of nucleotide oligomerization domain-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the pathogenesis of various inflammatory diseases. The natural product oridonin possesses a novel mechanism for NLRP3 inhibition and a unique binding mode with NLRP3, but its poor anti-inflammatory activity limits further application. After virtual screening of diverse natural product libraries, dehydrocostus lactone (DCL) was considered as a potential NLRP3 inhibitor. DCL effectively inhibited caspase-1 cleavage and release of IL-1β in mouse and human macrophages at an extremely low concentration of 10 nM, comparable to MCC950. Mechanistically, our study assigned DCL a novel role in disrupting NLRP3 inflammasome assembly and ASC oligomerization. Excluding the influence on potassium/chloride ion efflux, calcium ion influx, and production of mitochondrial ROS, DCL formed a covalent bond with cysteine 280 in NACHT domain of NLRP3, thereby inhibiting the interaction between NLRP3 and NEK7. Furthermore, DCL exhibited protective effects in mouse models of NLRP3 inflammasome-mediated diseases, including dextran sulfate sodium-induced colitis, 2,4,6-trinitrobenzenesulfonic acid-induced Crohn's disease, LPS-induced septic shock, and monosodium urate-induced peritonitis. Our findings identify NLRP3 as the direct target of DCL, positioning DCL as a promising lead compound for treatment of NLRP3 inflammasome-related diseases.

Alzheimer's disease (AD) is one of the leading causes of dementia in the elderly, and no effective treatment is currently available. Cathepsin B (CTSB) is involved in key pathological processes of AD, but the underlying mechanisms and its relevance to AD diagnosis and treatment remain unclear. In the present study, we found that CTSB expression was abnormally elevated in the hippocampus of 3×Tg mice and was regulated by miR-96-5p. Abnormalities in the miR-96-5p/CTSB signaling pathway were detected in the serum of both mild cognitive impairment and AD patients, and the combination of serum miR-96-5p and CTSB demonstrated strong diagnostic efficacy for cognitive impairment (AUC = 0.7536). Abnormalities in the miR-96-5p/CTSB signaling pathway in AD may be associated with Aβ pathology, and neuronal CTSB can be released extracellularly to reactivate adjacent astrocytes. Ultimately, the reconstitution of the miR-96-5p/CTSB signaling pathway effectively rescued astrocyte reactivity and memory impairment in AD. Our findings suggest that the neuron-derived inflammatory mediator CTSB reactivates adjacent astrocytes and mediates memory impairment in early AD. The combination of serum miR-96-5p and CTSB represents potential serum biomarkers for cognitive impairment, and targeting the neuronal miR-96-5p/CTSB pathway may serve as a promising therapeutic strategy for AD.

Aging increases the global burden of disease, yet its molecular basis remains incompletely understood. Recent studies indicate that reversible epigenetic drift—spanning DNA methylation clocks, histone codes, three-dimensional chromatin, and noncoding RNA networks—constitutes a central regulator of organismal decline and age-related diseases. How these epigenetic layers interact across different tissues—and how best to translate them into therapeutic strategies—are still open questions. This review outlines the specific mechanisms by which epigenetic changes influence aging, highlighting their impact on genomic instability, stem-cell exhaustion, and mitochondrial dysfunction. We critically evaluate emerging rejuvenation strategies—partial OSKM reprogramming, CRISPR–dCas9 epigenome editing, NAD⁺/sirtuin boosters, HDAC inhibitors, microbiota transfer, and precision lifestyle interventions—detailing their efficacy in resetting epigenetic age and restoring tissue homeostasis. Integrating single-cell multiomics and second-generation epigenetic clocks, we propose a roadmap for translating these insights into safe, personalized antiaging medicine.

Tumor-associated macrophages (TAMs) are prominent constituents of solid tumors, and their prevalence is often associated with poor clinical outcomes. These highly adaptable immune cells undergo dynamic functional changes within the immunosuppressive tumor microenvironment (TME), engaging in reciprocal interactions with malignant cells. This bidirectional communication facilitates concurrent phenotypic transformation: tumor cells shift toward invasive mesenchymal states, whereas TAMs develop immunosuppressive, pro-tumorigenic traits. Increasing evidence highlights metabolic reprogramming, characterized by dysregulation of lipid metabolism, amino acid utilization, and glycolytic activity, as the fundamental molecular basis orchestrating this pathological symbiosis. However, a comprehensive understanding of how metabolic reprogramming specifically coordinates the mutual polarization of tumor cells and TAMs is lacking. This review thoroughly examines the molecular mechanisms governing this co-polarization process, detailing critical transcriptional regulators, essential signaling pathways, and the maintenance of adaptive phenotypes within the TME. Furthermore, this review critically assesses promising therapeutic strategies aimed at disrupting this alliance, including the use of metabolically targeted agents, engineered chimeric antigen receptor macrophages, and TAM-selective nanoparticle delivery systems. These insights provide a crucial foundation for the development of next-generation cancer immunotherapies focused on reprogramming pathological polarization dynamics to overcome treatment resistance and improve clinical outcomes.

The morphological patterns of lung adenocarcinoma (LUAD) are recognized for their prognostic significance, with ongoing debate regarding the optimal grading strategy. This study aimed to develop a clinical-grade, fully quantitative, and automated tool for pattern classification/quantification (PATQUANT), to evaluate existing grading strategies, and determine the optimal grading system. PATQUANT was trained on a high-quality dataset, manually annotated by expert pathologists. Several independent test datasets and 13 expert pathologists were involved in validation. Five large, multinational cohorts of resectable LUAD (patient n = 1120) were analyzed concerning prognostic value. PATQUANT demonstrated excellent pattern segmentation/classification accuracy and outperformed 8 out of 13 pathologists. The prognostic study revealed a distinct prognostic profile for the complex glandular pattern. While all contemporary grading systems had prognostic value, the predominant pattern-based and simplified IASLC systems were superior. We propose and validate two new, fully explainable grading principles, providing fine-grained, statistically independent patient risk stratification. We developed a fully automated, robust AI tool for pattern analysis/quantification that surpasses the performance of experienced pathologists. Additionally, we demonstrate the excellent prognostic capabilities of two new grading approaches that outperform traditional grading methods. We make our extensive agreement dataset publicly available to advance the developments in the field.

Immunoglobulin A nephropathy (IgAN), the most prevalent primary glomerulonephritis globally, is characterized by mesangial IgA deposition and heterogeneous clinical trajectories. Historically, management relied on renin–angiotensin system inhibition and empirical immunosuppression, yet high lifetime kidney failure risk persists despite optimized care. This review synthesizes advances in molecular pathogenesis, highlighting how the traditional multi-hit hypothesis—while foundational for targeted therapy development—fails to capture IgAN's recurrent, self-amplifying nature. We introduce the “spiral hypothesis” as a dynamic model of cyclical immune-injury cascades, better explaining disease chronicity and necessitating sustained maintenance therapy. Emerging targeted therapies—including B-cell targeted agents (e.g., APRIL/BAFF inhibitors), complement inhibitors (e.g., iptacopan), and mucosal immunomodulators (e.g., TRF-budesonide)—enable early intervention addressing both upstream immunological drivers and downstream fibrotic pathways. We critically evaluate treat-to-target frameworks, defining remission endpoints (proteinuria <0.3 g/day, hematuria resolution, estimated glomerular filtration rate slope <−1 mL/min/year) and emphasizing biomarker-guided personalization. The paradigm shift toward proactive management prioritizes individualized therapeutic sequencing of novel agents based on dynamic risk stratification. Future priorities include optimizing protocols for high-risk phenotypes and refining long-term safety monitoring to ensure sustainable efficacy.

Serotonin (5-hydroxytryptamine; 5-HT) is an evolutionarily conserved monoamine neurotransmitter that plays critical roles in various physiological systems, functioning as a neurotransmitter, hormone, and paracrine signaling molecule. This review synthesizes current research on 5-HT metabolism (biosynthesis, transport, and degradation), 5-HT receptor-mediated signaling pathways (seven receptor families and 14 subtypes), and broad biological functions of 5-HT. We emphasize the roles of 5-HT in both health and disease, with a particular focus on its emerging significance in the tumor immune microenvironment. Studies have shown that dysregulated 5-HT signaling is associated with various pathological conditions, including functional gastrointestinal disorders, psychiatric diseases, metabolic disorders, and cancer progression. Notably, this review describes novel mechanisms by which 5-HT modulates tumor immunity, including its effects on macrophage polarization, dendritic cell function, T cell activity, and PD-L1 expression, and it explores the therapeutic potential of targeting 5-HT-associated pathways. Promising therapeutic strategies that target 5-HT include combining selective serotonin reuptake inhibitors with immune checkpoint inhibitors, inhibiting key metabolic enzymes (e.g., Tph1 and MAO-A), and developing receptor subtype-specific agents (e.g., 5-HT₇R antagonists). These findings position the 5-HT system as a pivotal target for next-generation precision therapeutics across multiple disease domains.

Mitochondrial diseases are a heterogeneous group of inherited disorders caused by pathogenic variants in mitochondrial DNA (mtDNA) or nuclear genes encoding mitochondrial proteins, culminating in defective oxidative phosphorylation and multisystem involvement. Key pathogenic mechanisms include heteroplasmy driven threshold effects, excess reactive oxygen species, disrupted mitochondrial dynamics and mitophagy, abnormal calcium signaling, and compromised mtDNA repair, which together cause tissue-specific energy failure in high demand organs. Recent advances have expanded the therapeutic landscape. Precision mitochondrial genome editing—using mitochondrial zinc finger nucleases, mitochondrial transcription activator-like effector nucleases, DddA-derived cytosine base editor, and other base editing tools—enables targeted correction or rebalancing of mutant genomes, while highlighting challenges of delivery and off-target effects. In parallel, metabolic modulators (e.g., coenzyme Q10, idebenone, EPI-743) aim to restore bioenergetics, and mitochondrial replacement technologies and transplantation are being explored. Despite these promising strategies, major challenges remain, including off-target effects, precise delivery, and ethical considerations. Addressing these issues through multidisciplinary research and clinical translation holds promise for transforming mitochondrial disease management and improving patient outcomes. By bridging the understanding of mitochondrial dysfunction with advanced therapeutic interventions, this review aims to shed light on effective solutions for managing these complex disorders.

Neurodegenerative diseases present significant therapeutic challenges, primarily due to the restrictive nature of the blood–brain barrier (BBB), which limits drug delivery to the brain. While the BBB is crucial for protecting the brain from harmful substances, it also hinders the effectiveness of treatments for neurodegenerative diseases. Consequently, there is an urgent need for innovative drug delivery systems capable of bypassing the BBB to improve therapeutic outcomes. Exosomes, as endogenous nanoscale carriers, offer substantial promise for brain-targeted drug delivery. Their unique characteristics, including the ability to cross biological barriers, high biocompatibility, intrinsic targeting capacity, natural intracellular transport mechanisms, and robust stability, render them highly promising candidates for drug delivery in the treatment of neurodegenerative disorders. This review delves into various engineering strategies for exosome-mediated targeted drug delivery and provides an in-depth analysis of the structural and functional properties of the BBB under normal and pathological conditions. We emphasize the potential of exosomes as drug delivery vehicles for the central nervous system, particularly in addressing neurodegenerative disorders. Furthermore, we address the key obstacles to the clinical application of exosome-based therapies and propose future research directions aimed at optimizing these methods to develop more effective treatment strategies.

Natural killer (NK) cells are pivotal effectors in innate antitumor immunity by mediating cytotoxicity, secreting cytokines, or expressing cell membrane receptors, which facilitate interactions with other immune cells. The cytotoxic activity and immune function of NK cells are governed by dynamic receptor–ligand interactions, cytokine networks, and metabolic–epigenetic crosstalk within the tumor microenvironment (TME). Recent years, NK cell-based therapies are emerging as a promising clinical approach for antitumor treatment, owing to their rapid response, unique recognition mechanisms, potent cytotoxic capabilities, and memory-like characteristics, along with their low risk of posttreatment adverse effects and cost effectiveness. However, immunosuppression and metabolic reprogramming driven by TME subvert NK cell surveillance, impairing its antitumor function. This review comprehensively details molecular mechanisms underpinning NK cell dysfunction, including dysregulated activating/inhibitory receptor signaling, metabolic reprogramming, and epigenetic silencing of effector genes. We further synthesize advances in clinical strategies to restore NK cytotoxicity including ex vivo expansion for adoptive transfer, chimeric antigen receptor-NK engineering, TME-remodeling agents, immune checkpoint blockade, cytokine-based therapies, and NK cell engagers targeting tumor antigens. By bridging mechanistic insights with translational applications, this work provides a framework for rationally designed NK cell-based immunotherapies to overcome resistance across solid and hematologic malignancies.