Chronic wounds—such as diabetic foot ulcers (DFUs), pressure ulcers (PUs), and venous leg ulcers (VLUs)—pose a serious clinical challenge due to their prolonged inflammatory phase and impaired healing. Increasing evidence reveals that dysregulated immune responses are central to the pathogenesis of chronic wounds. A complex interplay between innate and adaptive immune cells, including macrophages, neutrophils, and T cells, contributes to chronic inflammation, extracellular matrix (ECM) degradation, and tissue repair failure. While current treatments target symptoms, they often overlook the underlying immunopathology. This review provides a comprehensive analysis of the immunomodulatory mechanisms governing chronic wound healing, emphasizing the distinct immune landscapes in DFUs, PUs and VLUs. It explores immunotherapeutic strategies including cytokine-based therapies, protease inhibitors, and biomaterials with immunoregulatory functions. Special attention is given to the emerging roles of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (EVs) in modulating inflammation, promoting angiogenesis, and enhancing tissue regeneration. Recent clinical trials of these therapies are also critically evaluated to bridge preclinical findings with translational relevance. By integrating immunology, regenerative medicine, and clinical insights, this review highlights novel targets and strategies for immunomodulation, providing a valuable framework for advancing precision therapies in chronic wound care.

Third-generation (third-gen) epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the management of advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, a head-to-head comparison of efficacy and safety among third-gen EGFR TKIs is lacking. Seven randomized controlled trials with 3012 patients were included. All third-gen TKIs significantly prolonged progression-free survival (PFS) compared to first-generation (first-gen) TKIs, with no significant differences in PFS or objective response rate among the third-gen TKIs. Furmonertinib ranked highest for PFS (HR, 0.82; 95% credible intervals [CrI], 0.72–0.94). Aumolertinib demonstrated the best intracranial control (HR, 0.74; 95% CrI, 0.63–0.89). Osimertinib (HR, 0.90; 95% CrI, 0.83–0.99) and lazertinib (HR, 0.89; 95% CrI, 0.79–1.00) showed overall survival benefits over first-gen TKIs. Furmonertinib, aumolertinib, and osimertinib had lower rates of severe treatment-related adverse events (TRAEs), while befotertinib exhibited the highest risk of grade ≥3 TRAEs (RR, 3.96; 95% CrI, 2.35–7.17). This study is the first head-to-head comparison of third-gen EGFR-TKIs using a Bayesian network meta-analysis, offering critical insights into efficacy and safety. Our results support personalized selection of third-gen EGFR TKIs for patients with advanced EGFR-mutated NSCLC, particularly for subpopulations with CNS metastases or different mutation subtypes.

Extracellular vesicles (EVs) can cross the blood–brain barrier and enter the systemic circulation, potentially acting as peripheral biomarkers of stroke neuropathology. Here, we investigated alterations in EV RNA cargoes extracted from rat brain and plasma before and after stroke induction via middle cerebral artery occlusion and subsequent human neural stem cells (hNSCs) transplantation. EV RNA coexpression profiles were assessed, and digital source tracking was used to determine EV origin. The therapeutic effects of intra-arterial delivery of hNSCs on ischemic rat brains were quantified, focusing on functional recovery, resolution of ischemic lesions, and the microenvironment. Stroke induced distinct EV secretion patterns, with a notable increase in EV secretion from non-neuronal cells. hNSCs transplantation caused minimal immune rejection and transplanted cells survived in the brain for over a week. Stem cell-derived EVs were detected in peripheral blood, indicating prolonged systemic distribution after transplantation. Gene regulatory network analyses identified specific EV miRNAs that play crucial roles in neurogenesis, wound healing, angiogenesis, and blood–brain barrier integrity. An integrated analysis of EV RNAs in brain and plasma samples revealed that stroke increased correlations in RNA expression between brain and plasma and that hNSCs transplantation reversed the effect. Brain- and plasma-derived EVs carry similar molecular information after stroke, suggesting that plasma-derived EV RNAs reflect stroke pathophysiology. Intra-arterial transplantation of hNSCs improved outcomes after stroke in rats, by promoting endogenous neurogenesis and maintaining blood–brain barrier integrity. The identified EV miRNAs provided a new mechanism by which hNSCs transplantation regulates neural regeneration through the miR-204-5p/EFNB3 axis.

Cancer-associated fibroblasts (CAFs) are pivotal stromal components that shape the tumor microenvironment through their remarkable heterogeneity and dynamic functions. This review comprehensively examines the biology of CAFs, starting with their diverse cellular origins and induction mechanisms via key signaling pathways. We highlight the spatial-temporal heterogeneity of CAF subsets and propose an updated classification system that encompasses eight functionally distinct subtypes based on recent single-cell transcriptomic studies. The tumor-promoting roles of CAFs are explored in depth, including their contributions to tumor behavior through novel mechanisms such as neutrophil extracellular traps formation, and multidrug resistance via metabolic reprogramming. A major focus is placed on CAF-mediated immunotherapy resistance through immune checkpoint regulation, recruitment of immunosuppressive cells, and metabolite secretion. This review also highlights key technologies that are advancing CAF research, including patient-derived 3D models, artificial intelligence-enhanced spatial multiomics, clustered regularly interspaced short palindromic repeats (CRISPR)-engineered mouse systems, and machine learning approaches for analyzing CAF heterogeneity and function. Finally, we evaluate therapeutic strategies targeting CAF activation, secreted factors, and immune crosstalk, while critically analyzing ongoing clinical trials. Overall, this review not only clarifies the biology of CAFs but also provides a translational framework for developing next-generation stromal-targeted therapies to overcome treatment resistance in cancer.

Cancer is a leading cause of morbidity and mortality worldwide. There exists a correlation between certain cancers and dietary factors. Several known carcinogens are present in the standard American diet, also known as the Western Diet. Additionally, food preparation methods can initiate carcinogenesis. Various dietary components, particularly plant-based foods, contain bioactive phytochemicals, have demonstrated potential anticancer effects through various molecular mechanisms. Consuming a wide variety of these so-called “cancer-fighting” foods may lead to synergism in preventing and slowing cancer progression. The nutritional intervention is also beneficial in cancer therapy, including avoiding malnutrition and cachexia and alleviating cancer therapy-induced symptoms as well as the use of specific diets that may augment concomitant therapies. This review aims to explore these concepts and highlight the need for their integration into medical school curriculum, particularly osteopathic medical education, as nutrition is closely interrelated to the whole-person patient care approach. These are fundamental concepts that do not gain the recognition they deserve in the typical medical school curriculum, and this may be reflected in clinical outcomes if not appropriately addressed. Addressing this gap in clinical medicine may reduce the risk of cancer, improve patient outcomes, build trust, and decrease the burden of cancer-related healthcare costs.

Given the lack of reliable indicators for predicting prognosis and treatment response in giant cell tumor of bone (GCTB) patients, this study aimed to identify new prognostic factors by analyzing the effect of tumor-associated macrophages (TAMs) on prognosis and denosumab treatment responsiveness. The expression of CD68⁺TAMs, CD163⁺TAMs, and IRF8⁺TAMs was detected using polychromatic fluorescence immunohistochemistry in 162 GCTB samples. TAM density was quantified through computer-aided image analysis, and spatial parameters, including nearest neighbor distance (NND) and effective percentage (EP), were measured using HALO software. Results showed that higher densities of CD68⁺ and CD163⁺ TAMs were significantly associated with inferior progression-free survival (PFS). A smaller NND was linked to shorter PFS. Additionally, higher CD68⁺ EP was associated with poorer PFS, whereas higher CD163⁺ EP correlated with better PFS. Receiver operating characteristic curve analysis demonstrated that TAM parameters' predictive performance was comparable to Campanacci and surgical approach in three subgroups. The ineffective denosumab-treated group had significantly higher TAMs EP compared to the effective group. In conclusion, TAMs significantly influence the prognosis of GCTB patients and are correlated with certain invasive tumor phenotypes. Elevated TAMs levels may be associated with reduced efficacy of denosumab treatment.

Promoting thermogenesis in adipose tissue to enhance energy expenditure is widely regarded as a promising strategy for obesity treatment. However, the development of effective thermogenic drugs remains challenging. Our screenings identified the natural compound Akebia Saponin D (ASD) as a potent brown fat thermogenesis activator in mice, showing effects through mitochondrial brown fat uncoupling protein 1 (UCP1)-dependent pathways. ASD was found to significantly mitigate high-fat diet-induced obesity and enhance the mitochondrial quality of brown adipocytes to promote thermogenesis. Utilizing human protein microarrays, cellular thermal shift assay, and drug affinity responsive target stability, along with microscale thermophoresis and molecular docking analysis, we identified ubiquitin carboxyl-terminal hydrolase 4 (USP4) as a direct target of ASD. ASD interacts with USP4 and promotes the deubiquitination of peroxisome proliferator-activated receptor gamma, thus inhibiting its proteasomal degradation and enhancing the transcriptional activation of UCP1 in brown adipocytes. Additionally, USP4 knockdown was shown to attenuate brown fat thermogenesis induced by ASD. In summary, our findings demonstrate that ASD promotes brown fat thermogenesis by targeting USP4, highlighting its potential as a promising natural small molecule for obesity treatment.

Histone lactylation, particularly histone H3 lysine 18 lactylation (H3K18la), modulates gene expression profile in diverse cellular processes, which has emerged as a critical factor in cardiovascular disease pathogenesis. However, its specific role in cardiac hypertrophy remains unclear. This study investigates the mechanism of H3K18la in promoting cardiac hypertrophy using transverse aortic constriction-induced mice model and a phenylephrine-induced hypertrophic cardiomyocyte model. We found that elevated levels of Pan-Kla and H3K18la were detected in hypertrophic left ventricular tissues and cardiomyocytes, accompanied by increased heart and left ventricle weights, enlarged cardiomyocyte cross-sectional areas and heightened expression of ANP, BNP, and β-MHC. Clinical observations revealed a positive correlation between serum lactate levels and hypertrophic cardiomyopathy in patients. Furthermore, inhibition of lactylation reversed these effects, suggesting a direct role of H3K18la in hypertrophic gene expression. Mechanistically, H3K18la was found to interact with GATA4, enhancing its transcriptional activity as demonstrated by increased ANP promoter activity. Moreover, suppression of GATA4 mitigated the hypertrophic response, highlighting its crucial role downstream of H3K18la. Our findings identify H3K18la lactylation as a novel epigenetic mechanism driving cardiac hypertrophy through GATA4 activation. This implicates potential therapeutic targets for hypertrophic heart diseases.

The aryl hydrocarbon receptor (AhR) functions as a ligand-dependent transcription factor, serving as a pivotal environmental sensor that significantly influences both physiological and pathological processes. The inactivated state of AhR is present in the cell cytoplasm and transfer into the nucleus upon activation by a variety of ligands. It subsequently regulates a variety of processes including cellular metabolism, organ and tissue development, and maintenance of immune homeostasis. Despite substantial advancements over the past decade, the mechanisms by which AhR specifically regulates immune cell function in response to environmental factors and influences disease progression remain not fully elucidated. This review systematically analyzes the basic structure and major signaling pathways of AhR, its physiological functions in maintaining organismal homeostasis and its mechanism of action on various types of immune cells, and their therapeutic potential in autoimmune diseases, inflammatory disorders, tumor microenvironment, and neurodegenerative diseases. Translating immune-metabolic reprogramming mechanisms into clinical applications represents a pivotal challenge in AhR research. And this review integrates and analyzes the great potential of AhR as a pleiotropic therapeutic target for regulating immunity and treating a series of diseases, offering actionable frameworks for future exploration.

Immune checkpoint blockade has become an effective strategy for inhibiting tumor growth, especially immune checkpoint inhibitors that target the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, which have shown significant effects in tumor immunotherapy. In this study, we found that naturally sourced Cordyceps militaris extract can effectively downregulate the protein expression level of PD-L1 in human colorectal cancer cell lines. Further systematic isolation, purification, and analysis of its active components revealed that cordycepin (COR) is the key active molecule mediating PD-L1 degradation. Mechanistically, COR specifically and selectively targets the ubiquitin E3 ligase HMG-CoA reductase degradation protein 1, thus promoting the degradation of PD-L1 protein through the ubiquitin–proteasome pathway. This process significantly enhances the cytotoxic killing effect of effector T lymphocytes against colorectal cancer cells, ultimately achieving robust antitumor effects. Furthermore, this study also revealed that COR exhibits potential synergistic therapeutic effects when combined with anti-CTLA4 antibodies in preclinical tumor treatment. In summary, COR, as the primary bioactive component of Cordycepsmilitaris, demonstrates considerable potential to act as a small-molecule immune checkpoint modulator and inhibitor, thereby providing a novel therapeutic strategy for the immunotherapy of colorectal cancer.

The proliferation of fibroblast-like synoviocytes (FLS) and macrophage-mediated inflammation are the main clinical features of rheumatoid arthritis (RA). Studies showed that insulin-like growth factor-2 mRNA binding protein-3 (IGF2BP3) may be involved in regulating the biological functions of different immune cells and FLS. Therefore, the identification of drugs that target IGF2BP3 has important clinical significance for improving RA. Molecular docking and surface plasmon resonance (SPR) analyses were used to identify a small molecule compound targeting IGF2BP3, celastrol (CEL). We subsequently examined the effects of CEL on RAW264.7 cells and FLS. IGF2BP3 knockout (KO) arthritis mice were used to identify the targets and mechanism of CEL in relieving RA. We found that CEL could bind to IGF2BP3 closely and reduce its expression. Additionally, CEL not only inhibited RA-FLS proliferation but also decreased the inflammatory activation of macrophages. The IGF2BP3–RASGRF1–mTORC1 was critical for CEL-mediated amelioration of RA. KO-IGF2BP3 arthritis mice further showed that the protective effect of CEL against arthritis depended on IGF2BP3. Collectively, this study revealed that CEL inhibited the IGF2BP3/RASGRF1/mTORC1 axis to reduce cell proliferation and inflammatory activation, thereby alleviating the progression of RA. Our study suggests that clinical attention should be given to IGF2BP3 inhibitors, such as CEL.

Gefitinib is the most frequently employed anti-lung cancer drug, but its clinical effectiveness is often compromised due to the development of drug resistance. Given that gefitinib failure to long-term inhibition of the growth of lung carcinoma cell lines, which mirrors the resistance observed in clinical patients, new approaches to improve the curative effect of gefitinib should be found. Surprisedly, inhibiting separase with the specific inhibitor Sepin-1 has been found to effectively enhance gefitinib-induced cytotoxic in lung cancer cell by promoting the development of PANoptosis, which includes pyroptosis, apoptosis, and necroptosis. Moreover, in vivo experiments also demonstrated that the combination of Sepin-1 and gefitinib can induce significant regression of lung xenograft tissues. Mechanically, loss of separase plus gefitinib decreases the expression of PTBP1 and TAK1. Overexpression of PTBP1 or TAK1 suppresses this interaction-induced PANoptosis by promoting the inactivation of RIPK1. In addition, clinical data showed that better effective of gefitinib maybe associated with lower separase expression or higher PANoptosis marker expression in patient lung carcinoma tissues. Thus, these findings provide a novel anti-lung cancer strategy and highlight separase as a potential target for overcoming gefitinib resistance in lung cancer treatment.

Oculocutaneous albinism (OCA) represents a genetically heterogeneous autosomal recessive condition marked by reduced melanin production in cutaneous and ocular tissues. This disorder primarily arises from mutations in the TYR gene, which encodes tyrosinase—the rate-limiting enzyme in melanogenesis. Such genetic defects lead to impaired or absent tyrosinase activity, consequently causing melanin deficiency. Currently, no curative treatment exists for OCA1. In this study, we investigated the efficacy of AAV vector-based gene therapy in two murine models of OCA1, evaluating its potential as a therapeutic intervention. B6 albino mice were injected with three AAV8 vectors containing distinct promoters at different dosages, among which AAV8.hRPE65p.hTYRco showed the best therapeutic effect at a dose of 1 × 10⁹ GC/eye. This RPE-targeted strategy restored the expression of functional tyrosinase and melanin deposition in the RPE layer. More importantly, the retinal structure and visual function were maintained at nearly normal levels for up to 12 months, with no obvious toxicity. In addition, we demonstrated that the suprachoroidal cavity delivery of AAV8.hRPE65p.hTYRco restored the expression of tyrosinase and relieved ocular dysfunction in Wistar rats for at least 12 months. The results revealed a long-term, effective, safe strategy for treating OCA1.

Messenger RNA (mRNA) vaccines, as a novel class of biotherapeutics, leverage mRNA technology to instruct cells to produce specific antigens, thereby inducing an immune response. In recent years, significant progress has been made in applying these vaccines to infectious disease prevention and cancer treatment. Compared with traditional vaccines, mRNA vaccines offer high programmability, as well as greatly enhanced stability and immunogenicity, achieved through nucleotide modifications and advanced delivery systems such as lipid nanoparticles. However, many challenges remain in the design and delivery of mRNA vaccines, particularly for complex conditions like cancer. This review explores the latest advances and future prospects of mRNA vaccines in both infectious disease prevention and cancer therapy. It discusses the mechanisms of tumor immune escape and examines the potential of mRNA vaccines to overcome tumor immune resistance. The review also analyzes strategies for tumor vaccine design and the development of novel delivery systems, projecting the future role of mRNA vaccines in cancer therapy. By providing theoretical guidance and technical insights, this review aims to expand the development of mRNA vaccines across broader disease areas. It offers both a theoretical framework and a practical reference for researchers focused on infectious disease control and precision cancer immunotherapy. Ultimately, these insights will help advance the clinical application of next-generation mRNA therapeutics.

Circadian rhythms are intrinsic 24-h biological cycles that govern various physiological processes. In addition to the hypothalamic suprachiasmatic nucleus, the circadian system is organized in multiple peripheral tissues, such as the brain, heart, bone, liver, and lung. Emerging evidence suggests that disruptions in these rhythms, which are regulated by a network of clock genes, play pivotal roles in human health. A deeper understanding of the interplay between circadian rhythms and tissue homeostasis holds significant potential for the development of targeted therapies aimed at improving human health. This review explores the link between circadian rhythms and tissue homeostasis, delving into their biological functions, including influences on metabolic homeostasis, neuroendocrine signaling, immune and oxidative stress responses, tissue repair, and autophagy activity. It also summarizes the connections between circadian disruptions and circadian disruption-related diseases, including degenerative diseases, cardiometabolic disorders, and cancers. Furthermore, this review offers valuable perspectives on the treatment of circadian disruption-related diseases. By revealing the regulatory influence of circadian rhythms on human health and disease, this work aims to inspire the development of novel strategies for the prevention, diagnosis, and treatment of circadian disruption-related diseases.

Acute spontaneous intracerebral hemorrhage (ICH) remains a severe and challenging cerebrovascular condition, associated with high rates of morbidity and mortality. The pathophysiology of injury following ICH involves mass effect, increased intracranial pressure, hematoma expansion, and toxicity from blood-breakdown products. Over the past decade, substantial progress has been made in risk stratification, therapeutic strategies, and outcome prognostication. Although case-fatality rates have declined with advances in neuroimaging, acute care, and surgical techniques, functional outcomes remain poor, with little improvement. Several trials have investigated the optimal medical and surgical treatments for ICH, but none have shown significant improvements in outcomes or survival. This review aims to provide a comprehensive overview of ICH, including its epidemiology, associated costs, pathophysiological mechanisms, and management approaches. Herein, we explored recent advancements in neuroimaging techniques and their roles in diagnosing ICH and predicting patient outcomes. Additionally, we assessed the impact of prehospital and in-hospital management practices, such as pharmacological and surgical interventions, and discussed the implications of delays before final treatment. By summarizing current research and evidence-based practices, this review aims to highlight established and emerging strategies for improving outcomes for patients with ICH and identify areas for future research and development in the field.

During the course of cancer, metastatic cells frequently enter a state of dormancy that can be controlled by the immune system. In our laboratory, we developed a preclinical mouse model of metastatic immunodormancy. Dormant spontaneous metastases are controlled by the immune system of wild-type mice. Depletion of the host immune system causes these metastases to awaken and progress. Dormant metastases are compared with nude metastases and overt metastases that have never been in dormancy. The findings of the study indicate that the dormant metastases exhibit a unique and differentiated phenotype. This is evidenced by their varied response to nutrient-restrictive conditions, chemotherapeutic agents, and cytokines in vitro. Furthermore, dormant metastases exhibit a distinctive transcriptional pattern of gene expression, which is predominantly promoted by the Ch25h gene. Additionally, the analysis revealed differential expression of microRNAs, with elevated levels of mir-142-3p being expressed de novo. The microenvironment of dormant metastases shows an increase in T lymphocytes (cytotoxic and helper T lymphocytes and γδ T cells) and neutrophils. Immune-controlled dormant metastases exhibit a unique phenotype that can be exploited to discover new biomarkers, as well as to develop therapies to eradicate them or control overt metastases.

Anemia poses a life-threatening risk to individuals with chronic kidney diseases (CKDs). Insufficient production of erythropoietin (EPO) from the injured kidney is the major reason for anemia, while lack of EPO would further aggravate the kidney injury and make a “vicious cycle.” In this study, we dissected the change of endogenous EPO signaling in the injured kidney by spatial transcriptomic analysis and validated the dual beneficial effects of local recombinant EPO administration on both anemia correction and kidney protection. Next, we constructed an injury-responsive EPO-producing (iREP) element to sense the kidney damage signal and drive the synthesis and secretion of native EPO. After intrarenal implantation of iREP-engineered HEK–293T embryonic kidney cells, the mouse kidney would automatically produce more EPO when sensing injury signal, which in turn enhanced red blood cell count and protected the kidney from further injury. Moreover, we cloned urine-derived SOX9+ epithelial cells (USCs) from healthy donors. The USCs can be transplanted into mouse kidneys, which makes them an alternative candidate cell for iREP engineering. Altogether, the current work proposed a potential approach based on an engineered “smart” cell to treat CKDs.

Atherosclerosis remains the primary driver of cardiovascular and cerebrovascular morbidity and mortality. A pivotal event in its pathogenesis is the phenotypic conversion of vascular smooth muscle cells (VSMCs), particularly the transition from a contractile to a macrophage-like state. Using a murine model of atherosclerosis, we demonstrate that this process is orchestrated by a progressively disrupted perivascular immune milieu characterized by an expansion of CD44⁺ memory CD4⁺ T cells at the expense of CD44⁻ naive CD4⁺ T cells. Within this niche, CD44⁺ natural regulatory T cells (nTregs) actively promote VSMCs macrophage-like reprogramming, whereas their CD44⁻ counterparts exert an opposing, protective effect. Reciprocally, macrophage-like VSMCs foster the trans-differentiation of nTregs into pathogenic Th17 cells, amplifying vascular inflammation. In contrast, induced Treg cells (iTregs) display phenotypic stability and potently inhibit VSMCs macrophage-like switching, restrict pathological VSMCs migration, and curtail VSMCs survival. Systemic infusion of iTregs selectively remodels the perivascular immune microenvironment toward an antiatherogenic profile. Adoptive transfer of iTregs at early disease stages decreased the abundance of macrophage-like VSMCs, attenuated plaque burden, and these benefits were partially mediated by transforming growth factor β signaling. Collectively, iTreg-based cellular therapy represents a promising strategy to intercept VSMCs macrophage-like transformation and limit atherosclerotic progression.

Childhood blood pressure (BP) is associated with increased arterial stiffness later in life. This study aimed to investigate the contributions of BP across different life stages to midlife arterial stiffness and the mediating role of metabolic factors. Using data from the Hanzhong Adolescent Hypertension Study, 1448 participants aged 6–18 years at baseline were prospectively followed for 30 years into adulthood. We used linear regression models to examine the associations between BP at different life stages and brachial-ankle pulse wave velocity (baPWV). In addition, parallel multiple mediation analyses were conducted to evaluate the mediating roles of blood glucose and lipid metabolism in these associations. Significant associations between BP and adult baPWV were observed across childhood, adulthood, and cumulative long-term BP burden, with BP in adulthood showing the strongest association. Additionally, the triglyceride–glucose index was identified as a mediator in the relationship between adult BP and midlife baPWV, with the mediation effects more pronounced among males. Our findings suggest that the detrimental impact of elevated BP on arterial stiffness begins early in life and intensifies over the lifespan, particularly during adulthood. Furthermore, the association between adult BP and arterial stiffness appears to be partially mediated by insulin resistance.

The tremor-dominant (TD) subtype of Parkinson's disease (PD) is characterized by prominent tremor symptoms. However, the temporal and causal relationships between brain structural alterations in TD patients remain unexplored. A total of 61 TD patients and 61 matched healthy controls (HCs) were included in this study. The gray matter volume (GMV) of the bilateral precuneus (PCUN) was significantly reduced in TD patients. A structural covariance network analysis seeded with the left pallidum (PAL.L), which had the most significant differences, revealed a substantial reduction in covariance with precentral gyrus in TD patients. We performed a causal structural covariance network analysis using the TD duration as a pseudotime series. The PCUN, with the highest out-degree in the cortex, regulates numerous regions, including the supplementary motor area and the extensive temporal lobe. Machine learning was utilized to construct a model that accurately assesses the surgical prognosis based on the above cortical volume and clinical scale, with the aim of assisting in clinical deep brain stimulation (DBS) treatment. These findings suggested a progressive pattern of GMV changes extending from the PAL.L to the PCUN region and continuing to other brain regions, providing insights into the progression of TD and enhancing DBS treatment strategies.

Fibrotic disease involves excessive fibrous connective tissue accumulation in organs, leading to dysfunction and irreversible damage. Metabolic alterations can sometimes contribute to fibrosis development. This study aimed to develop dual agonists for farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor alpha (PPARα), targeting anti-fibrosis and metabolic regulation. Benzoxazole derivatives were found to potently activate both FXR and PPARα in hepatocytes. Among them, MHY5396 showed the most potent effects with low EC₅₀ values. MHY5396 reduced lipid synthesis and enhanced beta-oxidation in hepatocytes, decreasing lipid accumulation. It also suppressed TGFβ-induced fibrosis in hepatic stellate cells. In a methionine/choline-deficient diet mouse model, MHY5396 reduced lipid accumulation, liver damage, and fibrosis. In a thioacetamide-induced liver fibrosis model, MHY5396 had an anti-fibrotic effect comparable to obeticholic acid, a potent FXR agonist. MHY5396 also significantly reduced inflammation and fibrosis in renal cells and a folic acid-induced renal fibrosis mouse model. Pharmacokinetic studies showed that orally administered MHY5396 was well absorbed (F = 98.6%) and primarily metabolized by hepatic CYP1A2 with negligible urinary excretion. Overall, MHY5396, with dual FXR and PPARα agonist activity, exhibited significant anti-fibrotic and metabolic regulatory properties in liver and kidney fibrosis models, presenting a novel therapeutic potential for fibrotic diseases.

Esophageal squamous cell carcinoma (ESCC) tissues exhibit abnormal N6-methyladenosine (m6A) modification and regulator levels, but the specific effects of this dysregulation on ESCC remain unclear. WASF3 levels were significantly elevated in ESCC tissues, and ESCC patients with high WASF3 expression had significantly worse prognosis. WASF3 suppressed the proliferation of ESCC cells and inhibited colony formation and cell cycle progression. Mechanistically, METTL3 interacted with WASF3 and mediated m6A modification of its mRNA. Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) enhanced WASF3 translation by binding to the m6A site in its 3′ untranslated region, and highly expressed WASF3 activated the mitogen-activated protein kinase (MAPK) signaling pathway by interacting with phosphorylated p38 (p-p38), thereby promoting ESCC progression. Moreover, removal of the m6A modification of WASF3 mRNA inhibited WASF3 expression, ESCC cell proliferation, and abolished the ability of WASF3 to bind to p-p38 and activate MAPK signaling. LNP small interfering RNA targeting WASF3, both alone and in combination with paclitaxel, could successfully suppress ESCC tumorigenesis. Our findings demonstrate that WASF3 plays a pivotal role in ESCC and highlight the functional significance of the METTL3/m6A/WASF3/IGF2BP2 axis in regulating ESCC progression, which could facilitate the development of novel prognostic and therapeutic targets for ESCC.

This study aimed to identify novel phenotypes in patients with exacerbations of chronic obstructive pulmonary disease (ECOPD) to enable precise management, as current phenotypic classifications show limited utility in predicting patient prognosis. By analyzing data from a robust, retrospective multicenter registry (n = 13,449) and leveraging 133 biomarkers with penalized Cox models, we developed a six-phenotype latent class analysis model. Phenotype 1 is distinguished by elevated direct bilirubin (Dbil) and lactate dehydrogenase (LDH). Phenotype 2 features a higher percentage of lymphocytes (LYMPH_pct) and lower percentage of neutrophils (NEUT_pct). Phenotype 3 is marked by increased generalized cardiovascular disease (gCVD) and reduced NEUT_pct. Phenotype 4 is related to higher NEUT_pct and lower LYMPH_pct. Phenotype 5 is associated with a higher prevalence of gCVD and surgical trauma history. Phenotype 6 stands out for its higher rates of respiratory failure and elevated pulse at admission. Compared with Phenotype 1, patients in Phenotype 6 have a significantly higher risk of all-cause mortality in both the development and validation sets, with adjusted hazard ratios of 2.06 (95% CI: 1.38–3.08) and 2.51 (95% CI: 1.43–4.04), respectively. These findings reveal novel ECOPD subgroups with significant prognostic differences, providing a crucial framework for implementing precision health management and improving patient outcomes.

Mucosal-associated invariant T (MAIT) cells are a highly conserved population of immune cells that can be activated via the major histocompatibility complex class I-related protein pathway or cytokine pathways, playing a central role in immune surveillance. This review provides comprehensive information on their thymic developmental origin, tissue-specific distribution, and microbial regulatory networks, with a focus on analyzing the bidirectional regulatory mechanisms in diseases. In infectious diseases, MAIT cells eliminate pathogens through the rapid release of cytokines; however, sustained antigen exposure leads to functional exhaustion. In autoimmune diseases, their migration disorders and proinflammatory cytokine secretion of MAIT cells exacerbate tissue damage. In the tumor microenvironment, they play a paradoxical role, being capable of mediating antitumor effects while also being reprogrammed into a protumor phenotype. Based on their tissue targeting ability and functional plasticity, we discuss novel strategies for targeted therapy, including engineering chimeric antigen receptor–MAIT cells to enhance tumor killing, blocking exhaustion pathways to reverse functional impairment, and regulating the microbiota–metabolic axis to reprogram cell activity. This review integrates cutting-edge evidence, reveals the translational potential of MAIT cells as a cross-disease regulatory hub, and provides a theoretical framework for precision immunotherapy.

Lichen secondary metabolites have shown potential in cancer therapy, but strategies to enhance cancer-specific selectivity are needed. Here, we synthesized depside compounds structurally related to tumidulin (TU) and diffractaic acid (DA) and screened them in vitro, identifying SB4 and SB5 as potent hits. Affinity-based proteomics revealed direct binding to voltage-dependent anion channel 1 (VDAC1), prohibitin (PHB), and matrix metalloproteinase-9 (MMP9), which regulate cancer stemness, motility, metabolism, and apoptosis. SB4 and SB5 exhibited strong cytotoxicity, suppressed cancer stem cell characteristics, inhibited cell motility, impaired mitochondrial respiration, induced reactive oxygen species, and promoted apoptosis. Notably, they reversed cetuximab-induced cancer stemness in colorectal adenocarcinoma-enriched stem cells. In vivo, SB4 and SB5 displayed higher tumor, liver, and intestinal bioavailability than TU and DA following intraperitoneal administration. Pharmacokinetic analyses indicated SB4 had a comparable absorption profile to SB5 with distinct systemic exposures differences. In a CT26/near-infrared fluorescent protein tumor model, SB4 markedly inhibited tumor growth and modulated key markers of stemness, motility, metabolism, and apoptosis in tumor tissues. Collectively, these findings demonstrate that SB4 and SB5 are promising candidates for colorectal cancer therapy by targeting VDAC1/PHB/MMP9.

Antimicrobial-resistant bacteria, a growing worldwide concern, reduce the effectiveness of antibiotics against a wide range of microbial infections. Various bacterial species have quickly developed antibiotic resistance since the first mention of penicillin resistance in 1947. A rise in mortality, more extended hospital stays, more healthcare expenditures, and morbidity are all brought about by these bacteria that are resistant to antibiotics. To develop resistance, bacteria may undergo genetic changes, engage in horizontal gene transfer, produce β-lactamase, activate efflux pumps, form biofilms, and alter their metabolism to become less susceptible to drugs. Environmental factors and sublethal antibiotic exposure exacerbate resistance, particularly in cases of persistent infections caused by biofilms. This tendency is prompted by the overuse of antibiotics in both human and veterinary medicine, as well as inadequate infection control measures and environmental pollution. This review presents an extensive survey of antimicrobial resistance across bacterial taxa, with a focus on the physiological and genetic processes underlying this phenomenon. It delves into the current therapeutic landscape and showcases cutting-edge methods—such as artificial intelligence-driven antibiotic discovery and resistance prediction—to inform the development of next-generation antibiotics and containment systems.

The precise identification of immune cell type responses to alcoholic steatohepatitis (ASH) at the single-cell level remains unresolved. Therefore, in this study, we analyzed heterogeneous immune leukocytes associated with ASH at the single-cell level using high-dimensional single-cell RNA sequencing in alcoholic liver disease (ALD)-induced and healthy control mice. A t-distributed stochastic neighbor embedding plot for dimensionality reduction and 2D visualization was used to visualize heterogeneous immune cell types. Moreover, singleR was used for automated cell annotation to identify the cell types and differentially expressed genes from each cell type and their subsets. We observed a decline in the population of B cells and their subsets, with up and downregulated genes signifying an innate proinflammatory response as an important indication of alcohol-induced liver fibrosis. Additionally, neutrophil deficiency in the alcohol-induced mouse group was associated with ASH. An increase in eosinophils diverts further complications in liver fibrosis, suggesting the functional heterogeneity of granulocyte subsets. Overall, our findings may assist in discovering potential ALD biomarker cell types that are significantly reduced by frequent alcohol exposure and enhance our understanding of the circulating immune leukocytes that lead to alcohol-induced liver fibrosis.

Thyroid cancer is the most common endocrine malignancy, with incidence rising steadily worldwide. Although most cases are differentiated thyroid carcinomas with excellent prognosis, a small subset, such as anaplastic thyroid cancer, demonstrates aggressive behavior and poor survival outcomes. Recent decades have witnessed a transformation in thyroid cancer diagnostics and management, driven by improvements in high-resolution ultrasound, fine-needle aspiration biopsy, molecular profiling, and standardized risk stratification systems such as the Thyroid Imaging Reporting and Data System. Despite these advances, overdiagnosis and overtreatment remain key clinical challenges. Accurate risk stratification and management strategies are critical, especially for distinguishing indolent nodules from aggressive subtypes. This review provides a comprehensive overview of thyroid cancer pathogenesis, clinicopathological classification, diagnostic approaches, and evolving therapeutic strategies, ranging from active surveillance to targeted and immunotherapy-based treatments. By integrating molecular diagnostics with conventional parameters, the article underscores how precision medicine can reduce treatment burden, improve outcomes, and guide personalized care. This review offers valuable insight into the biological complexity of thyroid cancer and highlights the need for continued refinement of diagnostic criteria and therapeutic frameworks in clinical practice.

Achieving clinical remission in rheumatoid arthritis (RA) remains a significant challenge in current therapeutic strategies. While transplantation of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) has shown promising outcomes, therapeutic responses vary considerably among patients. In this study, we characterized the immune profiles of nonresponders and identified elevated expression of inducible costimulator (ICOS) in peripheral immune cells as a critical barrier to effective treatment. This upregulation, combined with the presence of ICOS ligand (ICOSL) on UC-MSCs, activated T cells to secrete inflammatory cytokines through the Phosphatidylinositol 3-kinase / Protein kinase B / Mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. To overcome this limitation, we identified silybin as a potential adjunctive agent. Further investigations demonstrated that silybin acts as a competitive binding inhibitor, effectively targeting the PI3K/AKT/mTOR pathway and reducing downstream cytokine release. The combined application of silybin and UC-MSCs significantly enhanced immunoregulatory effects, as validated through in vitro analyses with patient-derived samples and in vivo experiments using a collagen-induced arthritis mouse model. This study highlights a novel, personalized therapeutic approach for RA, offering insights into improving clinical outcomes through targeted interventions.

Ischemic stroke remains a leading cause of global disability and death. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as potent lipid-lowering agents with expanding therapeutic potential. Beyond robust low-density lipoprotein cholesterol reduction, accumulating evidence suggests these drugs may confer benefits in ischemic stroke prevention and management. However, challenges regarding accessibility, real-world efficacy, and integration into combination therapies persist, necessitating a comprehensive evidence synthesis. This review systematically consolidates the molecular mechanisms of PCSK9 inhibition and classifies current inhibitors. We delineate recent preclinical advances underscoring their neuroprotective and vasculoprotective effects, alongside critical findings from major clinical trials. These developments highlight promising avenues for both secondary prevention and acute-phase treatment strategies. Collectively, this synthesis establishes a foundational framework for positioning PCSK9 inhibitors as transformative agents in stroke therapeutics and paves the way for precision neurovascular medicine.

Human endogenous retroviruses (HERVs), remnants of ancient retroviral infections, comprise nearly 8% of the human genome and play dual roles in physiological regulation and disease pathogenesis. Once considered genomic “fossils,” HERVs are now known to dynamically influence gene expression, immunity, and homeostasis via epigenetic regulation, molecular mimicry, and viral mimicry. Their structural components, including long terminal repeats and conserved viral genes, enable them to act as regulatory elements and potential sources of novel antigens. However, the causal mechanisms linking the dysregulation of HERVs to diseases—the technical challenges in their detection and quantification, as well as their therapeutic potential—remain poorly systematized. This review synthesizes the molecular architecture and evolutionary trajectories of HERVs, emphasizing their tissue-specific expression patterns. We further delineates their pathogenic roles in diseases including cancer, autoimmune conditions, and neurodegenerative disorders. Finally, we discuss emerging strategies targeting HERVs, including epigenetic modulators, immunotherapies, and gene editing, alongside ongoing clinical trials and translational challenges. By integrating molecular insights with clinical perspectives, this work provides a foundational framework for leveraging HERVs as biomarkers and therapeutic targets in precision medicine.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that play a central role in regulating immune responses by linking innate and adaptive immunity. In recent decades, substantial progress has been made in understanding the development, classification, and diverse functions of DCs. However, a comprehensive overview integrating recent advances in the biology and therapeutic targeting of DCs remains lacking. This review systematically summarizes the origin, developmental pathways, and subset heterogeneity of DCs, including classical type 1 and 2 DCs, plasmacytoid DCs, monocyte-derived DCs, and Langerhans cells. Moreover, it further details the core biological functions of DCs, including antigen capture, migration, and maturation; antigen presentation; activation of adaptive immunity; induction of immune tolerance; and modulation of innate immune responses. The pathological roles of DCs in diseases such as cancer, diabetes, and infectious diseases are discussed, highlighting emerging DC-based therapeutic strategies. Importantly, this review provides a summary of both preclinical studies and clinical trials involving DC-targeted therapies, offering a translational perspective. This work aims to deepen the understanding of DC immunobiology and to provide a valuable foundation for the development of novel DC-based immunotherapies.

Cancer continues to be one of the primary causes of death worldwide. Although there has been substantial progress in clinical cancer care, the outcomes for cancer patients still remain poor. The rapid advancements of artificial intelligence (AI) will revolutionize cancer management by addressing current obstacles in oncology research and practice, ultimately enhancing healthcare accuracy and patient outcomes. Increasing evidence demonstrates that AI-based models can improve the accuracy and efficiency of cancer diagnosis and treatment by leveraging multilayer data. Cancer patients could greatly benefit from AI's promising prospects, yet few AI models have been authorized for clinical use. A comprehensive understanding of AI's basic principles, applications, and potential impacts is essential to foster its clinical translation. In this review, we provide an overview of fundamental AI techniques, encompassing machine learning and deep learning. Moreover, we summarize recent studies on AI's transformative role in cancer diagnosis, classification, and personalized treatment planning. Furthermore, we discuss the current challenges that hinder the widespread use of AI, propose potential solutions, and outline future directions. Overall, through systematic analysis of existing preclinical and clinical evidence, this review highlights the substantial potential of AI technology and provides valuable guidance for future research in AI-driven oncology.

Trained immunity as a critical regulator of host defense and disease pathogenesis bridges the gap between innate and adaptive immunity. For decades, the classic dichotomy of innate immunity and adaptive immunity has shaped our knowledge of immune function. Innate immunity has traditionally been regarded as a rapid, nonspecific first line of defense without memory capacity, while adaptive immunity is characterized by slower, antigen-specific responses and long-term immune memory. However, emerging evidence that innate immunity exhibits memory-like properties challenges the paradigm. Basically, innate immune cells with nonspecific memory retain functional imprints of prior encounters with diverse stimuli. Here, we comprehensively explore the intricate molecular and cellular mechanisms that underpin trained immunity, encompassing epigenetic inheritance, metabolic reprogramming, and transcriptional rewiring. Its dual roles are highlighted in health and disease. On one hand, it bolsters host defense against a broad spectrum of pathogens from bacteria to viruses, and enhances vaccine efficacy through heterologous protection. On the other hand, its dysregulation contributes to infection, inflammation, and cancer progression. As for the promising opportunities on therapeutic intervention, the challenges in precisely modulating trained immunity are tackled to offer a holistic perspective on the dynamically evolving field.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers characterized by highly invasive growth into the surrounding peripancreatic fat tissue, where tumor cells can directly interact with adipocytes. Due to poor response to the currently available (radio)chemotherapies, there is an urgent need for advanced therapy concepts. The present study shows that ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13), a key factor in blood coagulation, is significantly overexpressed in human PDAC. Immunohistochemical analysis revealed that ADAMTS13 expression is associated with prolonged survival and negatively correlated with vascular density. In vitro and in vivo experiments demonstrate its partial induction by leptin. Mechanistically, CRISPR/Cas-mediated ADAMTS13 knockout in PDAC cells resulted in reduced migration and invasion. In an avian xenograft tumor model, ADAMTS13 loss led to increased vascularization, decreased vascular length, and diminished tumor growth, accompanied by reduced expression of multiple key angiogenic and angioplastic factors. Furthermore, loss of ADAMTS13 was associated with decreased expression of mesenchymal markers. In conclusion, we identified an aberrant expression and alternative function of ADAMTS13 in PDAC linked to tumor progression, plasticity, and angiogenesis, partly induced by the peripancreatic fat tissue, making this metalloproteinase an interesting target for personalized therapies.

Diabetes is associated with an increased risk of coronavirus disease 2019 (COVID-19)-associated morbidity and mortality. COVID-19 vaccines substantially reduce the risk of serious COVID-19 outcomes, making them important for individuals with diabetes. However, the effects of the COVID-19 vaccines on glucose control in patients with diabetes remain unclear. Here, we demonstrate that COVID-19 vaccine boosters impair insulin sensitivity in both mice and patients with type 2 diabetes (T2D). In mice, the administration of four vaccine doses elevated the levels of SARS-CoV-2 spike protein and impaired glucose tolerance and insulin sensitivity. Mechanistically, we showed that the SARS-CoV-2 spike protein, guided by the mRNA COVID-19 vaccine, interferes with insulin signaling by binding to angiotensin-converting enzyme 2, TLR4, and ER. We found that 66% of T2D patients exhibited aggravated insulin resistance to booster shots of the mRNA COVID-19 vaccine. Furthermore, treatment with metformin improved insulin signaling variations induced by COVID-19 vaccine boosters in mice. These findings indicate that COVID-19 vaccine boosters impair insulin sensitivity in T2D and that metformin may mitigate these effects. These results maintain the risk–benefit ratio in favor of COVID-19 vaccination for the prevention of severe clinical outcomes, yet highlight the need for close glycemic monitoring of patients with diabetes after receiving mRNA COVID-19.

The prognosis of metastatic castration-resistant prostate cancer (mCRPC) remained unsatisfactory currently. Chidamide is a well tolerated, selective histone deacetylase (HDAC) inhibitor, but the efficacy in mCRPC remained uncertain. From August 2020 to October 2022, a total of 18 patients were enrolled. The primary endpoint was to assess the safety and the secondary endpoints including efficacy and biomarker analysis. The common adverse events (AEs) included anemia, anorexia, hypoalbuminemia, hyponatremia, nausea and fatigue. Grade 3 toxicities included anemia and thrombocytopenia, and no DLT was observed in this study. The median progression-free survival (PFS) was 3.7 months (95% CI, 0.922–6.611 months), and the median OS was 11.0 months (95% CI, 2.232–19.768 months). The results of the RNA-seq profile indicated the high immune cell infiltration and the upregulation of immune cell functions in tumor tissues was associated with the efficacy of chidamide, as revealed by GSEA and ssGSEA. Furthermore, chidamide has been demonstrated to upregulate immune response-related pathways in CRPC cells. Our study suggested that chidamide plus abiraterone is well tolerated in mCRPC, and preliminary evidence suggests that it may improve the survival of patients with mCRPC. Furthermore, combining chidamide with immunotherapy could be another promising option for further enhancing its efficacy.

Hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) insertion constitutes a frequent and severe complication. However, there is a lack of robust predictive biomarkers for post-TIPS HE, so far. This study evaluated the usefulness of neurofilament light chains (NfL) and glial fibrillary acidic protein (GFAP) in serum for predicting post-TIPS HE. Around 144 patients with cirrhosis from three centers were prospectively included and monitored for the occurrence of post-TIPS overt HE, liver transplantation, and death. Serum NfL and GFAP were evaluated before TIPS insertion using the single molecule array technology. In a subgroup of patients sequential NfL and GFAP levels were assessed at 30- and 180-days post-TIPS. While higher NfL levels (sHR 1.01, p = 0.036) were independently associated with post-TIPS OHE after adjusting for other risk factors, GFAP levels had no predictive ability. Consistently, only elevated NfL levels were associated with a higher risk of death/liver transplantation in multivariable analyses. Sequential measurements of NfL at 30 and 180 days after TIPS revealed that NfL levels remain constant until Day 30 followed by a decrease at day 180. Notably, GFAP levels did not change over time. Thus, NfL could be a valuable biomarker for identifying high-risk patients for post-TIPS HE.