BACKGROUND:Epidermal growth factor receptor (EGFR) inhibitors and other targeted therapies frequently cause cutaneous toxicities, impairing patient quality of life and treatment adherence. This study investigated the molecular mechanisms underlying the protective effects of Xiao Zhen Fang (XZF), a traditional Chinese medicine formula, against EGFR inhibitor-induced dermatotoxicity. METHODS:An erlotinib-induced mouse model of cutaneous toxicity was established. Transcriptomic and serum metabolomic profiles were collected and integrated to identify differentially expressed genes (DEGs), metabolites, and pathways. Protein-protein interaction (PPI) networks, machine learning algorithms, and enrichment analyses were applied, with selected biomarkers validated by Western blotting. To explore the role of PANoptosis, in vivo experiments with the caspase inhibitor Z-VAD-FMK were conducted, and skin barrier-related proteins were examined. RESULTS:XZF reduced the incidence of rash, alleviated erythema and swelling, improved body weight, and decreased epidermal thickness in the cutaneous toxicity model. Multi-omics analysis revealed significant alterations in inflammatory and lipid metabolism pathways. Key preventive and therapeutic biomarkers, including cytokine signaling and stem cell-related genes, were identified. PANoptosis-related proteins such as Caspase-1, Gasdermin D, IL-1β,RIPK1,ZBP1,ASC and MLKL were markedly upregulated in the model but suppressed by XZF pretreatment. Furthermore, XZF modulated expression of TGM3, STAT6, P65, P53, KRT1, and KRT14 to restore skin barrier function. Co-treatment with Z-VAD-FMK weakened these regulatory effects, confirming PANoptosis as a critical mechanism. CONCLUSION:XZF alleviates EGFR inhibitor-induced cutaneous toxicity by modulating inflammatory signaling pathways, lipid metabolism, stem cell regulatory mechanisms, and PANoptosis. This integrative multi-omics study systematically elucidates the therapeutic potential of XZF and highlights PANoptosis as a novel target for the prevention and treatment of drug-induced skin toxicity.

BACKGROUND:Diarrheal irritable bowel syndrome (IBS-D) is a functional gastrointestinal disorder characterized by abdominal pain accompanied by recurrent diarrhea that significantly impacts the quality of life and mental health of patients. AIM:To investigate the clinical efficacy of Xifeng Huashi and its effects on the mental status of patients diagnosed with IBS-D. METHODS:Data from 128 patients with IBS-D treated at the Nanjing University of Chinese Medicine Affiliated Hospital of Integrated Traditional Chinese and Western Medicine between June 2023 and May 2024 were divided into control and research groups, with 64 patients in each group. The control group received conventional treatment with Western medicine alone, whereas the research group was prescribed Xifeng Huashi. Differences in specific indices between the two groups were observed and compared using relevant assessment tools. RESULTS:The research group showed a higher total effective rate (92.19% vs 76.56%; P = 0.027) and lower traditional Chinese medicine symptom score (5.07 ± 3.11 vs 7.38 ± 3.68; P < 0.001) than the control group. Post-treatment, the research group exhibited significantly lower levels of pro-inflammatory cytokines (tumor necrosis factor-α: 18.80 ± 4.02 ng/L vs 21.09 ± 4.10 ng/L, P = 0.002; interleukin-6:14.84 ± 4.06 ng/L vs 19.80 ± 4.42 ng/L, P < 0.001) and higher levels of the anti-inflammatory cytokine interleukin-10 (48.53 ± 5.02 ng/L vs 46.06 ± 4.94 ng/L, P = 0.006). Moreover, markers of intestinal mucosal barrier function (diamine oxidase: 6.53 ± 2.35 ng/mL vs 7.66 ± 2.40 ng/mL, P = 0.008; D-lactate: 0.18 ± 0.04 mmol/L vs 0.20 ± 0.06 mmol/L, P = 0.004; lipopolysaccharides: 44.77 ± 8.16 pg/mL vs 48.20 ± 8.15 pg/mL, P = 0.019) were significantly improved in the research group. In addition, Self-rating Anxiety Scale (37.33 ± 5.73 vs 39.59 ± 6.36; P = 0.036) and Self-rating Depression Scale scores (34.77 ± 6.71 vs 38.06 ± 6.52; P = 0.006) were lower in the research group. The recurrence rate was significantly lower in the research group than in the control group (18.64% vs 40.82%, P = 0.001). CONCLUSION:Xifeng Huashi is effective for the treatment of IBS-D and manifests advantages in improving clinical symptoms and mental status, as well as reducing the short-term relapse rate.

BackgroundIn recent years, androgenetic alopecia (AGA) has emerged as a significant public health concern due to its high prevalence and progressive nature. In addition to progressive scalp thinning and hair loss, patients often experience psychological distress and diminished quality of life. While standard treatments such as finasteride and minoxidil are effective, their side effects and adherence issues limit long-term use, making the exploration of safe and accessible intervention strategies essential. Dietary supplements, claimed to promote hair growth by inhibiting androgen pathways and improving the follicular microenvironment, have become an attractive adjunct for both clinicians and patients due to their low cost and ease of use. However, existing studies have limitations, including the diversity of supplements, small sample sizes, and the lack of direct comparisons among different supplements, making it unclear how they compare in terms of efficacy and safety. This study aims to use a network meta-analysis (NMA) to compare the effectiveness and safety of various dietary supplements based on outcomes such as hair density and terminal hair density, providing evidence-based support for clinical decision-making.MethodsA systematic search was conducted in English-language databases such as PubMed, Cochrane Library, Embase, and Web of Science for randomized controlled trials (RCTs) investigating the use of dietary supplements for treating AGA. Stata 16.0 software was used for network meta-analysis, and Revman 5.4 software was utilized for evaluating study quality and bias risk; additionally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework was applied to rate the certainty (quality) of evidence for the included studies.ResultsA total of 19 RCTs involving 1,658 AGA patients were included, with 894 patients in the supplement group and 764 in the control group. Sixteen dietary supplements were investigated. Results showed that compared with placebo, standardized plant extracts (Nutrafol), apple extract (AMSbzs, AMS), tocotrienols, pumpkin seed oil (PSO), and a compound extract of Cistanche and Laminaria (MK-R7) significantly improved hair density. Multi-component supplements (ALRV5XR), standardized plant extracts (Nutrafol), and probiotics effectively increased terminal hair density. In blind doctor assessments, PSO, capsaicin-isoflavones (CI), saw palmetto extract (ESR), Omega 3&6, Lambdapil, Nutrafol, and Multi-component supplements (AGA-P) showed higher hair regeneration scores than placebo or conventional treatments. No significant differences were found between interventions in terms of the terminal-to-vellus hair ratio. Overall, all dietary supplements were found to be well-tolerated.ConclusionDietary supplements have a positive impact on hair density, terminal hair density, and blind doctor evaluations in patients with androgenetic alopecia, with good tolerability. They may serve as beneficial adjuncts or alternatives to conventional treatments. Future large-scale, high-quality RCTs are needed to verify these findings.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251130173, Identifier CRD420251130173.

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality and is characterized by disruption of P53-dependent cell death pathways. The present study investigated the effects of sanggenon C (SC), a natural polyphenolic compound, on cell death regulation focusing on the murine double minute 2 (MDM2)-P53 axis. SC was evaluated in NSCLC cell lines with different TP53 statuses and in xenograft and lung colonization models. SC preferentially induced apoptotic cell death in TP53 wild-type cells compared with TP53-mutant or TP53-null cells, accompanied by reduced clonogenic survival, migration, and invasion in P53-proficient cells, as well as decreased tumor burden and lung colonization in vivo in a TP53-dependent manner. Mechanistically, SC enhanced P53 protein stability by reducing ubiquitination and prolonging its half-life without altering TP53 mRNA expression, as demonstrated by cycloheximide chase and ubiquitination assays. DARTS-LC-MS/MS identified 72 candidate SC-associated proteins, and subsequent biochemical validation, including microscale thermophoresis and co-immunoprecipitation, implicated MDM2 as an SC-associated binding partner, further supported by molecular docking and molecular dynamics analyses. Consistently, SC decreased MDM2 protein abundance, while MDM2 overexpression partially attenuated SC-induced P53 stabilization. These findings indicate that SC induces P53-mediated apoptotic cell death in association with modulation of the MDM2-P53 axis.

Background and Aim Xifenghuashi formula (XFHS),a traditional Chinese medicine,shows promising effects in treating diarrhea-predominant irritable bowel syndrome (IBS-D),but its mechanisms are unclear.This study aims to confirm XFHS's efficacy in IBS-D treatment and its influence on the gut microbiota-bile acid-farnesoid X receptor (FXR)-fibroblast growth factor19/15 (FGF19/15) axis. Experimental procedure A randomized,double-blind,placebo-controlled clinical trial was conducted to assess XFHS's effectiveness.In animal experiments,IBS-D rat models were induced by oral gavage of senna along with restraint stress and divided into six groups:the IBS-D group,XFHS group (administered XFHS),ANTIBIOTIC group (administered antibiotic-s),A+XFHS group (administered antibiotics and XFHS),FGF401 (a FGFR4 receptor inhibitor) group (administered FGF401),and F+XFHS group (administered FGF401 and XFHS).Human and rat fecal samples,along with rat liver and terminal ileum samples,were analyzed for bile acid concentration,16S rRNA sequencing,and western blotting. Results and Conclusion XFHS could enhance the abundance of bile salt hydrolase (BSH)-active bacteria and decrease the abundance of short-chain fatty acids (SCFAs)-producing bacteria in the IBS-D patients to a certain extent,and the same trend was found in the IBS-D rats.XFHS reduced the concentration of total fecal bile acids (including primary,conjugated,and unconjugated bile acids) in IBS-D patients and rats.However,this effect was eliminated by fibroblast growth factor receptor 4 (FGFR4) blockade in IBS-D rats.Furthermore,XFHS increased the protein expression of FXR and FGF15 in the terminal ileum,FGFR4 in the liver,and decreased the expression of cytochrome P450 7A1 (CYP7A1) in the liver.Overall,XFHS alleviated symptoms of IBS-D and restored the homeostasis of the gut microbiota and bile acid metabolism by regulating the gut microbiota-bile acid-FXR-FGF15-FGFR4 axis. Trial registration number (if clinical trial) ITMCTR,ITMCTR2100004795

Salvia miltiorrhiza Bunge, known as danshen in China, is a key medicinal herb in traditional Chinese medicine that has long been used for the treatment of cardiovascular and cerebrovascular disorders. Its principal bioactive constituents fall into two broad categories: water-soluble phenolic acids (primarily including danshensu, salvianic acid A, salvianolic acid B, and rosmarinic acid) and lipid-soluble diterpenoids (primarily including tanshinone I, tanshinone IIA, cryptotanshinone, and dihydrotanshinone). Accumulating evidence shows that these active components exert diverse pharmacological effects, including anti-tumor, anti-inflammatory, antioxidant, and anti-neurodegenerative activities, via modulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Consistently, these components hold promising therapeutic potential against various diseases, including cancer, atherosclerosis, Alzheimer's disease, and diabetic nephropathy. Nevertheless, there is still a lack of a comprehensive and systematic summary of the precise mechanisms by which the active ingredients of danshen exert their therapeutic actions against the aforementioned diseases via the PI3K/Akt signaling pathway. To address this gap, this review systematically summarizes the regulatory effects of danshen's active components on the PI3K/Akt signaling pathway, aiming to clarify their therapeutic potential in various pathological conditions and thereby provide novel insights for the basic research and clinical application of danshen.

Tracking the in vivo fate of nanodrugs remains a significant challenge. In this study, we developed a dual-fluorescence-labeled macromolecular lipid (TPE-PEG2000-ICG; TIP) and a corresponding dual-fluorescence-labeled icaritin microemulsion (TIP-IC-MEs) that could in real time trace both nanocarrier distribution and structural integrity. The design couples the aggregation-caused quenching (ACQ) of indocyanine green (ICG) with the aggregation-induced emission (AIE) of tetraphenylethylene (TPE) via a flexible polyethyleneglycol 2000 (PEG2000) chain. The TPE-AIE moiety could enhance the ACQ effect of the ICG channel, greatly increasing its quenching sensitivity in aqueous environments. This improvement significantly reduced the fluorescence recovery rate of TIP upon probe release from the formulation, which improved the accuracy and reliability of TIP when studying the in vivo fate of nanoformulations. TIP-IC-MEs exhibited favorable physicochemical stability, pH-responsive drug release and in vivo safety. In vitro and in vivo studies further elucidated the critical role of the protein corona in modulating hepatic targeting and clearance pathways of TIP-IC-MEs. Proteomic analysis demonstrated that TIP-IC-MEs selectively recruited specific protein corona components associated with immune recognition, cellular transport, and metabolic reprogramming within the hepatocellular carcinoma model. These corona constituents collectively facilitated tumor-targeted delivery of TIP-IC-MEs through a "cell-hitchhiking" mechanism. This study revealed a dual, context-dependent regulatory role of the protein corona on the in vivo behavior of nanoformulations, providing a novel imaging technology and a mechanistic foundation for rational nanocarrier design and supports the clinical translation of nanomedicines.

The pre-metastatic niche (PMN), a permissive microenvironment within distant organs or tissues that is established before disseminated tumor cells arrive, promotes tumor colonization, survival, and proliferation. Because PMN formation is a critical step in the metastatic cascade, strategies to disrupt its development are a key focus of anticancer therapy. Recent research has highlighted that depression and chronic stress are significant modulators of cancer progression and metastasis. Increasing evidence suggests that depression facilitates PMN formation via neuroendocrine-immune alterations and that antidepressant interventions might decrease metastatic spread. This review consolidates current insights into the links between depression and PMN formation, explores relevant research models, and evaluates the antitumor potential of antidepressants. Perspectives from oncology and psycho-neuroimmunology are merged to inform the development of novel strategies for combating metastasis.

Isatidis Radix, the root of Isatis indigotica, is a traditional Chinese medicine used against influenza. However, its chemical profile responsible for direct anti-influenza activity remains poorly characterized. This present study aims to classify the anti-influenza constituents of Isatidis Radix and to investigate their direct interactions with the key viral targets, neuraminidase (NA) and hemagglutinin (HA). To this end, A compound library comprising 91 constituents was assembled (78 isolated and 13 acquired), including nine undescribed compounds. Surface plasmon resonance (SPR) was employed to assess binding affinities to NA and HA. Antiviral activity of the compound library was validated in influenza A (H1N1)-infected A549 cells, and molecular docking simulations were performed to explore binding modes. SPR screening revealed that 63.7% and 71.4% of the library showed moderate-to-strong binding to NA and HA, respectively, with alkaloids and lignans as the predominant active classes. Notably, compounds 8, 15, 48, and 87 exhibited nanomolar KD values (0.49–4.22 nM for NA; 0.63–6.26 nM for HA), comparable to oseltamivir and arbidol. Cellular assays demonstrated that 76.9% of tested compounds showed antiviral activity (EC50 < 200 μM), with indole alkaloids and glycosylated lignans being most potent. Integrative SPR and cellular data confirmed a positive correlation between dual-target binding and antiviral efficacy. These findings establish that the anti-influenza activity of Isatidis Radix arises from multi-component, multi-target actions on NA and HA, providing a scientific basis for its clinical use and quality control.

To address the safety and specificity limitations of conventional chemotherapy, this study developed a novel folic acid-modified (3-glucan (LNT-FA) nanodelivery system to enhance the therapeutic efficacy of doxorubicin (DOX). Leveraging the intrinsic immunomodulatory properties of (3-glucan, DOX-loaded triple-helix nanoparticles were successfully constructed via solvent-regulated self-assembly. Physicochemical characterization revealed that the DOX@LNT-FA nanoparticles possessed a hydrodynamic diameter of 98.62 +/- 0.60 nm, an encapsulation efficiency of 38.1 +/- 0.38%, and a drug loading capacity of 9.45 +/- 0.24%. Furthermore, the nanoparticles exhibited excellent pH-sensitive release profiles, superior biocompatibility, and active targeting capability. Notably, in vivo studies confirmed that DOX@LNT-FA significantly inhibited tumor growth with an impressive inhibition rate of 86%, while effectively mitigating the systemic toxicity associated with free DOX. Mechanistically, the nanoparticles suppressed the NF-kappa B signaling pathway, which is strongly associated with (3-glucan's immunomodulatory function, to produce anticancer effects. Collectively, this (3-glucan-based nanosystem synergistically combines high drug loading with immunomodulatory effects, offering a safe and precise strategy with significant potential for clinical translation in cancer therapy.

PD-1 inhibitors are a promising treatment for melanoma, but over 50

The incidence of cancer is increasing year by year, becoming a major public health problem worldwide. Tumor is a complex ecosystem, and tumor cells can escape recognition and killing by the immune system through a variety of mechanisms. Among them, adenosine (ADO) stands out as a highly immunosuppressive compound derived from the degradation of adenosine triphosphate (ATP) released by dying or stressed cells. ADO is prevalent in the tumor microenvironment of most solid tumors, promoting tumor cell proliferation, migration, invasion, angiogenesis, and chemotherapy resistance. Adenosine receptors (ARs) on tumor and immune cells, when activated by ADO, inhibit tumor antigen presentation and immune cell activation, suppressing tumor immunity. Targeting the adenosine pathway is thus a key focus in tumor immunotherapy. Natural compounds like alkaloids, flavonoids, and polyphenols show promise in modulating adenosine pathways by interfering with its production, transport, or receptor signaling, potentially reversing tumor immunosuppression. This paper reviews adenosine's metabolic pathways and its role in the tumor microenvironment, exploring how natural substances can regulate these pathways, offering new insights for cancer prevention and treatment.

BACKGROUND:Sjogren's syndrome (SS) is distinguished by immune cells infiltration of exocrine glands, with T helper (Th) cells playing a crucial role in its progression. Total glucosides of paeony (TGP), the main compounds of Chinese medicine Paeonia lactiflora Pall, can treat many autoimmune diseases including SS. PURPOSE:To explore the impact and mechanism of TGP on differentiation and functionality of Th1 and Th17 cells in the SS model, and to provide novel insights into potential therapeutic strategies for this condition. STUDY DESIGN:Non-Obese Diabetic (NOD) mice and spleenic naive CD4+T cells of mice were employed to detect the relevant molecules of Th1 and Th17 with TGP administration to elucidate the mechanism by which TGP affected SS through Th cell differentiation. METHODS:NOD mice were intragastrically administered with TGP (720, 360 mg/kg), Hydroxychloroquine (HCQ, 80 mg/kg), and Paeoniflorin (PF, 300 mg/kg) for 16 weeks, respectively. In vitro, naive CD4+T cells from spleen of mice were incubated with TGP (60, 30 μg/ml) and PF (25 μg/ml) for 3 days. The measurements were conducted on saliva flow, tear flow, as well as the pathology of submandibular glands (SMG) and lacrimal glands (LG). Flow cytometry was utilized to identify the percentage of Th1, Th17, and regulatory T cells (Treg) in peripheral blood CD4+T cells and naive CD4+T cells, respectively. Furthermore, the expression levels of factors related to Th1 and Th17 in SMG, LG and spleenic naive CD4+T cells were analyzed using RT-qPCR, ELISA, immunohistochemical staining as well as Western blotting. RESULTS:In comparison to NOD mice administered with vehicle, TGP treatment enhanced tear and saliva flow, ameliorated pathological damage in SMG and LG, down-regulated the percentages of Th1 and Th17 lymphocytes, and suppressed the expression of Th1 and Th17 cell-related factors in SMG and LG at both mRNA and protein levels. Moreover, TGP could prevent naive CD4+T cells from differentiating into Th1 and Th17 subsets by suppressing the mRNA and protein expression of Th1 and Th17 related factors, leading to a reduction of effector cytokines including IFN-γ and IL-17A in the cell culture supernatant. CONCLUSION:TGP inhibits differentiation and function of Th1 and Th17 cells, which facilitates the amelioration of SS symptoms.

Programmed cell death protein 1 (PD-1) inhibitors are integral to contemporary cancer immunotherapy. However, their objective response rate in microsatellite-stable colorectal cancer (MSS CRC) remains below 5 %. This limited efficacy is primarily due to insufficient tumor-infiltrating lymphocytes (TILs), a consequence of the combined effects of low tumor immunogenicity and impaired dendritic cell (DC)-mediated antigen presentation. The combination of ursolic acid (Ua) and ginsenoside Rg3 (Rg3) enhances TIL infiltration by inducing immunogenic cell death (ICD) in tumor cells and promoting DC maturation. Due to their poor oral bioavailability, an oral ZIF nanoplatform was engineered with a chitosan oligosaccharide (Cos) and inulin (In) bilayer coating [(In/Cos)@Ua-Rg3-ZIF] for targeted delivery of Ua and Rg3 to the CRC microenvironment. Efficient dual-drug co-loading was achieved with a loading efficiency of 24.07 wt%. After oral administration, the (In/Cos) coating protects the formulation from degradation in the upper gastrointestinal tract, while specific enzymatic cleavage by colonic microbiota releases Ua-Rg3-ZIF into tumor tissues. The ZIF platform responds to elevated adenosine triphosphate (ATP) in the tumor microenvironment, enabling controlled release of Ua and Rg3 to enhance cytotoxic T lymphocyte (CTL) levels. In vivo studies demonstrate that combining (In/Cos)@Ua-Rg3-ZIF with α-PD-1 results in an 80.86 % tumor inhibition rate, significantly outperforming monotherapies. This strategy presents an innovative oral delivery system capable of resisting gastrointestinal degradation and facilitating microbiota-responsive drug release, effectively enhancing antitumor immunity and improving the therapeutic outcome of immunotherapy in MSS CRC.

The low infiltration and insufficient tumor recognition of cytotoxic-T-lymphocytes (CTLs) are the two primary reasons for the low objective response rate of programmed death-1 protein (PD-1) inhibitors in treating microsatellite-stable colorectal-cancer (MSS-CRC). Ginsenoside Rg1 (Rg1) and atractylenolide-I (Att) can promote CTLs infiltration and recognition of CTLs by facilitating dendritic cells (DCs) maturation and upregulating tumor MHC-I expression, respectively, and the combination of two drugs is expected to improve the efficacy of PD-1 inhibitors. However, due to their poor water solubility and limited tumor targeting, the intratumoral delivery of both drugs faces challenges. Our previously reported a tumor-apoptotic-body-membrane (Ab) modified zeolitic-imidazolate-framework (ZIF) for co-delivering Rg1 and Att (Ab@Rg1/Att-ZIF). It could be transported by monocytes/macrophages into the deep tumor regions, however, partial formulations would be degraded by intracellular lysosomes. To overcome this, we innovatively incorporated inulin into Ab@Rg1/Att-ZIF, constructing an Ab/In@Rg1/Att-ZIF delivery system. By virtue of the Ab and inulin coating on its surface, the system could be specifically phagocytosed by monocytes/macrophages while maintaining stability in the lysosomal. Furthermore, after being transported to CRC tissues, inulin of the Ab/In@Rg1/Att-ZIF is enzymatically degraded by enzymes secreted by intratumoral bacteria, releasing Rg1 and Att to promote DCs maturation and upregulate tumor MHC-I expression, respectively. Ab/In@Rg1/Att-ZIF significantly inhibits tumor growth by enhancing CTLs infiltration and recognition, synergizing with PD-1 inhibitors to achieve a tumor suppression rate of approximate to 80 %, which is markedly higher than the combined efficacy of Ab@Rg1/Att-ZIF. This study provides new insights for the immunotherapy of MSS-CRC and the intratumoral co-delivery of drugs.

Context:Intestinal fibrosis, a severe complication of Crohn's disease (CD), arises from multifactorial interactions, including chronic inflammation, genetic predisposition, gut microbiota dysbiosis, and impaired mucosal barrier function. Objectives:Since intestinal fibrosis often leads to irreversible stenosis and obstruction symptoms, this article will focus on a series of reviews on the progress of traditional Chinese and Western medicine in the diagnosis and treatment of intestinal fibrosis in CD. Methods:We conducted a systematic literature search in PubMed, CNKI, and Wanfang databases using the keywords: 'Crohn's disease', 'intestinal fibrosis', and 'Traditional Chinese Medicine (TCM)'. The initial search yielded 216 articles. After removing duplicates (n = 146), 70 articles underwent full-text screening based on predefined criteria. Results:Current diagnostic modalities for CD-related intestinal fibrosis are well-established. However, neither pharmacological agents nor TCM therapies have demonstrated definitive efficacy in reversing fibrosis in clinical settings. Conclusions:Despite the current absence of clinically approved antifibrotic drugs, this review synthesizes critical advances in mechanistic understanding and emerging therapeutic strategies. We highlight the urgent unmet clinical need and propose integrative medicine as a promising paradigm shift for fibrosis management. While no therapies yet fully reverse established fibrosis, this review provides three key contributions: Systematically maps molecular pathways from inflammation to fibrosis, identifies knowledge gaps in TCM translational research, and proposes a "control-prevent-reverse" framework for future drug development. These insights are timely given the rising CD prevalence in China and increasing NIH funding for antifibrotic research.

BACKGROUND Hepatic organoid-based modelling, through the elucidation of a range of in vivo biological processes and the recreation of the intricate liver microenvironment, is yielding groundbreaking insights into the pathophysiology and personalized medicine approaches for liver diseases. AIM This study was designed to analyse the global scientific output of hepatic organoid research and assess current achievements and future trends through bibliometric analysis. METHODS Articles were retrieved from the Web of Science Core Collection, and CiteSpace 6.3.R1 was employed to analyse the literature, including outputs, journals, and countries, among others. RESULTS Between 2010 and 2024, a total of 991 articles pertaining to hepatic organoid research were published. The journal Hepatology published the greatest number of papers, and journals with an impact factor greater than 10 constituted 60% of the top 10 journals. The United States and Utrecht University were identified as the most prolific country and institution, respectively. Clevers H emerged as the most prolific author, whereas Huch M had the highest number of cocitations, suggesting that both are ideal candidates for academic collaboration. Research on hepatic organoids has exhibited a progressive shift in focus, evolving from initial investigations into model building, differentiation research in stem cells, bile ducts, and progenitor cells, to a broader spectrum encompassing lipid metabolism, single-cell RNA sequencing, and therapeutic applications. The phrases exhibiting citation bursts from 2022 to 2024 include “drug resistance”, “disease model”, and “patient-derived tumor organoids”. CONCLUSION Research on hepatic organoids has increased over the past decade and is expected to continue to grow. Key research areas include applications for liver diseases and drug development. Future trends likely to gain focus include patient-derived tumour organoids, disease modelling, and personalized medicine.

The liver is the most commonly metastasized organ in colorectal cancer (CRC), and distant metastasis is the primary cause of mortality from CRC. In recent years, researchers have discovered that tumor cells create a “pre-metastatic niche (PMN)” favorable to metastasis before reaching the metastatic location. This review discusses the many processes and mechanisms that lead to PMN formation in CRC, including gut microbiota, stem cell stimulation, immunocyte interactions, and the induction of extracellular vesicles that carry important information. It examines research methods and diagnostic and therapeutic approaches for treating metastatic CRC with PMN. The crucial significance of PMN formation in metastatic CRC is also highlighted.

Establishing functional vascular systems within three-dimensional tissue constructs is crucial for their successful use in disease modeling, drug testing, and regenerative medicine. Current methods face challenges in creating small- to medium-sized microvessels and precisely controlling key vascular features, such as vascular density, vessel diameter, and network connectivity, to generate hierarchical, multiscale vascular systems that mimic natural functionality. In this study, we developed a composite hydrogel incorporating polystyrene microtubes (PS-MTs) to improve control over microvessel morphogenesis and functionality. PS-MTs were fabricated via core-sheath electrospinning, fragmented by ultrasonication, and incorporated into fibrin gels. Scanning electron microscopy revealed both micro- and nano-topographic features of the embedded PS-MT fragments. Endothelial cells (ECs) and fibroblasts were cocultured in this composite hydrogel under interstitial flow conditions for 7 d. The PS-MTs exhibited excellent biocompatibility, and the composite hydrogel showed no adverse effects on the cell viability of EC-fibroblast cocultures on chip. Fluorescence and confocal microscopy revealed a 40% increase in vascular area fraction and more than a twofold increase in average vessel diameter in the high PS-MT density group (>4%) compared to controls. Perfusion assays using a fluorescent microbead suspension demonstrated a 71% increase in the field-average speed of microbead flow, indicating enhanced perfusability, consistent with the observed morphological changes. Additionally, permeability assays showed a 66% decrease in dextran permeability, suggesting improved vascular barrier integrity. In conclusion, incorporating PS-MTs into fibrin hydrogels effectively modulated the structural organization and functional maturation of microvascular networks in a dose-dependent manner. This strategy holds promises for advancing the biofabrication of functional, multiscale vascular networks for engineered tissues. By tuning PS-MT density within the composite hydrogel, this approach enables local modulation of vessel morphogenesis, offering a flexible strategy for engineering application-specific vascular architectures.

Gastric cancer, recognized as one of the most lethal malignancies globally, progresses through a complex, multi-stage development. Elucidating the pathogenic mechanisms behind gastric carcinogenesis and identifying early diagnostic biomarkers are pivotal for decreasing the prevalence of gastric cancer. Using datasets on gastric cancer and its transformation from gastritis, we employed machine learning to create an early diagnostic model, identifying key genes and evaluating accuracy. We prioritized genes in the gastritis-to-cancer progression, identifying a central driver gene. Pathway analysis revealed its transformation role. Tissue microarrays and rat models validated the driver genes and networks, confirmed in cell and organoid models. We also identified cell types secreting CHI3L1 using single-cell RNA sequencing and multiplex immunohistochemistry, exploring their prognostic significance. We identified 12 driver genes potentially involved in the gastritis-to-cancer transformation, with CHI3L1, MMP12, CXCL6, IDO1, and CCL20 emerging as the top five genes via a early gastric cancer diagnostic model. CHI3L1 was pinpointed as the central driver across the gastritis-to-cancer spectrum, with its upregulation, along with CD44, β-catenin, and c-Myc, noted in gastric precancerous lesions. In vitro and organoid studies revealed CHI3L1’s role in activating the CD44-β-catenin pathway to induce malignancy. Furthermore, our findings indicate that fibroblasts and dendritic cells are the principal sources of CHI3L1 secretion, a factor that is associated with poor prognosis in gastric cancer. This study highlights CHI3L1 as a key gene driving the progression from gastritis to gastric cancer, primarily by activating the CD44-β-catenin pathway, which enhances malignant cell traits. CHI3L1 is mainly secreted by fibroblasts and dendritic cells, and its high levels are linked to poor gastric cancer prognosis.