Ischemic stroke accounts for approximately 80% of all stroke cases worldwide and remains a leading cause of long‑term neurological disability and mortality. Intravenous thrombolysis and endovascular thrombectomy constitute the mainstay of acute reperfusion therapies, yet their clinical utility is severely constrained by narrow therapeutic time windows. Even when large‑vessel recanalization is successfully achieved, a considerable proportion of patients still suffer poor functional outcomes due to futile reperfusion and ischemia‑reperfusion injury. Historically, preclinical studies have largely focused on direct neuronal protection against calcium overload, oxidative stress and ferroptosis. Unfortunately, most promising neuroprotective agents that exhibited robust benefits in rodent models have failed to demonstrate satisfactory efficacy in phase‑Ⅱ and phase‑Ⅲ clinical trials. One critical contributor to such translational failure is the disregard for the pathological disturbance within the cerebral vascular microenvironment. Instead of merely regarding neuronal death as an autonomous cellular event, accumulating evidence indicates that sequential biochemical disruption of perivascular microenvironment acts as an initiating amplifier that propagates damage toward brain parenchyma after ischemic insult. The cerebral vascular microenvironment centers on brain microvessels and comprises endothelial cells, endothelial glycocalyx, basement membrane, pericytes, astrocytic end‑feet, perivascular microglia, as well as interstitial ions, inflammatory mediators, reactive oxygen species and extracellular matrix components. Distinct from the concept of neurovascular unit which emphasizes functional coupling between neurons, glia and vessels, the vascular microenvironment highlights dynamic biochemical homeostasis in perivascular interstitial space. Following cerebral ischemia, injured brain tissue can be spatially divided into the irreversibly damaged infarct core, metabolically‑stressed ischemic penumbra and mildly‑affected peripheral regions. These three zones lack rigid anatomical boundaries and evolve dynamically depending on reperfusion timing, presenting divergent features in blood perfusion, blood‑brain barrier integrity, cellular viability and immune‑inflammatory profiles. Four interrelated pathological cascades jointly disrupt microenvironmental homeostasis: calcium‑overload‑triggered cytotoxic cascades; blood‑brain barrier breakdown resulting from glycocalyx shedding, tight‑junction dissociation and matrix metalloproteinase‑driven basement‑membrane degradation; inflammatory‑immune dysregulation dominated by microglial phenotypic reprogramming; and mutual crosstalk between coagulation disturbance and neuroinflammation that exacerbates secondary brain injury. Multiple molecular layers orchestrate these pathological alterations. Excessive activation of HIF‑1α, NF‑κB and MAPK/ERK signaling pathways promotes barrier leakage, pro‑inflammatory factor secretion and extracellular‑matrix remodeling. Epigenetic modulation mediated by non‑coding RNAs including miRNAs and lncRNAs reshapes vascular microenvironment via three major patterns: modulating endothelial‑pericyte barrier integrity, switching microglia‑astrocyte inflammatory phenotypes, and driving metabolic reprogramming among multiple cell populations within microdomains. In addition, metabolic shift toward glycolysis among endothelial cells, microglia, astrocytes and compromised neurons establishes self‑amplifying vicious cycles of energy depletion and oxidative stress in perivascular niches. Targeted theranostic approaches oriented toward vascular microenvironment bring new opportunities for precision medicine of ischemic stroke. Magnetic nanoprobes and near‑infrared fluorescent probes respond to elevated reactive oxygen species, pH shift and inflammatory signals, enabling in situ visualization of pathological signatures of microenvironment and risk evaluation of hemorrhagic transformation. Function‑tailored nanodelivery systems exert multi‑modal protective effects: reactive oxygen species‑responsive polymeric micelles deliver calcium chelators to block calcium‑overload‑initiated injury cascades; nanozymes scavenge reactive oxygen/nitrogen species and revert microglial pro‑inflammatory polarization; biomimetic membrane‑coated nanoparticles accumulate at micro‑thrombosis sites to break thrombo‑inflammatory loops and mitigate no‑reflow phenomenon; ferroptosis‑inhibitor‑loaded nanocarriers eliminate excessive labile iron within perivascular toxic microdomains. During subacute and recovery phases, spatiotemporally controlled release of angiogenic factors by nanocarriers facilitates maturation of newly‑formed microvessels rather than blind vascular sprouting, which helps reconstruct intact blood‑brain barrier and restore microenvironmental homeostasis. Nevertheless, substantial translational bottlenecks still impede clinical transformation of these nanomedicines, including potential biosafety risks caused by in vivo material accumulation, protein‑corona‑induced impairment of targeting capacity, intrinsic blood brain barrier transport obstacles, lack of unified quality‑control criteria for large‑scale manufacture, reliance on high‑end clinical imaging instruments, and prominent interspecies discrepancies between experimental animals and human patients. On the basis of summarizing spatiotemporal pathological characteristics, multi‑level regulatory mechanisms and cutting‑edge microenvironment‑oriented diagnostic and interventional strategies, the present review advocates a conceptual shift from isolated neuronal protection to comprehensive reconstruction of perivascular vascular microenvironment homeostasis. Such perspective provides theoretical foundations for expanding therapeutic time windows and inspires future development of novel therapeutic modalities for ischemic stroke.

This study aims to explore the effects and mechanisms of the traditional Chinese medicine Cordyceps sinensis(CS) in ameliorating heart aging and injury in mice based on animal experiments and network pharmacology. A mouse model of heart aging was established by continuously subcutaneous injection of D-galactose(D-gal). Thirty mice were randomly assigned into a normal group, a model group, a low-dose CS(CS-L) group, a high-dose CS(CS-H) group, and a vitamin E(VE) group. Mice in these groups were administrated with normal saline, different doses of CS suspension, or VE suspension via gavage daily. After 60 days of treatment with D-gal and various drugs, all mice were euthanized, and blood and heart tissue samples were collected for determination of the indicators related to heart aging and injury in mice. Experimental results showed that both high and low doses of CS and VE ameliorated the aging phenotype, improved the heart index and myocardial enzyme spectrum, restored the expression levels of proteins associated with cell cycle arrest and senescence-associated secretory phenotypes(SASP), and alleviated the fibrosis and histopathological changes of the heart tissue in model mice. From the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP),259 active ingredients of CS were retrieved. From Gene Cards and OMIM, 2 568 targets related to heart aging were identified, and 133common targets shared by CS and heart aging were obtained. The Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes( KEGG) pathway enrichment revealed that the pathways related to heart aging involved oxidative stress,apoptosis, inflammation-related signaling pathways, etc. The animal experiment results showed that both high and low doses of CS and VE ameliorated oxidative stress and apoptosis in the heart tissue to varying degrees in model mice. Additionally, CS-H and VE activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1) pathway and inhibited the expression of key proteins in the nuclear factor-κB(NF-κB) pathway in the heart tissue of model mice. In conclusion, this study demonstrated based on network pharmacology and animal experiments that CS may alleviate heart aging and injury in aging mice by reducing oxidative stress,apoptosis, and inflammation in the heart via the Nrf2/HO-1/NF-κB pathway.
Animals ; Cordyceps/chemistry* ; Mice ; NF-E2-Related Factor 2/genetics* ; NF-kappa B/genetics* ; Aging/genetics* ; Male ; Signal Transduction/drug effects* ; Network Pharmacology ; Drugs, Chinese Herbal/pharmacology* ; Heme Oxygenase-1/genetics* ; Heart/drug effects* ; Humans ; Myocardium/metabolism* ; Membrane Proteins/genetics*

This study aimed to investigate the effect of Dahuang Zhechong Pills(DHZCP) in delaying heart aging(HA) and explore the potential mechanism. Network pharmacology and molecular docking were employed to explore the targets and potential mechanisms of DHZCP in delaying HA. Furthermore, in vitro experiments were conducted with the DHZCP-containing serum to verify key targets and pathways in D-galactose(D-gal)-induced aging of cardiomyocytes. Active components of DHZCP were searched against the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCSMP), and relevant targets were predicted. HA-related targets were screened from the GeneCards, Online Mendelian Inheritance in Man(OMIM), and DisGeNET. The common targets shared by the active components of DHZCP and HA were used to construct a protein-protein interaction network in STRING 12.0, and core targets were screened based on degree in Cytoscape 3.9.1. Metaspace was used for Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses of the core targets to predict the mechanisms. Molecular docking was performed in AutoDock Vina. The results indicated that a total of 774 targets of the active components of DHZCP and 4 520 targets related to HA were screened out, including 510 common targets. Core targets included B-cell lymphoma 2(BCL-2), serine/threonine kinase 1(AKT1), and hypoxia-inducible factor 1 subunit A(HIF1A). The GO and KEGG enrichment analyses suggested that DHZCP mainly exerted its effects via the phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway, HIF-1α signaling pathway, longevity signaling pathway, and apoptosis signaling pathway. Among the pathways predicted by GO and KEGG enrichment analyses, the PI3K/AKT/HIF-1α signaling pathway was selected for verification. The cell-counting kit 8(CCK-8) assay showed that D-gal significantly inhibited the proliferation of H9c2 cells, while DHZCP-containing serum increased the viability of H9c2 cells. SA-β-gal staining revealed a significant increase in the number of blue-green positive cells in the D-gal group, which was reduced by DHZCP-containing serum. TUNEL staining showed that DHZCP-containing serum decreased the number of apoptotic cells. After treatment with DHZCP-containing serum, the protein levels of Klotho, BCL-2, p-PI3K/PI3K, p-AKT1/AKT1, and HIF-1α were up-regulated, while those of P21, P16, BCL-2 associated X protein(Bax), and cleaved caspase-3 were down-regulated. The results indicated that DHZCP delayed HA via multiple components, targets, and pathways. Specifically, DHZCP may delay HA by reducing apoptosis via activating the PI3K/AKT/HIF-1α signaling pathway.
Proto-Oncogene Proteins c-akt/genetics* ; Drugs, Chinese Herbal/pharmacology* ; Signal Transduction/drug effects* ; Apoptosis/drug effects* ; Myocytes, Cardiac/cytology* ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics* ; Phosphatidylinositol 3-Kinases/genetics* ; Animals ; Rats ; Humans ; Molecular Docking Simulation ; Aging/metabolism* ; Protein Interaction Maps/drug effects* ; Heart/drug effects* ; Network Pharmacology

Jiuwei Xifeng Granules have become a Chinese patent medicine in the market. Because the formula contains Os Draconis, a top-level protected fossil of ancient organisms, the formula was to be improved by replacing Os Draconis with Ostreae Concha. To evaluate whether the improved formula has the same effectiveness and safety as the original formula, a randomized, double-blind, parallel-controlled, equivalence clinical trial was conducted. This study enrolled 288 tic disorder(TD) of children and assigned them into two groups in 1∶1. The treatment group and control group took the modified formula and original formula, respectively. The treatment lasted for 6 weeks, and follow-up visits were conducted at weeks 2, 4, and 6. The primary efficacy endpoint was the difference in Yale global tic severity scale(YGTSS)-total tic severity(TTS) score from baseline after 6 weeks of treatment. The results showed that after 6 weeks of treatment, the declines in YGTSS-TSS score showed no statistically significant difference between the two groups. The difference in YGTSS-TSS score(treatment group-control group) and the 95%CI of the full analysis set(FAS) were-0.17[-1.42, 1.08] and those of per-protocol set(PPS) were 0.29[-0.97, 1.56], which were within the equivalence boundary [-3, 3]. The equivalence test was therefore concluded. The two groups showed no significant differences in the secondary efficacy endpoints of effective rate for TD, total score and factor scores of YGTSS, clinical global impressions-severity(CGI-S) score, traditional Chinese medicine(TCM) response rate, or symptom disappearance rate, and thus a complete evidence chain with the primary outcome was formed. A total of 6 adverse reactions were reported, including 4(2.82%) cases in the treatment group and 2(1.41%) cases in the control group, which showed no statistically significant difference between the two groups. No serious suspected unexpected adverse reactions were reported, and no laboratory test results indicated serious clinically significant abnormalities. The results support the replacement of Os Draconis by Ostreae Concha in the original formula, and the efficacy and safety of the modified formula are consistent with those of the original formula.
Adolescent ; Child ; Child, Preschool ; Female ; Humans ; Male ; Double-Blind Method ; Drugs, Chinese Herbal/therapeutic use* ; Tic Disorders/drug therapy* ; Treatment Outcome

Qualitative and quantitative analysis methods for chemical components of different processed products of Corni Fructus were established to systematically characterize and identify these components, and the content of the main differential components was determined. The chemical components of different processed products of Corni Fructus were collected using ultra-high performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS). Through analysis of self-built databases, literature, and reference standards, a total of 93 components were obtained, including 19 iridoids, 15 flavonoids, 16 organic acids, eight triterpenoids, eight tannins, four amino acids, two polysaccharides, five olefins, and 16 other compounds. Additionally, by using multivariate statistical methods, the differential components between different processed products of Corni Fructus were screened under the conditions of VIP>1.0 and FC<0.5 or FC>2.0 and P<0.05. The PCA and OPLS-DA results showed differences in the chemical components between different processed products of Corni Fructus. A total of 21 differential components were screened, including tartaric acid, morroniside, and rutin. On this basis, ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry(UPLC-QqQ-MS/MS) was used to determine the content of 10 main common differential components, including gallic acid, morroniside, ursolic acid, loganin, swertiamarin, rutin, 5-hydroxymethylfurfural, cornuside Ⅰ, quercetin, and oleanolic acid. The above 10 components showed a good linear relationship within the determined concentration range, with the precision, stability, repeatability, and sample recovery rate all meeting the requirements. Compared with that in Corni Fructus, the content of iridoid glycosides in wine-prepared Corni Fructus and wine-and honey-prepared Corni Fructus decreased, while the content of gallic acid, rutin, quercetin, 5-hydroxymethylfurfural, ursolic acid, and oleanolic acid increased. Compared with wine-prepared Corni Fructus, wine-and honey-prepared Corni Fructus showed varying degrees of increase in all other components, except for a slight decrease in gallic acid content. In summary, this study clarified the influence of different processing methods on the chemical components of Corni Fructus, providing a theoretical basis for the scientific connotation, overall quality evaluation, and clinically rational application of Corni Fructus processing in the future.
Tandem Mass Spectrometry/methods* ; Chromatography, High Pressure Liquid/methods* ; Cornus/chemistry* ; Drugs, Chinese Herbal/chemistry* ; Fruit/chemistry*

Medical institutions, with their clinical practice foundation and abundant human use experience data, have become important carriers for the inheritance and innovation of traditional Chinese medicine(TCM) and the "cradles" of the preparation of new TCM. To effectively promote the transformation of new TCM originating from the TCM clinical practice in medical institutions and establish an effective evaluation index system for the transformation of new TCM conforming to the characteristics of TCM, consensus experts adopted the literature research, questionnaire survey, Delphi method, etc. By focusing on the policy and technical evaluation of new TCM originating from the TCM clinical practice in medical institutions, a comprehensive evaluation from the dimensions of drug safety, efficacy, feasibility, and characteristic advantages was conducted, thus forming a comprehensive evaluation system with four primary indicators and 37 secondary indicators. The expert consensus reached aims to encourage medical institutions at all levels to continuously improve the high-quality research and development and transformation of new TCM originating from the TCM clinical practice in medical institutions and targeted at clinical needs, so as to provide a decision-making basis for the preparation, selection, cultivation, and transformation of new TCM for medical institutions, improve the development efficiency of new TCM, and precisely respond to the public medication needs.
Medicine, Chinese Traditional/standards* ; Humans ; Consensus ; Drugs, Chinese Herbal/therapeutic use* ; Surveys and Questionnaires

Objective To investigate the clinical characteristics,treatment responses,and prognosis of patients with idiopathic multicentric Castleman disease(iMCD)complicated by autoimmune hemolytic anemia(AIHA). Methods The patients diagnosed with iMCD in Peking Union Medical College Hospital from January 2010 to December 2023 and having complete baseline blood routine data were retrospectively enrolled in the study.The iMCD patients were further assigned into AIHA and non-AIHA groups based on baseline laboratory examinations,and the clinical characteristics and prognosis were compared between the two groups. Results A total of 341 patients with iMCD were enrolled in this study,including 277(81.2%)exhibiting anemia at baseline.Five(1.8%)patients were identified as having iMCD-AIHA,all of whom were iMCD-not otherwise specified type complicated by warm antibody-type AIHA,and two of them were simultaneously diagnosed with Evans syndrome.The timing relationship between the first onset of AIHA and iMCD diagnosis varied,with 2 patients experiencing their first hemolytic episode prior to the diagnosis of iMCD.In terms of treatment,the therapy targeting iMCD was effective in alleviating AIHA.The AIHA group had a poorer prognosis(HR=4.61,95% CI=1.08-19.80,P=0.040)and a lower 5-year survival rate(90% vs.60%,P=0.024)than the non-AIHA group.Conclusions iMCD-AIHA is clinically rare,and AIHA can occur at different stages of iMCD.Although the primary treatment principle remains targeting iMCD,great attention should be paid to the exacerbation of immune dysfunction caused by AIHA and the possible adverse prognosis it may bring.
Humans ; Anemia, Hemolytic, Autoimmune/diagnosis* ; Castleman Disease/diagnosis* ; Retrospective Studies ; Male ; Female ; Prognosis ; Adult ; Middle Aged ; Aged ; Young Adult ; Adolescent

Objective:To observe the efficacy and safety of combined lienal polypeptide injection therapy in the treatment of Mycoplasma pneumoniae pneumonia（MPP）in children aged 3 to 14 years old in multiple clinical centers.Methods:A randomized，controlled，multi-center clinical study design was adopted.A total of 240 hospitalized children aged 3 to 14 years old with MPP from 7 hospitals from September 1，2023 to January 31，2024 were included.According to the severity of pneumonia，they were divided into the mild MPP group with 80 cases and the severe MPP/refractory MPP（SMPP/RMPP）group with 160 cases，and then randomly divided into the control group and the experimental group at a ratio of 1 ∶1，using the random number table method.After screening，subjects entered a treatment period of 5 to 7 days.The control group was treated with azithromycin，while the experimental group was treated with azithromycin plus lienal polypeptide injection .The recovery of lung CT，length of hospital stay，duration of fever，cough score，whether mild cases developed into severe or refractory cases，duration of hormone use，use of intravenous immunoglobulin（IVIG），bronchoscopy treatment，and immune function were observed between the two groups to evaluate the efficacy of lienal polypeptide injection.Adverse events after medication，vital signs，blood routine，urine routine，liver function，myocardial enzymes，renal function，and electrocardiogram were observed to evaluate the safety. Results:A total of 231 subjects have completed the trial in the 7 hospitals，including 118 cases in the experimental group and 113 cases in the control group.Main observation index：the rate of lung CT aggravation in the experimental group was lower than that in the control group（2.6% vs 15.3%， P<0.01），and the difference was statistically significant.Secondary indexes：there were no statistically significant differences in the length of hospital stay，duration of fever，cough score，duration of hormone use，whether IVIG treatment was used，the number of bronchoscopy treatment cases，and immunoglobulin between the two groups（all P>0.05）.However，the rate of cases of plastic bronchitis（PB）found under bronchoscopy in the experimental group was lower than that in the control group（0 vs 18.8%， P=0.03），and the difference was statistically significant.Among the mild MPP（72 cases），there were no statistically significant differences in the length of hospital stay，duration of fever，cough score，duration of hormone use，whether IVIG treatment was used，the number of bronchoscopy treatment cases，and the improvement rate of lung CT between the two groups（all P>0.05）.However，compared with the control group，the rate of cases developing into SMPP/RMPP in the experimental group was less（24.3% vs 48.6%， P=0.03），and the difference in IgG before and after treatment was small［0.53（-0.04，1.18）g/L vs 1.33（0.48，2.25）g/L， P=0.01］.Among the SMPP/RMPP cases（159 cases），the rate of cases of PB found under bronchoscopy in the experimental group was less than that in the control group（0 vs 20%， P=0.04），and the rate of cases with aggravated lung CT in the experimental group was less than that in the control group（1.3% vs 19.5%， P<0.01），and the improvement rate of lung CT in the experimental group was higher than that in the control group（88.8% vs 75.3%， P=0.03），with statistically significant differences.There were no statistically significant differences in the length of hospital stay，duration of fever，cough score，duration of hormone use，whether IVIG treatment was used，the number of bronchoscopy treatment cases，and immunoglobulin between the two groups（all P>0.05）.Two cases in the experimental group developed rashes，which improved after the drug was discontinued.There were no serious adverse reactions such as abnormal vital signs like dyspnea and cyanosis due to the use of lienal polypeptide injection.There were no obvious changes in blood routine，liver function，myocardial enzymes，renal function，electrocardiogram，and urine routine values before and after medication compared with the baseline. Conclusion:The combined use of lienal polypeptide injection in the treatment of MPP in children can reduce the probability of the transformation from mild cases to SMPP/RMPP，reduce the rate of aggravation of the image findings，promote the absorption of lung inflammation，reduce the rate of PB found under bronchoscopy，and has good safety.

Objective To investigate the effect of protocatechuic acid(PCA)on Toll-like receptor 4(TLR4)/nu-clear factor-kappa B(NF-κB)signal pathway in rats with ulcerative colitis(UC).Methods After modeling,rats were divided into control group,model group(5%trinitrobenzene sulfonic acid(TNBS)induction),low(L-PCA),middle(M-PCA),high(H-PCA)dose protocatechuic acid group(rats were given with PCA at doses of 20,40 and 80 mg/kg respectively),and intervention model group(LPS,rats were given with PCA at doses of 80 mg/kg and 0.8 mg/kg LPS solution intraperitoneally),and 12 rats in each group were given the drug continu-ously for 14 days.After treatment,rats were evaluated by disease activity index(DAI),and the morphology and apoptosis of colon were observed by hematoxylin eosin(HE)staining and TUNEL staining.The protein levels of Occludin,Zona occludens 1(ZO-1),claudin-1,Tumor necrosis factor-α(TNF-α),interleukin(IL)-1β,IL-10,TLR4 and p-p65/p65 in colon were detected by Western blotting.The expression of TLR4 protein in colon was de-tected by immunohistochemical staining.Results Compared with control group,the colon of model group rat showed obvious injury,DAI score and positive rate of TUNEL were increased(P＜0.05),the relative protein ex-pression of TNF-α,IL-1β,TLR4 and p-p65 were increased(P＜0.05),the relative protein expression of Occlu-din,ZO-1,claudin-1 and IL-10 were decreased(P＜0.05).Compared with model group,colonic injury was allevi-ated in L-PCA,M-PCA and H-PCA groups,DAI score and positive rate of TUNEL were decreased(P＜0.05),the relative protein expression of TNF-α,IL-1β,TLR4 and p-p65 were decreased(P＜0.05),the relative protein expression of Occludin,ZO-1,claudin-1 and IL-10 were increased(P＜0.05).Compared with H-PCA group,co-lon injury was aggravated in LPS group,DAI score and positive rate of TUNEL were increased(P＜0.05),the rel-ative protein expression of TNF-α,IL-1β,TLR4 and p-p65 was increased(P＜0.05),the relative protein expres-sion of Occludin,ZO-1,claudin-1 and IL-10 was decreased(P＜0.05).Conclusions Protocatechuic acid can al-leviate TNBS-induced colon injury in UC rats,improve intestinal barrier function,and inhibit colon inflammatory response,the mechanism of which is related to the activation of TLR4/NF-κB signaling pathway.

Objective:Patients with metastatic urothelial carcinoma(mUC)usually receive platinum-based chemotherapy as the first-line treatment.Recently,antibody-drug conjugates(ADCs)combined with programmed death-1 antibody(PD-1 antibody)have shown promising efficacy and safety in the treatment of mUC.HER2 positivity is associated with poor prognosis,patients can benefit from anti-HER2 ADC therapy such as disitamab vedotin(RC48-ADC).This study aimed to evaluate the efficacy and safety of RC48-ADC combined with tislelizu-mab in treatment-na?ve patients with mUC.Methods:A retrospective analysis was performed on 70 mUC patients treated between July 2022 and December 2023,including 30 patients receiving RC48-ADC combined with tislelizumab(DT group)and 40 patients receiving gem-citabine plus cisplatin(GC group).Primary endpoints included objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS),overall survival(OS),and treatment-related adverse events(TRAEs).Results:The ORR(73.3%vs.47.5%)and DCR(86.7%vs.62.5%)were significantly higher in the DT group compared to the GC group(P<0.05).The DT group also demonstrated longer PFS(10.98 months vs.7.67 months,P<0.005)and prolonged OS(median OS:not reached vs.11.34 months).The most common TRAEs included myel-osuppression,gastrointestinal and hepatobiliary toxicities,fatigue,alopecia,and rash.No grade≥3 TRAEs or treatment-related deaths were reported.Conclusions:RC48-ADC combined with tislelizumab demonstrated superior efficacy and favorable safety in treatment-na?ve pa-tients with mUC,supporting its potential as a first-line therapeutic option.