BACKGROUND:HCC is a prevalent malignant tumor globally with high mortality. MiR-500a-3p plays critical roles in tumorigenesis and tumor progression. METHODS:To evaluate miR-500a-3p's role in HCC, we first analyzed its expression and prognostic value via qRT-PCR and TCGA (Kaplan-Meier analysis). We then performed extensive in vitro functional studies after cell transfection (mimics, anti-miR, SOCS2 OE), measuring proliferation, migration, invasion, glycolytic parameters (glucose consumption, lactate, ECAR, ATP), and apoptosis. A target relationship with SOCS2 was predicted bioinformatically and confirmed by dual-luciferase assay. Using the JAK2/STAT5 signaling pathway inhibitor Fedratinib, the activator Erythropoietin, and transfection with si-STAT5 and oe-STAT5, the molecular mechanism of miR-500a-3p in HCC was investigated. In vivo experiments established tumor-bearing mouse models to evaluate the effect of miR-500a-3p on tumor growth. RESULTS:miR-500a-3p was significantly upregulated in HCC tissues and cells, and was associated with poor patient prognosis. The overexpression of miR-500a-3p promotes the malignant progression of HCC cells. Mechanistically, miR-500a-3p directly targeted and negatively regulated SOCS2 expression. SOCS2 expression was suppressed in HCC, with its expression abrogating miR-500a-3p-mediated oncogenicity. miR-500a-3p activated the JAK2/STAT5 pathway by inhibiting SOCS2, thereby regulating the malignant biological behaviors of HCC cells. Both SOCS2 overexpression and JAK2 inhibitor treatment could reverse the activation of the JAK2/STAT5 axis and downstream effects induced by miR-500a-3p. MiR-500a-3p promoted tumor growth in tumor-bearing mice, accompanied by SOCS2 downregulation and JAK2/STAT5 pathway activation. CONCLUSION:This study reveals that miR-500a-3p promotes proliferation and glycolysis while inhibiting apoptosis of HCC cells by negatively regulating SOCS2 and activating the JAK2/STAT5 pathway.

Prexasertib (Prex) is a selective checkpoint kinase 1 and 2 (CHK1/2) inhibitor reported to induce the phosphorylation of AMP-activated protein kinase (AMPK) at threonine 172. However, the mechanism by which Prex regulates AMPK and whether this regulation contributes to Prex sensitivity is unknown. Here, we provide data that suggest that Prex directly binds to the cystathionine β-synthase (CBS) pockets of AMPK complex, leading to increased AMPKα Thr172 phosphorylation via CAMKK2 and LKB1. Intriguingly, Prex also functions as an ATP-competitive inhibitor of AMPK, and prolonged Prex treatment significantly inhibited AMPK in vivo. AMPK depletion enhanced cellular sensitivity to CHK1 inhibition, suggesting that Prex-induced cytotoxicity results from inhibition of CHK1 and AMPK. Exonuclease 1 (Exo1) hyperactivation following combined AMPK and CHK1 inhibition may represent a critical mechanism underlying Prex sensitivity. Our findings revealed an additional role of Prex in AMPK regulation and elucidated the functional significance of AMPK inhibition in CHK1 inhibitor-induced cell death.

Clear cell renal cell carcinoma (ccRCC) is a highly aggressive malignancy with limited treatment options. Although RASD2, which encodes a Ras-related GTP-binding protein, has been linked to melanoma progression, its role in ccRCC remains unclear. In this study, we systematically investigated the oncogenic functions and mechanisms of RASD2 in ccRCC. Clinically, RASD2 was significantly overexpressed in tumor tissues compared with adjacent normal tissues and correlated with poor patient prognosis. Functional studies demonstrated that RASD2 promotes proliferation, migration, and invasion of the ccRCC cells in vitro, findings further supported by xenograft models in nude mice. Mechanistically, RASD2 activated the P38/ERK-MAPK pathway, and inhibition experiments confirmed its necessity for RASD2-driven oncogenesis. Through co-immunoprecipitation and LC-MS/MS, we identified RAF1 as a key binding partner. RASD2 enhanced RAF1 phosphorylation at Ser338, thereby activating the P38/ERK-MAPK pathway. RAF1 phosphorylation at Ser338 was critical for ccRCC cell growth, migration, and invasion. The RAF1 inhibitor BAY43-9006 reduced p-RAF1 (Ser338)/RAF1 levels, suppressed ccRCC proliferation, migration, and invasion in vitro, and significantly inhibited tumor growth in vivo. These findings identify RASD2 as a novel oncoprotein that promotes ccRCC tumorigenesis through p-RAF1 (Ser338)-mediated P38/ERK-MAPK activation, suggesting RAF1 inhibition as a promising therapeutic strategy for ccRCC patients.

BackgroundTolerogenic dendritic cells have a pivotal function in treating autoimmune illnesses, atopic diseases, and neoplasms. The precise mechanism by which Tolerogenic dendritic cells function in gastric cancer remains incompletely understood. Therefore, this research explored potential genes with prognostic value related to Tolerogenic dendritic cells in gastric cancer, to identify novel therapeutic targets that could provide valuable insights for the clinical treatment of gastric cancer.ResultsFive prognostic genes (CXCL1, INHBA, ASCL2, RNASE1, and GPX3) were finally obtained to construct the risk model. Immune infiltration analysis revealed that GPX3 exhibited significant positive associations with various immune cell populations, particularly regulatory T cells. While ASCL2 was weakly associated with almost all immune cells. These results suggested that there was a complex correlation between prognostic genes and immune cells. The analysis of drug sensitivity demonstrated higher IC50 values for compounds such as BIBW2992 in high-risk group relative to low-risk group. A reverse pattern was observed for GSK269962A and similar drugs, which showed significantly higher IC50 values in low-risk group than high-risk group.ConclusionThe present study revealed five prognostic genes and constructed a predictive model, which provided a theoretical basis for the correlation linking Tolerogenic dendritic cells to gastric cancer, and established potential therapeutic strategies in managing gastric cancer. Single-cell analysis revealed that INHBA, ASCL2, and CD36 exhibited marked differential expression in dendritic cells.

The inhibitors of epidermal growth factor receptor (EGFR) have emerged as one of fastest-growing medications that are widely utilized to control the spread and proliferation of malignant tumors. Based on the structural features of quinazoline-containing EGFR inhibitors, a series of coumarin-deriving (Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylates as potential EGFR inhibitors were firstly constructed and evaluated for their antiproliferative effects against human pancreatic (PANC-1), gastric (SGC7901), hepatocellular (HepG2), breast (MDA-MB-231) and cervical (Hela) carcinoma cells. Strikingly, the IC50 values of a target molecule 5x against SGC7901 and MDA-MB-231 cells were respectively evaluated as 12.82 and 9.97 μM, which were slightly superior to that of fluorouracil (21.23 and 10.67 μM). Concurrently, the further investigations indicated that constructed (Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylates could evidently effect the colony formation, migration, invasion and adhesion of tumour cells in a dose-dependent manner. Subsequently, the feasibility of constructed (Z)-3-(2-(quinazolin-4-yloxy)phenyl)acrylates as potential EGFR inhibitors was ascertained by the relative surveys on molecular docking and molecular dynamics simulation analyses. This present work provided a necessary replenishment for the structural optimizations of quinazoline-containing EGFR inhibitors.

Gastric cancer is a prevalent malignant tumor, characterized by high morbidity and mortality rates globally. Long non-coding RNAs (lncRNAs), a class of transcripts exceeding 200 nucleotides in length, are non-protein-coding molecules that exert crucial regulatory functions in cellular biology. Investigating the regulatory mechanisms of lncRNAs in gastric cancer is essential. This study aimed to elucidate the functional role and molecular mechanisms of LINC00520 in gastric cancer. Initially, the GEO database was screened for differentially expressed genes associated with the malignant progression of gastric cancer. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was utilized to ascertain the LINC00520 expression in gastric cancer tissues. Subsequently, cellular functional assays were conducted to investigate the potential effects of LINC00520 on cellular behavior. The interaction between LINC00520, miR-519b-3p, and HIF1A was examined through bioinformatics analysis, and their binding interactions were confirmed using dual-luciferase reporter gene assays and RNA immunoprecipitation (RIP) assays. Our findings revealed a marked increase in the LINC00520 expression in gastric cancer tissues. Overexpression of LINC00520 was observed to enhance the malignant progression of gastric cancer cells. Through bioinformatics analysis, dual-luciferase reporter assays, and RIP assays, we demonstrated that LINC00520 upregulated HIF1A expression by competitively binding to miR-519b-3p, thereby acting as a molecular sponge. In conclusion, this study indicates that LINC00520, which is highly expressed in gastric cancer, exerts its effects by targeting the miR-519b-3p/HIF1A axis. These insights provide a foundation for developing diagnostic and therapeutic strategies for gastric cancer.

The adverse events associated with antitumour drugs have recently emerged as an increasingly significant clinical concern. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) serve as pivotal therapeutic agents for non-small cell lung cancer (NSCLC). However, considerable interindividual variability exists in drug exposure, along with a high incidence and severity of adverse events. In this study, we quantitatively investigated the impacts of EGFR TKI exposure and other covariates on the severity of the maximum grade of drug-related adverse events (MDRAE) in NSCLC patients treated with EGFR TKIs. Data were collected from 277 patients treated with gefitinib, icotinib, afatinib or osimertinib. Population pharmacokinetic (PopPK) models were constructed for each drug, and individual exposure metrics were derived through model simulations. Normalized individual exposures to different EGFR TKIs based on their IC50 values and MDRAE data were integrated to develop an ordinal logistic regression model for an exposure–safety analysis. A user-friendly nomogram was subsequently designed. The probability of high-grade MDRAE was significantly associated with normalized exposure levels, a history of EGFR TKI treatment, sex and other factors. Model simulations revealed substantial interindividual variability in drug exposure and the probability of different grades of MDRAE for the same treatment regimen. This study quantitatively elucidates the influences of drug exposure and other critical factors on safety, thereby contributing to the formulation of individualized treatment strategies to prevent and promptly address drug safety-related issues.

Background: Precision oncology drugs are a class of targeted drugs that are most effective in a molecularly defined subset of cancer patients. Pretreatment molecular profiling is integral to optimal patient selection. However, discordances between molecular profiling results and actual drug selection become evident in clinical practice. This study aimed to assess the discordances between molecular alterations and actual drug selection of non-small cell lung cancer (NSCLC) in China. Methods: This retrospective cohort study consecutively included NSCLC patients from a specialized oncology hospital and a general hospital in Beijing between November 2021 and June 2022. Discordances between molecular profiling results and first-line drug selection consisted of the following four scenarios: (1) not receiving any drugs after molecular profiling; (2) receiving precision oncology drugs before getting molecular profiling results or without molecular profiling results; (3) receiving precision oncology drugs without any targeted gene mutations; (4) not receiving precision oncology drugs with targeted gene mutation. Primary outcome was the proportion of discordances of included NSCLC patients in China. Secondary outcomes were the proportion of four scenarios of discordances. Findings: A total of 707 NSCLC patients were included, of whom 519 were diagnosed with adenocarcinoma, 172 with squamous cell carcinoma, and 16 with other pathological types. The proportion of molecular profiling in NSCLC patients was 62.4% (441/707), with adenocarcinoma patients accounting for the highest percentage at 83.4% (368/441). The proportion of discordances between molecular profiling results and first-line drug selection was 25.2% (178/707). 17.8% (126/707) patients did not receive any drugs after molecular profiling, 1.7% (12/707) received precision oncology drugs before getting molecular profiling results or without any molecular profiling results, 1.1% (8/707) received precision oncology drugs without any targeted gene mutations, 4.5% (32/707) did not received precision oncology drugs with targeted gene mutation. Interpretation: This study highlighted a quarter of NSCLC patients had the discordances between molecular profiling results and first-line drug selection in China, which may result in a loss of survival benefit to the patient, and a waste of the value of molecular profiling. Future studies need to evaluate and intervene the discordances to optimize the implementation of precision oncology therapy.

The Gastrin/CCKBR axis is essential for inhibiting intestinal sodium absorption, but its effects on intestinal glucose metabolism remain elusive. This study aims to determine the role of intestinal Gastrin/CCKBR on glucose absorption in the development of type 2 diabetes (T2D). Intestinal epithelial cell-specific Cckbr knockout mice and control wild-type mice are fed normal diet (ND, 10% fat) or high fat diet (HFD, 60% fat) to study the effect of intestinal Gastrin/CCKBR on blood glucose levels. Gastrin-SiO2 microspheres (20 mg kg(-1) d(-1)) are designed so that gastrin specifically stimulates intestinal CCKBR, without its absorption into the circulation. Mice with silenced intestinal Cckbr has pre-diabetes mellitus (Pre-DM) that rapidly progressed into T2D when fed HFD. Moreover, Gastrin-SiO2 microspheres markedly reduce glucose absorption in duodenum obtained from patients with T2D. In mice with HFD-induced T2D, Gastrin-SiO2 microspheres reduce intestinal glucose absorption by down-regulating intestinal SGLT1 and GLUT2 expressions and stimulating incretin secretion. This study shows the important role of intestinal Gastrin/CCKBR in intestinal glucose absorption. Gastrin-SiO2 microspheres may be a promising strategy for the treatment of patients with T2D.

Programmed cell death protein-1 (PD-1) inhibitors plus chemotherapy have been the standard of care in the first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma; however, the survival benefits are modest in patients with low programmed death ligand 1 (PD-L1) expression. Here we investigated the efficacy and safety of cadonilimab (PD-1/cytotoxic T lymphocyte antigen-4 (CTLA-4) bispecific antibody) plus chemotherapy as first-line treatment in G/GEJ adenocarcinoma. The prespecified interim analysis is reported here. This was a randomized, double-blind, placebo-controlled phase 3 study. Eligible patients were adults with untreated, unresectable, locally advanced or metastatic G/GEJ adenocarcinoma. Patients were randomized 1:1 to receive cadonilimab (10 mg kg−1 every 3 weeks) or placebo plus chemotherapy (every 3 weeks). The primary endpoint was overall survival (OS) in the intention-to-treat population (one-sided significance level, P = 0.025). Secondary endpoints included OS in patients with a PD-L1 combined positive score ≥5, progression-free survival, objective response rate, duration of response and safety. As of 18 August 2023, 610 patients from 75 study centers were randomized to cadonilimab (n = 305) or placebo (n = 305). With a median follow-up of 18.7 months, the cadonilimab group had a significantly longer median OS (14.1 versus 11.1 months; hazard ratio (HR) 0.66; 95 NCT05008783 . In a prespecified interim analysis of the randomized, double-blind phase 3 COMPASSION-15 trial, patients with advanced HER2-negative gastric/GEJ cancer treated with the anti-PD-L1/CTLA-4 bispecific Ab cadonilimab plus chemotherapy showed significantly improved overall survival compared with patients treated with placebo plus chemotherapy as first-line treatment.

PURPOSE:The flexible protein GRB2 interacts with HER1-4 on the cell surface and regulates the development of tumor cells; meanwhile, it is also an RBP that plays an important role in post-transcriptional regulation in eukaryotes, which affects every stage of mRNA synthesis, modification, splicing, and stabilization. Although some studies have found a connection between GRB2 and HER2-overexpression breast cancer, highlighting the potential of GRB2 as a novel biomarker that stimulates tumor growth, limited data were available to elaborate on their interaction mechanisms. METHODS:In this research, we found 396 different gene expressions between the Grb2-knockdown group and the SK-BR-3 group by the RNA sequencing approach. After GRB2 was knocked down, 956 alternative splicing events occurred. RESULTS:The fRIP-seq results showed that GRB2-binding reads were significantly enriched in the intron region, indicating that UUAGC and UUGGUUGG might be the binding motifs. An integration analysis of DEGs with the peak genes of fRIP-seq revealed that 63 genes possess GRB2 binding sites on their mRNAs or antisense RNAs. By integration analysis of AS events with the peak genes of fRIP-seq, 66 genes related to AS events were found. CONCLUSIONS:Above, these AS events may be regulated by GRB2 to promote the progression of HER2-overexpression breast cancer.

Background CMG901 is a novel first-in-class antibody-drug conjugate with a humanised anticlaudin 18.2 antibody linked to microtubule-disrupting agent monomethyl auristatin E. We aimed to assess the antitumour activity and safety of CMG901 in patients with advanced gastric or gastro-oesophageal junction cancer and other solid tumours. Methods KYM901 is a multicentre, open-label, single-arm, phase 1 trial consisting of dose-escalation and dose- expansion stages. Patients with advanced solid tumours, including gastric or gastro-oesophageal junction and pancreatic cancers, were recruited from 31 hospital sites in China. Eligible patients were aged 18 years or older, were refractory to standard therapy or had no available standard-of-care regimen, and had an Eastern Cooperative Oncology Group performance status score of 0-1, a life expectancy of at least 3 months, and at least one measurable lesion. Patients received intravenous CMG901 every 3 weeks (03-34 mg/kg in dose escalation and 22-30 mg/kg in dose expansion) until disease progression, unacceptable toxic effects, initiation of new antitumour therapy, study withdrawal, or death. Primary endpoints were adverse events and dose-limiting toxic effects in the dose-escalation phase, and objective response rate and recommended phase 2 dose in the dose-expansion phase. Confirmed objective response was defined as a partial or complete response that was verified by follow-up imaging at least 4 weeks after the initial assessment. Safety was assessed in all patients who received at least one dose of CMG901 with at least one post-dose safety evaluation. Antitumour activity was assessed in all patients who received at least one dose of CMG901 (full analysis set) and in all CMG901-treated patients with at least one post-dose imaging evaluation and no major protocol deviations (efficacy analysis set). Dose-expansion data for patients with pancreatic cancer will be published separately. Due to small sample sizes, results in patients with other solid tumours (n=2) are not planned for publication. This ongoing trial is registered with ClinicalTrials.gov, NCT04805307. Findings Between Dec 24, 2020, and Feb 23, 2023, 27 patients were enrolled in the dose-escalation phase (median age 570 years [IQR 480-630]; 14 [52%] male, 13 [48%] female) and 107 patients with gastric or gastro-oesophageal junction cancer in the dose-expansion phase (median age 560 years [440-640]; 57 [53%] male, 50 [47%] female). As of Feb 24, 2024, one dose-limiting toxic effect (grade 3 pancreatitis) occurred at 22 mg/kg, and the maximum tolerated dose was not reached in the dose-escalation phase. All 27 patients reported at least one treatment-emergent adverse event, most frequently vomiting (19 [70%]), decreased appetite (16 [59%]), proteinuria (16 [59%]), and anaemia (15 [56%]), and five (19%) had drug-related grade 3 or worse treatment-emergent adverse events. In 107 patients, grade 3 or worse treatment-emergent adverse events occurred in 73 (68%) patients and serious adverse events occurred in 54 (50%) patients in dose expansion. The most common grade 3-4 adverse events were neutrophil count decreased (22 [21%]), anaemia (15 [14%]), and vomiting (11 [10%]). One treatment-related death was reported. At median follow-up of 90 months (IQR 44-129), among 113 patients with gastric or gastro-oesophageal junction cancer in the 22-30 mg/kg cohort full analysis set across both the dose-escalation and dose-expansion phases, the confirmed objective response rate was 28% (95% CI 20-38; 32 of 113 patients). In the 109 patients included in the efficacy analysis set, the confirmed objective response rate was 29% (95% CI 21-39; 32 of 109 patients). Based on overall safety, activity, and pharmacokinetics of CMG901, 22 mg/kg was the proposed recommended phase 2 dose. Interpretation CMG901 showed a manageable safety profile and had promising antitumour activity in patients with advanced gastric or gastro-oesophageal junction cancer. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

Inflammatory myofibroblastic tumor (IMT) is a rare spindle-cell neoplasm. IMT currently suffers from a paucity of standardized diagnostic and therapeutic guidelines. The Chinese expert consensus committee on the diagnosis and treatment of IMT formed an "Expert consensus on the diagnosis and treatment of inflammatory myofibroblastic tumor". This consensus was developed through a comprehensive synthesis of expert opinions, an extensive review of the literature, and a series of offline and online deliberations. The committee aspires that this consensus will enhance the therapeutic outcomes and prognosis for patients with IMT in the future.

Background:It is a challenge for clinicians to choose the optimal third generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) treatment for individual patients. In this meta-analysis we compare the efficacy of five third-generation EGFR-TKIs, as first-line and second-line therapies for non-small cell lung cancer (NSCLC) patients, and their adverse events (AEs). Methods:A Bayesian hierarchical network meta-analysis was conducted to evaluate the hazard ratios (HR) of first-line therapeutic effects and AEs for these third-generation EGFR-TKIs comparing with first-generation EGFR-TKIs. Additionally, a simple comparison analysis was conducted to evaluate second-line therapeutic effects. Results:All third-generation TKIs exhibited superior efficacy compared to Gefitinib in first-line treatment. Furmonertinib achieved the lowest HR in the exon 19 deletions subgroup (HR: 0.35; 95 % CI: 0.23-0.54), while Lazertinib showed the most favorable HR in the exon 21 L858R subgroup (HR: 0.44; 95 % CI: 0.28-0.70) and among patients with brain metastases (HR: 0.33; 95 % CI 0.18-0.59). In the second-line setting, Furmonertinib achieved the highest numerically objective response rate across the overall population (74.0 %; 95 % CI: 68.0-80.0 %) and all evaluated subgroups. Adverse event analysis showed that Furmonertinib had the lowest overall AE incidence, and Lazertinib had the lowest rate of high-grade (≥ grade 3) AEs. Conclusions:All third-generation EGFR-TKIs exhibited favorable efficacy in both first- and second-line settings. Differences in AE profiles were also noted.

Tumor-infiltrating neutrophils (TINs) are highly heterogeneous and mostly immunosuppressive in the tumor immune microenvironment (TIME). Current biomarkers of TINs and treatment strategies targeting TINs have not yielded optimal responses in patients across cancer types. Here, we separated human and mouse neutrophils into three developmental stages, including promyelocyte (PM), myelocyte metamyelocyte (MC MM), and band segmented (BD SC) neutrophils. Based on this separation, we observed the predominance of human but not mouse MC MM-stage neutrophils in bone marrow (BM), which exhibit potent immunosuppressive and tumor-promoting properties. MCs MMs also occupy the majority of TINs among patients with 17 cancer types. Moreover, through the creation of a NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt (NCG)-Gfi1−/− human immune system (HIS) mouse model, which supports efficient reconstitution of human TIN, we found a significant increase of BM MCs MMs in tumor-bearing mice. By comparing the single-cell RNA sequencing analysis results of human neutrophils from both BM and tumors, we found that CD63 and Galectin-3 distinguish MC MM from neutrophil populations in cancer patients. Furthermore, we proposed a strategy with Fms-like tyrosine kinase 3 ligand to specifically induce the trans-differentiation of MCs MMs into monocytic cells, and trigger tumor control in NCG-Gfi1−/− HIS mice. Thus, our findings establish an essential role of human MC MM-stage neutrophils in promoting cancer progression, and suggest their potential as targets for developing potential biomarkers and immunotherapies for cancer.

Oral squamous cell carcinoma (OSCC) is associated with high morbidity and mortality, emphasizing the need for early detection through advanced biomarkers and non-invasive methods. This study analyzed Anaphase Promoting Complex Subunit 10 (ANAPC10) mRNA expression across various cancers using multi-platform tools to assess its diagnostic potential and clinical relevance. We developed a prognostic model linking ANAPC10 expression to survival outcomes using TCGA and GTEx data, and constructed a protein–protein interaction network via GeneMANIA. Functional studies, including cell culture and various assays, demonstrated that ANAPC10 is highly expressed in OSCC and correlates with poor prognosis. ANAPC10 was found to be involved in key pathways, including NF-κB signaling and cell cycle regulation. Knockdown experiments revealed that reducing ANAPC10 expression led to decreased cell proliferation, migration, and invasion, as well as inhibition of the PI3K/AKT/mTOR signaling pathway. These findings suggest that ANAPC10 is a promising biomarker for OSCC and a potential therapeutic target Clinical Trial Number: Not applicable.

This open-label phase II trial (NCT04542837) aimed to evaluate the efficacy and safety of KN046 combined with lenvatinib in patients with advanced hepatocellular carcinoma (HCC), and explore the potential response biomarkers. Participants received KN046 5 mg/kg every 3 weeks and lenvatinib 12 or 8 mg once daily. The primary endpoints were safety, tolerability, dose-limiting toxicity (DLT), and objective response rate (ORR) according to RECIST v1.1. A total of fifty-five participants were enrolled. The results meet the pre-specified primary endpoints. No DLT was observed in the safety run-in period. The incidence of serious adverse events and grade >= 3 treatment-related adverse events (TRAEs) was 30.9% and 47.3%, respectively. Grade >= 3 immunotherapy-related adverse events occurred in 3 (5.5%) participants. Five (9.1%) participants discontinued treatment due to TRAEs, all of which were grade 1-2. The ORR was 45.5% (95% CI, 31.97-59.45). The median progression-free survival was 11.0 (95% CI, 8.21-15.24) months. The median overall survival (OS) was 16.4 (95% CI, 11.20-not estimable) months, and 12-month OS rate was 60.0% (95% CI, 45.87-71.55). Circulating tumor DNA status before the third cycle of treatment was associated with prognosis. In conclusion, First-line KN046 plus lenvatinib shows promising efficacy for advanced unresectable or metastatic HCC.

Ischemic stroke (IS) affects 11 million people annually, posing substantial clinical and economic burdens. Current therapies remain limited by time sensitivity and variable efficacy, necessitating novel biomarkers. We developed a multi-omics framework to investigate senescence-associated gene regulation in IS. After normalizing GSE22255 and GSE58294 datasets, we systematically identified aging-related differentially expressed genes (DEGs). Functional annotation via Gene Set Enrichment Analysis (GSEA) and machine learning-driven Weighted Gene Co-expression Network Analysis (WGCNA) identified core genetic signatures validated in the GSE16561 cohort. Key regulators underwent single-gene profiling, immune microenvironment evaluation, and transcriptional network analysis. Reverse transcription-quantitative PCR (RT-qPCR) confirmed bioinformatics findings. We identified 132 senescence-related DEGs, with PTGS2 emerging as a key biomarker. Pathway analyses revealed significant NF-κB, HIF-1, and TGF-β signaling pathway activation. CIBERSORT-based immune profiling showed altered lymphocyte/macrophage ratios in IS patients. Drug-gene interaction analysis identified nine therapeutic compounds, including etodolac targeting NFE2L2 and PTGS2. A strong positive correlation (r = 0.72, p < 0.001) between NFE2L2 and PTGS2 expression was observed. This study establishes senescence-related genes as promising biomarkers and therapeutic targets for IS, particularly through NFE2L2-PTGS2 interactions, providing a foundation for developing immunomodulatory and targeted therapies.