BACKGROUND:Early-onset gastric cancer (EOGC) (≤45 years) exhibits distinct clinicopathological characteristics, and its incidence is rising. This study aimed to provide comprehensive insights into age-related differences in gastric cancer by retrospectively analyzing the clinicopathological characteristics, survival outcomes, recurrence dynamics, and distant metastasis patterns of EOGC compared with late-onset gastric cancer (LOGC). METHODS:We performed a retrospective analysis of data from 33 675 patients with gastric cancer in the Surveillance, Epidemiology, and End Results (SEER) database and Zhejiang Cancer Hospital, including 3208 patients with EOGC and 30 467 patients with LOGC. Restricted cubic spline analysis (RCS) was used to evaluate the nonlinear relationship between age and mortality risk. Propensity score matching (PSM) was used to balance baseline differences between groups. Survival outcomes-including overall survival (OS), cancer-specific survival (CSS), and disease-free survival (DFS)-were evaluated using Kaplan-Meier analysis, log-rank tests, and Cox proportional hazards models. Subgroup analyses were conducted to further explore prognostic heterogeneity. RESULT:Despite patients with EOGC presenting with unfavorable clinicopathological features, analyses of OS, CSS, DFS, and recurrence-related indicators consistently showed that EOGC is associated with a robust survival advantage across populations. As a representative finding, after PSM, the 5-year OS was 48.3% vs 43.1% in SEER (HR=0.83; P <.001) and 72.6% vs 64.3% in the Chinese cohort (HR=0.71; P <.001). Subgroup analysis further indicated that patients with EOGC exhibited a significant survival advantage with smaller tumor size, signet ring cell carcinoma subtype, and stages I to III (P for interaction <.05). In addition, the distant metastasis pattern in patients with EOGC differed from patients with LOGC, with patients with EOGC more frequently developing bone and ovarian metastases, whereas liver metastasis was less common. Patients with EOGC with peritoneal metastasis had poorer outcomes than patients with LOGC. In patients with EOGC, among different metastatic sites, those with distant lymph node metastasis have a relatively better prognosis, whereas patients with peritoneal metastasis have a less optimistic prognosis (HR=2.23; P =.031). CONCLUSION:Patients with surgically treated EOGC have significantly better prognoses than patients with LOGC. Furthermore, the distant metastasis patterns of EOGC differ from LOGC, carrying distinct prognostic implications for different metastatic sites.

Disulfidptosis represents a novel cell death mechanism triggered by disulfide stress, with potential implications for advancements in cancer treatments. Although emerging evidence highlights the critical regulatory roles of long non-coding RNAs (lncRNAs) in the pathobiology of lung adenocarcinoma (LUAD), research into lncRNAs specifically associated with disulfidptosis in LUAD, termed disulfidptosis-related lncRNAs (DRLs), remains insufficiently explored. Using The Cancer Genome Atlas (TCGA)-LUAD dataset, we implemented ten machine learning techniques, resulting in 101 distinct model configurations. To assess the predictive accuracy of our model, we employed both the concordance index (C-index) and receiver operating characteristic (ROC) curve analyses. For a deeper understanding of the underlying biological pathways, we referred to the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) for functional enrichment analysis. Moreover, we explored differences in the tumor microenvironment between high-risk and low-risk patient cohorts. Additionally, we thoroughly assessed the prognostic value of the DRLs signatures in predicting treatment outcomes. The Kaplan-Meier (KM) survival analysis demonstrated a significant difference in overall survival (OS) between the high-risk and low-risk cohorts (p<0.001). The prognostic model showed robust performance, with an area under the ROC curve exceeding 0.75 at one year and maintaining a value above 0.72 in the two and three-year follow-ups. Further research identified variations in tumor mutational burden (TMB) and differential responses to immunotherapies and chemotherapies. Our validation, using three GEO datasets (GSE31210, GSE30219, and GSE50081), revealed that the C-index exceeded 0.67 for GSE31210 and GSE30219. Significant differences in disease-free survival (DFS) and OS were observed across all validation cohorts among different risk groups. The prognostic model offers potential as a molecular biomarker for LUAD prognosis.

Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens.

Abstract The prognosis for pediatric high-grade gliomas associated with mutations in the H3-A3 histone gene is very poor. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant (DHG), we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens (TAs). We used the RCAS/tv-A system to target the expression of H3/G34R and PDGFb, and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. To identify TAs, we implemented a new computational workflow to identify nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two DHG patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele. Splenocytes isolated from successfully treated mice were analyzed through bulk TCR sequencing, and in comparison with control mice and publicly-accessible TCR libraries, 6 highly-represented TCR clonotypes were identified only in treated mice. In summary, we demonstrate that effective TAs can be extracted from RNAseq data, and can be targeted with DC vaccination to generate a systemic anti-tumor cytotoxic T cell response to eliminate DHG in a novel immunocompetent mouse model.

In the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for Non-Small Cell Lung Cancer (NSCLC), tumors exhibiting main bronchial infiltration (MBI) near the carina and those presenting with complete lung obstructive pneumonia/atelectasis (P/ATL) have been reclassified from T3 to T2. Our investigation into the Surveillance, Epidemiology, and End Results (SEER) database, spanning from 2007 to 2015 and adjusted via Propensity Score Matching (PSM) for additional variables, disclosed a notably inferior overall survival (OS) for patients afflicted with these conditions. Specifically, individuals with P/ATL experienced a median OS of 12 months compared to 15 months (p < 0.001). In contrast, MBI patients demonstrated a slightly worse prognosis with a median OS of 22 months versus 23 months (p = 0.037), with both conditions significantly correlated with lymph node metastasis (All p < 0.001). Upon evaluating different treatment approaches for these particular T2 NSCLC variants, while adjusting for other factors, surgery emerged as the optimal therapeutic strategy. We counted those who underwent surgery and found that compared to surgery alone, the MBI/(P/ATL) group experienced a much higher proportion of preoperative induction therapy or postoperative adjuvant therapy than the non-MBI/(P/ATL) group (41.3%/54.7% vs. 36.6%). However, for MBI patients, initial surgery followed by adjuvant treatment or induction therapy succeeded in significantly enhancing prognosis, a benefit that was not replicated for P/ATL patients. Leveraging the XGBoost model for a 5-year survival forecast and treatment determination for P/ATL and MBI patients yielded Area Under the Curve (AUC) scores of 0.853 for P/ATL and 0.814 for MBI, affirming the model's efficacy in prognostication and treatment allocation for these distinct T2 NSCLC categories.

BackgroundIn individuals receiving treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), those exhibiting positive PD-L1 expression might experience reduced progression-free survival (PFS). However, the effects on overall survival (OS) and the determination of efficacious treatment approaches are still not well-defined.MethodsIn our retrospective study, we examined data from 193 NSCLC patients with advanced EGFR mutations who received first-line TKI treatments, treated at two centers of Shaw Hospital in Zhejiang, China. This analysis covered a period from 1 January 2016 to 30 April 2023.ResultsPatients with PD-L1 positivity exhibited a markedly shorter average PFS (9.5 months versus 17.8 months, P < 0.001) and OS (44.4 months versus 65.7 months, P = 0.016) relative to those without PD-L1 expression. This difference in both PFS and OS remained statistically significant even after adjusting for multiple factors (P < 0.001 for PFS and P = 0.028 for OS). In the PD-L1-positive cohort, introducing combination antiangiogenic significantly extended both PFS (from 9.1 to 25.7 months, P = 0.026) and OS (from 42 to 53.5 months, P = 0.03). Post-first-line TKI therapy, 39.3% of PD-L1-positive patients and 54.5% of PD-L1-negative patients developed the T790M mutation (P = 0.212), with no notable difference in PFS from second-line TKI treatments between the groups. Additionally, subsequent combination therapy with immunotherapy markedly prolonged OS in the PD-L1-positive group. However, for PD-L1-negative patients, neither combination antiangiogenic therapy nor later-line immunotherapy demonstrated significant benefits in PFS or OS.ConclusionFor PD-L1-positive patients, combined antiangiogenic treatments and immunotherapy can significantly improve survival outcomes. In contrast, PD-L1-negative patients show less benefit from these therapies, highlighting the greater efficacy of these treatments in PD-L1-positive individuals.

BACKGROUND:The current pathologic N (pN) classification exhibits limitations in the prognostic stratification of patients with pT3-4N0-2M0 gastric cancer (GC). Therefore, this study aimed to develop and validate a new lymph nodal staging method based on the number of examined lymph nodes (ELNs) and lymph node ratio (LNR). METHODS:Data from 7883 patients with pT3-4N0-2M0 GC were collected from the Surveillance, Epidemiology, and End Results (SEER) database and Zhejiang Cancer Provincial Hospital. Optimal cutoff values for ELNs and LNR were determined using X-tile software. Kaplan-Meier methods, Log-rank tests, and Cox regression analyses were employed in this study. Patients were categorized into 3 new pN stages: new pN0 (pN0 with ELNs of >16), new pN1 (pN0 with ELNs of ≤16 or pN1-2 with LNR of ≤0.15), and new pN2 (pN1-2 with LNR of >0.15). The prognostic predictive power of both current and new pN staging was evaluated using the Akaike information criterion (AIC), Bayesian information criterion, concordance index (C-index), and receiver operating characteristic curve. RESULTS:The new pN classification exhibited excellent performance in Kaplan-Meier survival analysis. After adjusting for confounding factors, the new pN staging emerged as an independent prognostic indicator in patients with GC. In the SEER cohort, the new pN staging demonstrated enhanced prognostic prediction accuracy over the American Joint Committee on Cancer pN staging (AIC: 75578.85 vs 75755.06; C-index: 0.642 vs 0.630; P < .001). Similar findings were validated in the Chinese cohort. CONCLUSION:This study developed and validated an improved pN classification for patients with pT3-4N0-2M0 GC. Surgeons should consider ELNs and LNR when assessing postoperative prognosis in patients with GC.

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe I soform peptides from R NA splicing for I mmunotherapy target S creening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with “neoantigen-like” NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies.

Age-related macular degeneration (AMD) is the leading cause of severe irreversible central vision loss in individuals over 65 years old. Genome-wide association studies (GWASs) have shown that the region at chromosome 10q26, where the age-related maculopathy susceptibility (ARMS2/LOC387715) and HtrA serine peptidase 1 (HTRA1) genes are located, represents one of the strongest associated loci for AMD. However, the underlying biological mechanism of this genetic association has remained elusive. In this article, we extensively review the literature by us and others regarding the ARMS2/HTRA1 risk alleles and their functional significance. We also review the literature regarding the presumed function of the ARMS2 protein and the molecular processes of the HTRA1 protein in AMD pathogenesis in vitro and in vivo, including those of transgenic mice overexpressing HtrA1/HTRA1 which developed Bruch's membrane (BM) damage, choroidal neovascularization (CNV), and polypoidal choroidal vasculopathy (PCV), similar to human AMD patients. The elucidation of the molecular mechanisms of the ARMS2 and HTRA1 susceptibility loci has begun to untangle the complex biological pathways underlying AMD pathophysiology, pointing to new testable paradigms for treatment.

Abstract Juvenile presentation of HGG has been shown to frequently involve somatic mutations of the H3-3A gene, which encodes a histone H3 variant. To address the paucity of identified TSAs in DHG, we utilized a novel computational platform, Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS). The IRIS pipeline is designed to leverage large-scale cancer and normal transcriptomic data to identify peptide sequences that result from alternative splicing events that are highly enriched in cancer cells, and are predicted to bind the HLA class I alleles carried by the individual patient. To investigate whether peptide-pulsed dendritic cells (DC) together with checkpoint blockade might be a potential treatment modality for diffuse hemispheric glioma, H3 G34-mutant, we have developed a novel mouse model, and utilized a novel bioinformatics pipeline to identify tumor-associated peptide antigens. We used the RCAS/tv-A system to target the expression of H3/G34R and PDGF-B and to knock out p53 in neural progenitors in transgenic C57BL/6 neonatal mice. Three independent cell lines were obtained that expressed transcripts associated with oligodendrocyte and interneuron lineages, and formed lethal tumors after intracranial implantation. Implementing IRIS, we identified nonapeptides generated from alternative splicing of mRNAs that were highly enriched in the tumor transcriptomes of two H3/G34R patients, and predicted to bind the HLA-A*2:01 class I allele carried by these patients. Three of the candidate peptides were conserved in the mouse and also predicted to bind the H2-Kb MHC I allele carried by C57/BL6 mice. Using our syngeneic mouse model, we showed that DCs pulsed with these peptides together with anti-PD1 mAb provided a significant survival benefit compared with checkpoint inhibitor and DCs pulsed with peptides that were not predicted to bind the H2-Kb allele.

Normal-tension glaucoma (NTG) is a heterogeneous disease characterized by retinal ganglion cell (RGC) death leading to cupping of the optic nerve head and visual field loss at normal intraocular pressure (IOP). The pathogenesis of NTG remains unclear. Here, we describe a single nucleotide mutation in exon 2 of the methyltransferase-like 23 (METTL23) gene identified in 3 generations of a Japanese family with NTG. This mutation caused METTL23 mRNA aberrant splicing, which abolished normal protein production and altered subcellular localization. Mettl23–knock-in (Mettl23+/G and Mettl23G/G) and -knockout (Mettl23+/– and Mettl23–/–) mice developed a glaucoma phenotype without elevated IOP. METTL23 is a histone arginine methyltransferase expressed in murine and macaque RGCs. However, the novel mutation reduced METTL23 expression in RGCs of Mettl23G/G mice, which recapitulated both clinical and biological phenotypes. Moreover, our findings demonstrated that METTL23 catalyzed the dimethylation of H3R17 in the retina and was required for the transcription of pS2, an estrogen receptor α target gene that was critical for RGC homeostasis through the negative regulation of NF-κB–mediated TNF-α and IL-1β feedback. These findings suggest an etiologic role of METTL23 in NTG with tissue-specific pathology.

Cancer transcriptomes frequently exhibit RNA dysregulation. As the resulting aberrant transcripts may be translated into cancer-specific proteins, there is growing interest in exploiting RNA dysregulation as a source of tumor antigens (TAs) and thus novel immunotherapy targets. Recent advances in high-throughput technologies and rapid accumulation of multiomic cancer profiling data in public repositories have provided opportunities to systematically characterize RNA dysregulation in cancer and identify antigen targets for immunotherapy. However, given the complexity of cancer transcriptomes and proteomes, important conceptual and technological challenges exist. Here, we highlight the expanding repertoire of TAs arising from RNA dysregulation and introduce multiomic and big data strategies for identifying optimal immunotherapy targets. We discuss extant barriers for translating these targets into effective therapies as well as the implications for future research.

RNA sequencing (RNA-seq) is a powerful technology for studying human transcriptome variation. We introduce PAIRADISE (Paired Replicate Analysis of Allelic Differential Splicing Events), a method for detecting allele-specific alternative splicing (ASAS) from RNA-seq data. Unlike conventional approaches that detect ASAS events one sample at a time, PAIRADISE aggregates ASAS signals across multiple individuals in a population. By treating the two alleles of an individual as paired, and multiple individuals sharing a heterozygous SNP as replicates, we formulate ASAS detection using PAIRADISE as a statistical problem for identifying differential alternative splicing from RNA-seq data with paired replicates. PAIRADISE outperforms alternative statistical models in simulation studies. Applying PAIRADISE to replicate RNA-seq data of a single individual and to population-scale RNA-seq data across many individuals, we detect ASAS events associated with genome-wide association study (GWAS) signals of complex traits or diseases. Additionally, PAIRADISE ASAS analysis detects the effects of rare variants on alternative splicing. PAIRADISE provides a useful computational tool for elucidating the genetic variation and phenotypic association of alternative splicing in populations.

Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches.

We sought to define the landscape of alternative pre-mRNA splicing in prostate cancers and the relationship of exon choice to known cancer driver alterations. To do so, we compiled a metadataset composed of 876 RNA-sequencing (RNA-Seq) samples from five publicly available sources representing a range of prostate phenotypes from normal tissue to drug-resistant metastases. We subjected these samples to exon-level analysis with rMATS-turbo, purpose-built software designed for large-scale analyses of splicing, and identified 13,149 high-confidence cassette exon events with variable incorporation across samples. We then developed a computational framework, pathway enrichment-guided activity study of alternative splicing (PEGASAS), to correlate transcriptional signatures of 50 different cancer driver pathways with these alternative splicing events. We discovered that Myc signaling was correlated with incorporation of a set of 1,039 cassette exons enriched in genes encoding RNA binding proteins. Using a human prostate epithelial transformation assay, we confirmed the Myc regulation of 147 of these exons, many of which introduced frameshifts or encoded premature stop codons. Our results connect changes in alternative pre-mRNA splicing to oncogenic alterations common in prostate and many other cancers. We also establish a role for Myc in regulating RNA splicing by controlling the incorporation of nonsense-mediated decay-determinant exons in genes encoding RNA binding proteins.

A major question in human genetics is how sequence variants of broadly expressed genes produce tissue- and cell type-specific molecular phenotypes. Genetic variation of alternative splicing is a prevalent source of transcriptomic and proteomic diversity in human populations. We investigated splicing quantitative trait loci (sQTLs) in 1,209 samples from 13 human brain regions, using RNA sequencing (RNA-seq) and genotype data from the Genotype-Tissue Expression (GTEx) project. Hundreds of sQTLs were identified in each brain region. Some sQTLs were shared across brain regions, whereas others displayed regional specificity. These "regionally ubiquitous" and "regionally specific" sQTLs showed distinct positional distributions of single-nucleotide polymorphisms (SNPs) within and outside essential splice sites, respectively, suggesting their regulation by distinct molecular mechanisms. Integrating the binding motifs and expression patterns of RNA binding proteins with exon splicing profiles, we uncovered likely causal variants underlying brain region-specific sQTLs. Notably, SNP rs17651213 created a putative binding site for the splicing factor RBFOX2 and was associated with increased splicing of MAPT exon 3 in cerebellar tissues, where RBFOX2 was highly expressed. Overall, our study reveals a more comprehensive spectrum and regional variation of sQTLs in human brain and demonstrates that such regional variation can be used to fine map potential causal variants of sQTLs and their associated neurological diseases.

Background The insect gustatory system plays a central role in the regulation of multiple physiological behaviors and the co-evolution between insects and their hosts. The gustatory receptors (Gr) are important to allow insects to sense their environment. It is critical to the selection of foods, mates and oviposition sites of insects. In this study, the Gr family genes of the brown planthopper (BPH) Nilaparvata lugens Stål (Hemiptera: Delphacidae) were identified and analyzed, and their potential relationship to the fecundity of BPH was explored by RNA interference (RNAi). Results We identified 32 putative Gr genes by analyzing transcriptome and genome data from BPH. Most of these Gr proteins have the typical structure of seven transmembrane domains. The BPH Gr genes ( NlGrs ) were expressed in virtually all tissues and stages, whilst higher transcript accumulations were found in adult stages and in the midguts of females. Based on the phylogenic analysis, we classified NlGrs into five potential categories, including 2 sugar receptors, 2 Gr43a-like receptors, 7 CO 2 receptors, 5 bitter receptors and 13 NlGrs with unknown functions. Moreover, we found that 10 NlGrs have at least two alternative splicing variants, and obtained alternative splicing isoforms of 5 NlGrs . Finally, RNAi of 29 NlGrs showed that 27 of them are related to the transcript levels of two fecundity related genes vitellogenin and vitellogenin receptor. Conclusions We found 32 Gr genes in BPH, among which at least 27 are required for normal expression of fecundity markers of this insect pest. These findings provide the basis for the functional study of Grs and the exploration of potential genes involved in the monophagous character of BPH.

In insects, the gustatory system plays a crucial role in multiple physiological behaviors, including feeding, toxin avoidance, courtship, mating and oviposition. Gustatory stimuli from the environment are recognized by gustatory receptors. To date, little is known about the function of gustatory receptors in agricultural pest insects. In this study, we cloned a sugar gustatory receptor gene, NlGr11, from the brown planthopper (BPH), Nilaparvata lugens (Stal), a serious pest of rice in Asia; we then identified its ligands, namely, fructose, galactose and arabinose, by calcium imaging assay. After injection of NlGr11 double-stranded RNA, we found that the number of eggs laid by BPH decreased. Moreover, we found that NlGr11 inhibited the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and promoted the phosphorylation of protein kinase B (AKT). These findings demonstrated that NlGr11 could accelerate the fecundity of BPH through AMPK- and AKT-mediated signaling pathways. This is the first report to indicate that a gustatory receptor modulates the fecundity of insects and that the receptor could be a potential target for pest control.