Discovery and Optimization of Hsp110 and sGC Dual-Target Regulators for the Treatment of Pulmonary Arterial Hypertension.

Currently, bifunctional agents with vasodilation and ameliorated vascular remodeling effects provide more advantages for the treatment of pulmonary arterial hypertension (PAH). In this study, we first screened the hit 1 with heat shock protein 110 (Hsp110) inhibition effect from our in-house compound library with soluble guanylate cyclase (sGC) activity. Subsequently, a series of novel bisamide derivatives were designed and synthesized as Hsp110/sGC dual-target regulators based on hit 1. Among them, 17i exhibited optimal Hsp110 and sGC molecular activities as well as remarkable cell malignant phenotypes inhibitory and vasodilatory effects in vitro. Moreover, compared to riociguat, 17i showed superior efficacy in attenuating pulmonary vascular remodeling and right ventricular hypertrophy via Hsp110 suppression in hypoxia-induced PAH rat models (i.g.). Notably, our study successfully demonstrated that the simultaneous regulation of Hsp110 and sGC dual targets was a novel and feasible strategy for PAH therapy, providing a promising lead compound for anti-PAH drug discovery.

Ionic Polymerization-Based Synthesis of Bioinspired Adhesive Hydrogel Microparticles with Tunable Morphologies from Microfluidics.

Shape-anisotropic hydrogel microparticles have attracted considerable attention for drug-delivery applications. Particularly, nonspherical hydrogel microcarriers with enhanced adhesive and circulatory abilities have demonstrated value in gastrointestinal drug administration. Herein, inspired by the structures of natural suckers, we demonstrate an ionic polymerization-based production of calcium (Ca)-alginate microparticles with tunable shapes from Janus emulsion for the first time. Monodispersed Janus droplets composed of sodium alginate and nongelable segments were generated using a coflow droplet generator. The interfacial curvatures, sizes, and production frequencies of Janus droplets can be flexibly controlled by varying the flow conditions and surfactant concentrations in the multiphase system. Janus droplets were ionically solidified on a chip, and hydrogel beads of different shapes were obtained. The in vitro and in vivo adhesion abilities of the hydrogel beads to the mouse colon were investigated. The anisotropic beads showed prominent adhesive properties compared with the spherical particles owing to their sticky hydrogel components and unique shapes. Finally, a novel computational fluid dynamics and discrete element method (CFD-DEM) coupling simulation was used to evaluate particle migration and contact forces theoretically. This review presents a simple strategy to synthesize Ca-alginate particles with tunable structures that could be ideal materials for constructing gastrointestinal drug delivery systems.

Study on the occurrence state of main components of phosphogypsum dihydrate and its impurity distribution.

The dihydrate phosphoric acid process is the mainstream technique. However, the phosphogypsum (PG) produced contains high levels of impurities such as phosphorus and fluorine, severely constraining its valorization. In order to elucidate the occurrence patterns of phosphorus and fluorine impurities in PG, this study employed analytical methods including XRF, XRD, AMICS (Automated Mineralogy Integrated with Chemistry System), XPS, and chemical element balance analysis. We investigated the occurrence states of phosphorus, fluorine, silicon, iron, and aluminum elements in PG from wet-process phosphoric acid production, as well as the distribution characteristics of phosphorus and fluorine impurities. Additionally, we utilized Density Functional Theory (DFT) calculations to determine the binding energies of major minerals with water-soluble phosphate and fluoride groups, and analyzed the zeta potentials of gypsum and quartz mineral surfaces. The results indicate that the main mineral phases in PG are gypsum, quartz, potassium silicate minerals, aluminosilicate minerals, and hematite, predominantly occurring in monomineralic forms. Phosphorus impurities primarily exist in calcium silicate and hematite minerals, while fluorine is mainly associated with gypsum and potassium silicate minerals. DFT calculations demonstrate strong binding energies between calcium silicate and hematite minerals with PO4 3-, as well as between gypsum and quartz minerals with F-. The acidic conditions in the separation tank during wet-process phosphoric acid production may contribute to the distinctive distribution characteristics of phosphorus and fluorine impurities in PG.

Balancing Pd-H Interactions: Thiolate-Protected Palladium Nanoclusters for Robust and Rapid Hydrogen Gas Sensing.

The transition toward hydrogen gas (H2) as an eco-friendly and renewable energy source necessitates advanced safety technologies, particularly robust sensors for H2 leak detection and concentration monitoring. Although palladium (Pd)-based materials are preferred for their strong H2 affinity, intense palladium-hydrogen (Pd-H) interactions lead to phase transitions to palladium hydride (PdHx), compromising sensors' durability and detection speeds after multiple uses. In response, this study introduces a high-performance H2 sensor designed from thiolate-protected Pd nanoclusters (Pd8SR16), which leverages the synergistic effect between the metal and protective ligands to form an intermediate palladium-hydrogen-sulfur (Pd-H-S) state during H2 adsorption. Striking a balance, it preserves Pd-H binding affinity while preventing excessive interaction, thus lowering the energy required for H2 desorption. The dynamic adsorption-dissociation-recombination-desorption process is efficiently and highly reversible with Pd8SR16, ensuring robust and rapid H2 sensing at parts per million (ppm). The Pd8SR16-based sensor demonstrates exceptional stability (50 cycles; 0.11% standard deviation in response), prompt response/recovery (t90 = 0.95 s/6 s), low limit of detection (LoD, 1 ppm), and ambient temperature operability, ranking it among the most sensitive Pd-based H2 sensors. Furthermore, a multifunctional prototype demonstrates the practicality of real-world gas sensing using ligand-protected metal nanoclusters.

Applying 3D-printed prostheses to reconstruct critical-sized bone defects of tibial diaphysis (> 10 cm) caused by osteomyelitis and aseptic non-union.

BACKGROUND: Clinical repair of critical-sized bone defects (CBDs) in the tibial diaphysis presents numerous challenges, including inadequate soft tissue coverage, limited blood supply, high load-bearing demands, and potential deformities. This study aimed to investigate the clinical feasibility and efficacy of employing 3D-printed prostheses for repairing CBDs exceeding 10 cm in the tibial diaphysis. METHODS: This retrospective study included 14 patients (11 males and 3 females) with an average age of 46.0 years. The etiologies of CBDs comprised chronic osteomyelitis (10 cases) and aseptic non-union (4 cases), with an average defect length of 16.9 cm. All patients underwent a two-stage surgical approach: (1) debridement, osteotomy, and cement spacer implantation; and (2) insertion of 3D-printed prostheses. The interval between the two stages ranged from 8 to 12 weeks, during which the 3D-printed prostheses and induced membranes were meticulously prepared. Subsequent to surgery, patients engaged in weight-bearing and functional exercises under specialized supervision. Follow-up assessments, including gross observation, imaging examinations, and administration of the Lower Extremity Functional Scale (LEFS), were conducted at 3, 6, and 12 months postoperatively, followed by annual evaluations thereafter. RESULTS: The mean postoperative follow-up duration was 28.4 months, with an average waiting period between prosthesis implantation and weight-bearing of 10.4 days. At the latest follow-up, all patients demonstrated autonomous ambulation without assistance, and their LEFS scores exhibited a significant improvement compared to preoperative values (30.7 vs. 53.1, P < 0.001). Imaging assessments revealed progressive bone regeneration at the defect site, with new bone formation extending along the prosthesis. Complications included interlocking screw breakage in two patients, interlocking screw loosening in one patient, and nail breakage in another. CONCLUSIONS: Utilization of 3D-printed prostheses facilitates prompt restoration of CBDs in the tibial diaphysis, enabling early initiation of weight-bearing activities and recovery of ambulatory function. This efficacious surgical approach holds promise for practical application.

The Long Non-Coding RNA SNHG1 Predicts Severity of Acute Pancreatitis and Stimulates Pancreatic Cell Apoptosis and Inflammatory Response.

Acute pancreatitis (AP) is a common digestive emergency, needs early prediction and recognition. The study examined the clinical value of long non-coding RNA SNHG1 in AP, and explored its related mechanism for AP. A total of 288 AP cases and 150 healthy persons were recruited, the AP patients were grouped based on AP severity. AR42J cells were treated with 100nM caerulein to stimulate AP in vitro. qRT-PCR was performed for mRNA detection. Receiver operating characteristic (ROC) curve was drawn for diagnostic significance evaluation. The relationship of SNHG1 and miR-140-3p was verified via luciferase reporter and RNA immunoprecipitation (RIP) assay. AP cases had high expression of SNHG1, and it can differentiate AP cases from healthy people with the area under the curve (AUC) of 0.899. Severe AP cases had high values of SNHG1, which was independently related to AP severity. SNHG1 knockdown relieved caerulein-induced AR42J cell apoptosis and inflammatory response. miR-140-3p interacted with SNHG1, and reversed the role of SNHG1 in caerulein-induced AR42J cell injury. RAB21 was a candidate target of miR-140-3p, and was at high expression in AP cell models. SNHG1 may be a promising biomarker for the detection of AP, and serves as a potential biological marker for further risk stratification in the management of AP. SNHG1 knockdown can relieve inflammatory responses and pancreatic cell apoptosis by absorbing miR-140-3p.

Advances in CircRNAs in the Past Decade: Review of CircRNAs Biogenesis, Regulatory Mechanisms, and Functions in Plants.

Circular RNA (circRNA) is a type of non-coding RNA with multiple biological functions. Whole circRNA genomes in plants have been identified, and circRNAs have been demonstrated to be widely present and highly expressed in various plant tissues and organs. CircRNAs are highly stable and conserved in plants, and exhibit tissue specificity and developmental stage specificity. CircRNAs often interact with other biomolecules, such as miRNAs and proteins, thereby regulating gene expression, interfering with gene function, and affecting plant growth and development or response to environmental stress. CircRNAs are less studied in plants than in animals, and their regulatory mechanisms of biogenesis and molecular functions are not fully understood. A variety of circRNAs in plants are involved in regulating growth and development and responding to environmental stress. This review focuses on the biogenesis and regulatory mechanisms of circRNAs, as well as their biological functions during growth, development, and stress responses in plants, including a discussion of plant circRNA research prospects. Understanding the generation and regulatory mechanisms of circRNAs is a challenging but important topic in the field of circRNAs in plants, as it can provide insights into plant life activities and their response mechanisms to biotic or abiotic stresses as well as new strategies for plant molecular breeding and pest control.

Retraction of: "Risk factors for poor ovarian response in patients receiving in-vitro fertilization and embryo transfer".

The paper entitled "Risk factors for poor ovarian response in patients receiving in-vitro fertilization and embryo transfer" by Chen et al., which was published in Minerva Surgery 2023 June;78(3):303-4, has been retracted by the Publisher upon the authors' request; they asked for a retraction because the paper contains faulty data.

Update: The Role of Epigenetics in the Metabolic Memory of Diabetic Complications.

Diabetes, a chronic disease characterized by hyperglycemia, is associated with significantly accelerated complications, including diabetic kidney disease (DKD), which increase morbidity and mortality. Hyperglycemia and other diabetes-related environmental factors such as overnutrition, sedentary lifestyles and hyperlipidemia can induce epigenetic changes. Working alone or with genetic factors, these epigenetic changes, that occur without alterations in the underlying DNA sequence, can alter the expression of pathophysiological genes and impair functions of associated target cells/organs, leading to diabetic complications like DKD. Notably, some hyperglycemia-induced epigenetic changes persist in target cells/tissues even after glucose normalization, leading to sustained complications despite glycemic control, so called metabolic memory. Emerging evidence from in-vitro, in-vivo animal models and clinical trials with diabetes subjects identified clear associations between metabolic memory and epigenetic changes including DNA methylation, histone modifications, chromatin structure, and noncoding RNAs at key loci. Targeting such persistent epigenetic changes and/or molecules regulated by them can serve as valuable opportunities to attenuate, or erase metabolic memory, which is crucial to prevent complication progression. Here, we review these cell/tissue-specific epigenetic changes identified to-date as related to diabetic complications, especially DKD, and the current status on targeting epigenetics to tackle metabolic memory. We also discuss limitations in current studies, including the need for more (epi)genome-wide studies, integrative analysis using multiple epigenetic marks and Omics datasets, and mechanistic evaluation of metabolic memory. Considering the tremendous technological advances in epigenomics, genetics, sequencing, and availability of genomic datasets from clinical cohorts, this field is likely to see considerable progress in the upcoming years.

Factors affecting advance care planning in older adults with cancer.

INTRODUCTION: Advance care planning (ACP) has been widely endorsed and recommended for its many potential benefits, including improved end-of-life (EOL) care, enhanced satisfaction with care, and reduced anxiety and depression. However, little is known about the ACP completion rates and factors affecting ACP among older adults with cancer. This study's purpose was to examine biological, psychological, and social factors affecting ACP in this population. MATERIALS AND METHODS: Data from the 2002 to 2016 waves of exit interviews from the national longitudinal Health and Retirement Study were analyzed. The sample included 1088 decedents, aged 55 and over, who had a diagnosis of cancer. The exit interviews were completed by a proxy respondent (usually the next of kin of the decedents). ACP outcomes included: having EOL care discussion, durable power of attorney (DPOA), and advance directives (ADs). Multiple logistic regression models were conducted to examine the relationships between predictor variables and each of the three ACP outcome variables. RESULTS: Approximately 65% of the sample had ever discussed EOL care, 61.9% had an assigned DPOA, and 54.1% had ADs. Regression results showed that higher age, Black race, high school and above education, being widowed/never married, higher multimorbidity, and more limitations in activities of daily living and instrumental activities of daily living were significantly associated with the three ACP variables. Surprisingly, Black race was associated with higher odds of ever discussing EOL care and having ADs; high school and above education was associated with lower odds of all three ACP components. DISCUSSION: The majority of participants in this study had discussed EOL care, had an assigned DPOA, and had ADs. However, most participants were White/Caucasian and had completed high school education. Future research that includes more diverse and minoritized participants is needed. Also, the contrasting association of Black race and higher educational status with ACP outcomes warrant further exploration in future studies.

Synergistic ferrate(VI) and chlorine for reclaimed water disinfection: Microbial control and chlorine decay mitigation.

Chlorination is the most widely used disinfection technology due to its simplicity and continuous disinfection ability. However, the drawbacks of disinfection by-products and chlorine-resistant bacteria have gained increasing attention. Nowadays, ferrate (Fe(VI)) is a multifunctional and environmentally friendly agent which has great potential in wastewater reclamation and reuse. This study investigated synergistic Fe(VI) and chlorine technology for reclaimed water disinfection in terms of microbial control and chlorine decay mitigation. Specifically, synergistic disinfection significantly improved the inactivation efficiency on total coliform, Escherichia coli and heterotrophic bacteria compared to sole chlorination. Synergistic disinfection also exhibited superior performance on controlling the relative abundance of chlorine-resistant bacteria and pathogenic bacteria. In addition, the decay rate of residual chlorine was relatively lower after Fe(VI) pretreatment, which was beneficial for microbial control during the reclaimed water distribution process. Technical and economic analyses revealed that synergistic Fe(VI) and chlorine disinfection was suitable and feasible. Results of this study are believed to provide useful information and alternative options on the optimization of reclaimed water disinfection.

Short-Wave Infrared Light-Emitting Diodes Using Colloidal CuInS2 Quantum Dots with ZnI2 Dual-Passivation.

Short-wave infrared (SWIR) light-emitting diodes (LEDs) have emerged as promising technologies for diverse applications such as optical communication, biomedical imaging, surveillance, and machine vision. Colloidal quantum dots (QDs) are particularly attractive for SWIR LEDs due to their solution processability, compatibility with flexible substrates, and tunable absorption and luminescence. However, the presence of toxic elements or precious metals in most SWIR-emitting QDs poses health, environmental, and cost challenges. In this context, CuInS2 (CIS) QDs are known for low toxicity, cost-effective fabrication, and SWIR-light emitting capability. However, CIS QDs have not yet been directly utilized to fabricate SWIR LEDs to date, which is due to low particle stability, inefficient charge carrier recombination, and significantly blue-shifted luminescence after integrating into LED devices. To address challenges, we propose a dual-passivation strategy using ZnI2 as a chemical additive to enhance both the optical property of plain CIS QDs and charge carrier recombination upon LED device implementation. The resulting CIS-QD-based LEDs exhibit a stable SWIR electroluminescence (EL) peak (over 1000 nm) with a high EL radiance and a record external quantum efficiency in the SWIR region. Our study represents a significant step forward in SWIR-QLED technology, offering a pathway for the development of high-performance, low-cost, and nontoxic SWIR light sources.

Disinfection-residual bacteria (DRB) after chlorine dioxide treatment: Microbial community structure, regrowth potential, and secretion characteristics.

This study investigates the effects of chlorine dioxide (ClO2) disinfection on the community structure, regrowth potential, and metabolic product secretion of disinfection-residual bacteria (DRB) in secondary effluent (SE), denitrification filter effluent (DFE), and ultrafiltration effluent (UE). Results show that ClO2 effectively reduces bacteria in SE and UE, achieving log removal values exceeding 3 at 1 mg/L within 30 min. A salient positive correlation (R2 > 0.95) exists between changes in total fluorescence intensity and disinfection efficacy. Post-treatment, Acinetobacter abundance increased in SE, while Pseudomonas decreased in DFE and UE. At lower ClO2 concentrations, Staphylococcus, Mycobacterium, Aeromonas, and Lactobacillus increased in DFE, but decreased at higher concentrations. After storage, bacterial counts in disinfected samples exceeded those in the control group, surpassing 105 CFU/mL. Despite an initial decline, species richness and evenness partially recovered but remained lower than control levels. Culturing DRB for 72 h showed elevated extracellular polymeric substances (EPS) secretion, quantified as total organic carbon (TOC), ranging from 5 to 27 mg/L, with significantly higher EPS in the disinfection group. Parallel factor analysis with self-organizing maps (PARAFAC-SOM) effectively differentiated water sample types and EPS fluorescent substances, underscoring the potential of three-dimensional fluorescence as an indirect measure of ClO2 disinfection efficacy.

ANGPTL8 deficiency attenuates lipopolysaccharide-induced liver injury by improving lipid metabolic dysregulation.

Liver injury is closely related to poor outcomes in sepsis patients. Current studies indicate that sepsis is accompanied by metabolic disorders, especially those related to lipid metabolism. It is highly important to explore the mechanism of abnormal liver lipid metabolism during sepsis. As a key regulator of glucose and lipid metabolism, angiopoietin-like 8 (ANGPTL8) is involved in the regulation of multiple chronic metabolic diseases. In the present study, severe liver lipid deposition and lipid peroxidation were observed in the early stages of lipopolysaccharide (LPS) induced liver injury. LPS promotes the expression of ANGPTL8 both in vivo and in vitro. Knockout of ANGPTL8 reduced hepatic lipid accumulation and lipid peroxidation, improved fatty acid oxidation and liver function, and increased the survival rate of septic mice by activating the PGC1α/PPARα pathway. We also found that the expression of ANGPTL8 induced by LPS depends on TNF-α, and that inhibiting the TNF-α pathway reduces LPS-induced hepatic lipid deposition and lipid peroxidation. However, knocking out ANGPTL8 improved the survival rate of septic mice better than inhibiting the TNF-α pathway. Taken together, the results of our study suggest that ANGPTL8 functions as a novel cytokine in LPS-induced liver injury by suppressing the PGC1α/PPARα signaling pathway. Therefore, targeting ANGPTL8 to improve liver lipid metabolism represents an attractive strategy for the management of sepsis patients.

The Role of Neighborhood Socioeconomic Status in Institutionalization of Home Health Care Patients With and Without Alzheimer's Disease and Related Dementias.

OBJECTIVES: To assess whether neighborhood socioeconomic status (SES) moderates the association between Alzheimer's disease and related dementias (ADRD) and successful discharge to the community. In addition, to explore whether the role of neighborhood SES on successful discharge for patients with ADRD varies by the severity of ADRD. DESIGN: This is a retrospective cohort study. SETTING AND PARTICIPANTS: Medicare Fee-for-service beneficiaries, aged 65 or older, who received home health care in 2019. METHODS: We used linear probability regression models with successful discharge to the community as the main outcome, and neighborhood SES and ADRD as independent variables. Also, we modified the Functional Assessment Staging Tool (FAST) to measure ADRD severity. RESULTS: Our study results show ADRD and residing in neighborhoods with lower socioeconomic conditions were independently associated with lower probabilities of successful discharge to the community. We also found that the differences in probabilities of remaining at home between patients with and without ADRD were larger among those in neighborhoods with lower SES (ADRD∗less disadvantaged neighborhood, coeff: -0.01, P < .001; ADRD∗more disadvantaged neighborhood, coeff: -0.02, P < .001; ADRD∗most disadvantaged neighborhood, coeff: 0.032, P < .001). Among patients with ADRD, patients with the most advanced ADRD were less likely to remain in their homes and community when living in neighborhoods with lower SES. CONCLUSIONS AND IMPLICATIONS: Our study results show that when patients with ADRD receiving home health care live in neighborhoods with lower SES, they face further challenges to remaining in their homes and community. Public health officials and community planners should consider using area-level interventions to improve care and health outcomes for patients with ADRD. Also, further research aimed at identifying the specific factors and resources influencing lower care quality and poorer health outcomes in socioeconomically disadvantaged neighborhoods, particularly for patients with ADRD, can provide valuable insights for the development and implementation of targeted interventions.

Assessing stress causing factors and language related challenges among first year students in higher institutions in Pakistan.

This mixed-methods study delves into stress factors among first-year undergraduate students in universities across Punjab, Pakistan. Five hundred students underwent evaluation for stress levels and academic achievement, with 10 selected for further analysis. The Perceived Stress Scale (Cohen et al., 1983) and demographic sheets were utilized for data collection. Analysis revealed a significant negative correlation between perceived stress and academic achievement. While women exhibited higher stress levels but better academic performance, students from public sector universities reported greater stress and lower academic success. In-depth interviews identified key stressors including heavy academic workload, financial constraints, limited support systems, competitive academic environments, and language-related challenges, notably weak English-speaking skills. These findings underscore the urgent need for enhanced support services, increased financial aid accessibility, a balanced academic culture, and the implementation of language support programs in Southern Punjab's higher education institutions. Addressing these stressors is crucial for fostering the well-being and academic success of first-year students, emphasizing the importance of creating a supportive learning environment during this transitional phase. The study offers insights into the multifaceted nature of stress experienced by first-year students and highlights the imperative of addressing these stressors to promote a nurturing learning environment conducive to academic success. Future research should explore the effectiveness of interventions aimed at reducing stress among first-year students and investigate additional factors that may contribute to stress in this population.

Moderate/severe biatrial dilation predicts adverse events after ablation in atrial fibrillation with heart failure.

AIMS: To retrospectively compare the long-term outcomes following atrial fibrillation (AF) ablation between heart failure (HF) with preserved ejection fraction (EF) (HFpEF) and reduced/mildly reduced EF (HFr-mrEF) patients, and to identify novel predictors of adverse clinical events. METHODS: In total, 1402 AF patients with HF who underwent successful ablation were consecutively enrolled. Adverse clinical events including all-cause death, HF hospitalization, and stroke were followed up. Cox proportional hazards models were used to assess the associations between clinical factors and events. Kaplan-Meier analysis was performed to estimate the cumulative incidences of these events. A receiver operating characteristic curve was used to test the ability of these predictors. RESULTS: During a follow-up period of 42 ± 15 months, 265 (18.9%) patients experienced adverse clinical events after ablation. The cumulative incidence of adverse clinical events was significantly higher in HFr-mrEF than in HFpEF (25.4% vs. 15.7%, P < 0.001), the similar tendency was observed on all-cause death (10.5% vs. 6.5%, P = 0.011) and HF hospitalization (17.2% vs. 10.1%, P < 0.001). After multivariate adjustment, non-paroxysmal AF [hazard ratio (HR) 1.922, 95% confidence interval (CI) 1.130-3.268, P = 0.016], LAD ≥ 45 mm (HR 2.197, 95% CI 1.206-4.003, P < 0.001), LVEF (HR 0.959, 95% CI 0.946-0.981, P < 0.001), and RAD ≥ 45 mm (HR 2.044, 95% CI 1.362-3.238, P < 0.001) remained the independent predictors for developing adverse clinical events. A predictive model performed with non-paroxysmal AF, LAD ≥ 45 mm and RAD ≥ 45 mm yielded an area under curve of 0.728 (95% CI 0.696-0.760, P < 0.001). CONCLUSIONS: AF patients with HFpEF had better long-term outcomes than those with HFr-mrEF, and moderate/severe biatrial dilation could predict adverse clinical events following catheter ablation in AF and HF patients.

Multilevel Regulation of NF-κB Signaling by NSD2 Suppresses Kras-Driven Pancreatic Tumorigenesis.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer with a dismal overall prognosis. NSD2 is an H3K36-specific di-methyltransferase that has been reported to play a crucial role in promoting tumorigenesis. Here, the study demonstrates that NSD2 acts as a putative tumor suppressor in Kras-driven pancreatic tumorigenesis. NSD2 restrains the mice from inflammation and Kras-induced ductal metaplasia, while NSD2 loss facilitates pancreatic tumorigenesis. Mechanistically, NSD2-mediated H3K36me2 promotes the expression of IκBα, which inhibits the phosphorylation of p65 and NF-κB nuclear translocation. More importantly, NSD2 interacts with the DNA binding domain of p65, attenuating NF-κB transcriptional activity. Furthermore, inhibition of NF-κB signaling relieves the symptoms of Nsd2-deficient mice and sensitizes Nsd2-null PDAC to gemcitabine. Clinically, NSD2 expression decreased in PDAC patients and negatively correlated to nuclear p65 expression. Together, the study reveals the important tumor suppressor role of NSD2 and multiple mechanisms by which NSD2 suppresses both p65 phosphorylation and downstream transcriptional activity during pancreatic tumorigenesis. This study opens therapeutic opportunities for PDAC patients with NSD2 low/loss by combined treatment with gemcitabine and NF-κBi.