The mitotic kinase Aurora-A is frequently overexpressed in cancers and contributes to tumor progression and therapy resistance, yet the mechanisms underlying its role in drug resistance remain unclear. Here, we show that sorafenib treatment triggers Aurora-A phase separation, leading to its recruitment into stress granules (SGs), membraneless organelles that promote cancer cell survival. Aurora-A facilitates robust SGs assembly, thereby conferring sorafenib resistance. Mechanistically, upon sorafenib-induced SGs formation, Aurora-A binds RNA via positively charged lysine/ arginine residues within its intrinsically disordered region (IDR). Mutating these K/R residues with IDR of Aurora-A disrupts its RNA binding, impairs SGs assembly, and resensitizes cancer cells to sorafenib. Together, our work identifies Aurora-A as a kinase-activity-independent, RNA-binding scaffold essential for stress-adaptive biomolecular condensation, revealing a druggable phase-separation axis distinct from canonical Aurora-A kinase signaling.

Taxane-based chemotherapy is a main treatment modality for ovarian cancer and other solid tumors, but chemoresistance limits the clinical efficacy. Studies have shown tumor interaction with macrophages in the tumor microenvironment (TME) plays a significant role in taxane resistance, yet the underlying molecular mechanisms are poorly understood. In this study, we employed translatome profiling of paclitaxel-treated cancer cells, live-cell imaging analysis, gene knockdown/knockout, and in vitro cancer-macrophage coculture assays to unravel a novel chemoresistance mechanism mediated by tumor-macrophage interaction via the NOTCH2-JAG1 axis. The in vitro data were further validated by multiple xenograft, syngeneic and patient-derived xenograft mouse tumor models of ovarian cancer as well as ovarian cancer patient samples. We found paclitaxel selectively induced translational upregulation of NOTCH2 via cytoplasmic polyadenylation, and this NOTCH2 upregulation persisted after mitotic exit. Subsequent NOTCH2 activation by JAG1 expressed mainly on the neighboring macrophages promoted tumor cell survival and simulated cytokine release, such as CSF1 and IL-1β, that recruited JAG1-expressing macrophages, thus forming a positive feedback loop that further enhanced the pro-tumor NOTCH2 activity. Genetic depletion or pharmacological inhibition of NOTCH2 with the γ-secretase inhibitor attenuated macrophage infiltration and sensitized tumor response to paclitaxel in multiple preclinical models of ovarian cancer. Moreover, single-cell RNA sequencing analysis identified a JAG1-high macrophage subset that was enriched by paclitaxel treatment and attenuated by NOTCH inhibition. Clinically, high NOTCH2 expression in ovarian tumors was associated with recurrence and shorter progression-free survival of ovarian cancer patients. Paclitaxel-induced translational upregulation of NOTCH2 enables immediate juxtacrine activation by JAG1-positive macrophages, coupling tumor cell survival with immune remodeling in the tumor microenvironment to drive chemoresistance. Our results suggest NOTCH2 is a viable biomarker for paclitaxel resistance and that combining NOTCH2 inhibitor with taxane is an effective therapeutic strategy to selectively disrupt tumor-macrophage interaction and overcome macrophage-mediated taxane resistance in NOTCH2-positive tumors.

Metabolic reprogramming is a hallmark of gastric cancer (GC); however, the role of transcriptional regulators in modulating glycolysis remains incompletely understood. By integrating proteomic, transcriptomic, and CRISPR-based functional screening datasets, we identified WDR12, a WD40-family protein that is upregulated in GC and associated with poor patient survival. WDR12 silencing suppressed GC cell proliferation and tumor growth in vitro and in vivo and markedly reduced glycolytic flux. Mechanistically, WDR12 interacts with TDP43 and promotes its occupancy at the PFKFB4 promoter, thereby increasing PFKFB4 transcription. Restoration of PFKFB4 expression partially rescued the metabolic and proliferative defects caused by WDR12 knockdown. Together, these findings implicate WDR12 in GC metabolic reprogramming and suggest a potential metabolic vulnerability associated with WDR12-dependent regulation of PFKFB4 through TDP43.

Intestinal stem cells (ISCs) drive epithelial renewal and regeneration, yet how neural cues shape ISC behavior remains unclear. Here, we identify a neuronal checkpoint that directly restrains ISC regenerative output during injury. We show that vasoactive intestinal peptide (VIP)-producing enteric neurons directly signal to ISCs through the epithelial receptor VIP receptor 1 (VIPR1). In steady state, VIP-VIPR1 signaling restrains ISC hyperproliferation by engaging an extracellular signal-regulated kinase (ERK)-Notum-Wnt/β-catenin inhibitory axis. During colitis, VIPergic neurons expand within the ulcerated regions and amplify this pathway, thereby suppressing ISC-driven regeneration and exacerbating epithelial injury. Selective deletion of Vipr1 in the epithelium or in ISCs releases this neuronal brake, restores early regenerative activity, and markedly alleviates colitis. The ISC-suppressive function of VIP-VIPR1 signaling is conserved in human intestinal models. Together, these findings define VIPR1 as an ISC-intrinsic neuronal checkpoint that restricts ISC-driven epithelial regeneration and highlight epithelial VIPR1 blockade as a potential strategy to enhance mucosal regeneration in colitis.

Mucosal immunity deploys diverse defenses against fungal pathogens, yet the evolution of fungal resistance demands new antifungal strategies. Here, we uncover that intestinal epithelial cells secrete the host histidine methyltransferase METTL9 as a cross-kingdom, catalytic antifungal effector. Proteomic profiling revealed that exposure to Candida albicans induces robust METTL9 secretion into the intestinal lumen. Extracellular METTL9 directly binds the fungal zinc-scavenging protein PRA1, catalyzing histidine methylation of this zincophore to disrupt zinc acquisition-an essential micronutrient for fungal growth and virulence. This methylation-driven "nutritional sabotage" restricts C. albicans colonization and dissemination in vivo and also targets multidrug-resistant Candida auris, which retains PRA1. Clinically, reduced METTL9 levels in colonic mucosa from patients with inflammatory bowel disease correlate with increased C. albicans abundance, linking METTL9 to human antifungal mucosal homeostasis. Our findings reveal a host-derived, catalytic antifungal mechanism that bypasses conventional resistance pathways, establishing secreted methyltransferases as an arm of innate mucosal immunity.

Objective: Haprolid, a novel compound extracted from Myxobacterium, has been proven to possess selective toxicity towards various tumor cells, effectively inhibiting the growth of hepatocellular carcinoma (HCC). However, the underlying molecular mechanism remains unclear. Methods: To identify differentially expressed proteins (DEPs), isobaric tags for relative and absolute quantitation (iTRAQ) were employed. The clinical significance of DExH-Box Helicase 9 (DHX9) was determined using tissue microarrays in HCC patients. Changes in protein expression were detected using Western blotting, qPCR, and immunohistochemistry. Cell proliferation was evaluated using CCK-8 and crystal violet staining. Cell apoptosis was assessed using Alexa Fluor 647 Annexin V. Xenograft tumor experiments were conducted in animals. Results: iTRAQ screening identified DHX9 as a DEP. DHX9 was discovered to be highly expressed in HCC tissues, correlating with poor prognosis in patients. Haprolid downregulated DHX9 expression, while knockdown of DHX9 suppressed HCC cell proliferation and migration and promoted apoptosis. Meanwhile, overexpression of DHX9 mitigated the inhibitory effect of Haprolid on HCC cells. Knockdown of DHX9 inhibited the AKT signaling pathway, and SC79 reversed the inhibitory effect of DHX9 knockdown on HCC cells. Xenograft experiments confirmed that the knockdown of DHX9 inhibited HCC growth, while the overexpression of DHX9 attenuated the inhibitory effect of Haprolid on HCC growth. Conclusions: Haprolid inhibits the AKT signaling pathway by downregulating DHX9, ultimately suppressing HCC growth. This finding opens up new avenues for targeted HCC therapy.

Abstract While cancer cells overexpress lactate dehydrogenase A (LDHA) to support glycolytic flux and lactate production, the role of LDHB—which preferentially catalyzes lactate oxidation—remains unclear. Here, we demonstrate that LDHB, but not LDHA, is essential for mitotic progression in cancers. During mitosis, CDK1 phosphorylates LDHA at threonine 18, reducing its incorporation into the lactate dehydrogenase (LDH) tetramer. This results in LDHB-enriched tetramers that shift catalytic activity toward lactate oxidation, converting lactate and NAD⁺ into pyruvate and NADH. The generated NADH fuels oxidative phosphorylation and ATP production, thereby sustaining mitosis. Notably, LDHA-T18 phosphorylation occurs exclusively in tumor tissues. Our findings reveal a tumor-specific mechanism in which CDK1 reprograms LDH isoenzyme composition to direct lactate toward NADH production, ensuring energy homeostasis during mitosis. This underscores the therapeutic necessity of targeting both LDHA and LDHB in cancer.

This study aimed to investigate the prognostic impact of primary tumor resection in colonic neuroendocrine carcinoma (NECs) patients with liver metastasis, compare survival outcomes between left- and right-sided tumors, and develop a nomogram for predicting overall survival (OS) in this population. Data from 449 colonic NECs patients with liver metastasis (2010–2021) were extracted from the SEER database. Patients were stratified by primary tumor location (left vs. right colon) and surgical resection status. Propensity score matching (PSM) was applied to balance the groups and subsequently investigate survival differences between them. Survival differences were analyzed using Kaplan–Meier curves and Cox regression. A nomogram integrating independent prognostic factors was developed using LASSO regression and validated for 6-, 12-, and 24-month OS prediction. Model performance was assessed via ROC curves, calibration plots, and decision curve analysis (DCA). Right-sided colonic NECs predominated (85.1

Background:There are few data on ustekinumab treatment for Crohn's disease (CD) in a Chinese population. Our study is a real-world retrospective multicenter study aimed at exploring the effectiveness of ustekinumab in CD patients and comparing the effectiveness of first line and second line treatments. Methods:Laboratory indicators, CD activity index (CDAI) and simple endoscopic score for CD (SES-CD) scores of patients at the 8th, 16th and 24th weeks of treatment were collected, and the clinical remission rate, clinical response rate, endoscopic remission rate and endoscopic response rate were calculated, and the patients were divided into first line group and second line group for comparison. Results:A total of 102 patients were treated with ustekinumab, and 56 patients with a clinical data integrity rate greater than 70% were ultimately included. The clinical remission rate of the patients gradually increased at the 8th, 16th and 24th weeks of treatment, which were 34 cases (60.7%), 37 cases (66.1%) and 49 cases (87.5%), respectively. The clinical response rates for 8th, 16th and 24th weeks were 38 (67.8%), 42 (0.75%) and 51 (91.1%), respectively, and the endoscopic remission rate was 4% (2/50) at the 24th week. The clinical response rates of the first line group were higher than those of the second line group at the 16th and 24th weeks, with statistically significant differences. The clinical response time of patients receiving first line or second line treatment with ustekinumab was different, and the first line treatment group achieved clinical response more quickly. Conclusion:Ustekinumab is effective in the short-term treatment of CD patients in China, with first line treatment superior to second line treatment and faster than second line treatment.

Cells round up when they enter mitosis and maintain this rounded morphology until they pass the spindle assembly checkpoint during anaphase. However, the mechanisms that regulate and maintain this transient spherical state remain unclear. In this study, we demonstrate that both astral microtubules and Aurora B kinase are required to maintain cortex stability during prometaphase. Simultaneous inhibition of astral microtubules and Aurora B leads to severe and continuous deformation of mitotic cells, resulting in micronuclei containing chromosomes after the cells exit mitosis. Mechanistically, active Aurora B kinase reduces the activity of myosin light chain kinase through phosphorylation, which in turn decreases the motor activity of myosin II. Additionally, Aurora B kinase regulates the distribution of actin at the cortex by phosphorylating the intermediate filament protein vimentin. Blocking these phosphorylation events disrupts the para-cortex localization of vimentin around the cortex and leads to the dislocalization of actin at the cortex. These regulatory effects occur in highly mobile cells expressing vimentin. In summary, we show that during mitosis, Aurora B kinase coordinates the interactions between microtubules, actin, and intermediate filaments to stabilize the cortex of rounded mitotic cells, ensuring the successful completion of mitosis.

Background:Non-alcoholic fatty liver disease (NAFLD) represents a major public health issue, especially among individuals diagnosed with Type 2 diabetes mellitus (T2DM), where its prevalence can reach up to 70%. This research examines the relationship between the Healthy Eating Index 2020 (HEI-2020) and its individual components with the occurrence of NAFLD in T2DM patients, while also investigating the potential mediating effects of various metabolic indicators. Methods:Data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2018 were utilized. This cross-section study included 1,770 T2DM patients, who were divided into NAFLD and non-NAFLD groups using the Fatty Liver Index as a diagnostic tool. The HEI-2020, which assesses diet quality, was computed based on 24-h dietary recall data. Key metabolic indicators such as the triglyceride-glucose (TyG) index, metabolic score (MS), mean arterial pressure, uric acid levels, and total cholesterol were evaluated. Results:The findings indicated that higher HEI-2020 scores were associated with a lower likelihood of NAFLD (odds ratio 0.978, 95% confidence interval: 0.959-0.998), with the strongest inverse associations observed in the top quartiles of diet quality. Whole fruits, greens and beans, and saturated fat were crucial dietary factors. Mediation analysis demonstrated that the TyG index and MS accounted for 5.11 and 36.94% of the relationship between HEI-2020 and NAFLD, respectively. Conclusion:Greater adherence to the HEI-2020 is associated with a lower likelihood of NAFLD in T2DM patients, with metabolic indicators partially mediating this association. Enhancing diet quality, particularly by increasing the consumption of whole fruits and greens while reducing saturated fat intake, may be important in managing metabolic health and liver function in this vulnerable population.

Background:Hepatocellular carcinoma (HCC) is associated with poor prognosis and high mortality. Notchless homolog 1 (NLE1) is an important WD40 protein. Although several studies have shown that NLE1 is dysregulated in cancer, the function in hepatocarcinogenesis remains unclear. Methods:We screened for dysregulated WD40 proteins in HCC using data from the GSE5364 and GSE19665 datasets. A risk prediction model associated with WD40 proteins was constructed based on the TCGA database and validated with independent datasets (ICGC, GSE116174, and GSE14520). The significance of NLE1 was assessed using a genome-wide CRISPR screen and multiomics data from TCGA, CPTAC, multiple GEO datasets, and the single-cell dataset GSE166635. We further evaluated NLE1 expression in patient tissue microarrays. Kaplan-Meier plots, Cox regression analyses, and receiver operating characteristic (ROC) curves were used to evaluate the prognostic relevance of NLE1. Logistic regression was performed to analyse the associations between NLE1 expression and the clinical features of patients with HCC. Drug sensitivity to NLE1 was evaluated using organoid assays. Proliferation assays (CCK-8 and colony formation assays) were used to assess the effect of NLE1 on HCC cell growth. Results:We developed a risk prediction model based on WD40 proteins, which revealed significant differences in tumour immune cell infiltration between the high-risk and low-risk groups. In addition, high NLE1 expression was strongly associated with poor prognosis in HCC patients. Through organoid response characterization, we also found a significant correlation between NLE1 expression and sensitivity to the small molecules 17-AAG, AZD7762, and JQ1. Finally, enrichment analysis and proliferation assays confirmed that elevated NLE1 expression promotes HCC cell proliferation. Conclusion:NLE1 is an independent diagnostic and prognostic biomarker that promotes the proliferation of HCC.

BACKGROUND:The treatment strategy for pancreatic pseudocysts (PPC) is comprehensive and warrants multidisciplinary participation. However, at present, the treatment concepts for PPC are inconsistent. Moreover, the timing of interventional therapy is unclear, and complication management is insufficient. Therefore, the development of a multidisciplinary expert consensus on PPC is warranted. At present, endoscopic treatment is recommended for managing PPC in American Society for Gastrointestinal Endoscopy guideline and Chinese Consensus guidelines. CASE SUMMARY:In this study, we present a rare case of PPC identified by endoscopy and imaging examination, and successfully managed by endoscopic and percutaneous drainage. In detail, an obese patient with a history of recurrent pancreatitis presents an irregular, elliptical cystic low-density shadow in the pancreatic region. Endoscopic ultrasound combined with double knife incision technique was used to endoscopic drainage, resulting in a favorable prognosis. CONCLUSION:Ultrasound-guided endoscopic drainage for the management of PPC may provide additional insights to current clinical guidelines.

Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α2A-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.

BACKGROUND:Perianal fistulas pose dual challenges to Crohn's disease (CD) patients. Low patient compliance due to the complexity of existing examination methods plagues the treatment and follow-up management of perianal CD. AIM:To determine the accuracy of endoanal ultrasound (EUS) and shear wave elastography (SWE) for evaluating perianal fistulizing CD (PFCD) activity. METHODS:This was a retrospective cohort study. A total of 67 patients from August 2022 to December 2023 diagnosed with CD were divided into three groups: Non-anal fistula group (n = 23), low-activity perianal fistulas [n = 19, perianal disease activity index (PDAI) ≤ 4], high-activity perianal fistulas (n = 25, PDAI > 4) based on the PDAI. All patients underwent assessments including EUS + SWE, pelvic magnetic resonance [pelvic magnetic resonance imaging (MRI)], C-reactive protein, fecal calprotectin, CD activity index, PDAI. RESULTS:The percentage of fistulas indicated by pelvic MRI and EUS was consistent at 82%, and there was good consistency in the classification of perianal fistulas (Kappa = 0.752, P < 0.001). Significant differences were observed in the blood flow Limberg score (χ 2 = 8.903, P < 0.05) and shear wave velocity (t = 2.467, P < 0.05) between group 2 and 3. Shear wave velocity showed a strong negative correlation with magnetic resonance novel index for fistula imaging in CD (Magnifi-CD) score (r = -0.676, P < 0.001), a weak negative correlation with the PDAI score (r = -0.386, P < 0.05), and a weak correlation between the Limberg score and the PDAI score (r = 0.368, P < 0.05). CONCLUSION:EUS combined with SWE offers a superior method for detecting and quantitating the activity of perianal fistulas in CD patients. It may be the ideal tool to assess PFCD activity objectively for management strategies.

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, has a high global prevalence and can progress to metabolic dysfunction-associated steatohepatitis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of MASLD is primarily driven by disturbances in hepatic lipid metabolism, involving six key processes: increased hepatic fatty acid uptake, enhanced fatty acid synthesis, reduced oxidative degradation of fatty acids, increased cholesterol uptake, elevated cholesterol synthesis, and increased bile acid synthesis. Consequently, maintaining hepatic lipid metabolic homeostasis is essential for effective MASLD management. Numerous novel molecules and Chinese proprietary medicines have demonstrated promising therapeutic potential in treating MASLD, primarily by inhibiting lipid synthesis and promoting lipid oxidation. In this review, we summarized recent research on MASLD, elucidated the molecular mechanisms by which lipid metabolism disorders contribute to MASLD pathogenesis, and discussed various lipid metabolism-targeted therapeutic approaches for MASLD.

Purpose: Intestinal metaplasia plays a crucial role in the risk stratification of gastric cancer development. The objective of the study was to develop a prediction model for Operative Link on Gastric Intestinal Metaplasia (OLGIM) Stage III-IV.Methods: We analyzed 7945 high-risk gastric cancer individuals from 115 hospitals who underwent questionnaires and gastroscope. The participants were assigned to either the development or validation cohort randomly. Demographics and clinical characteristics were obtained. The outcome measurement was OLGIM III-IV. Univariate logistic regression was used for feature selection and multivariate logistic analysis was performed to develop the nomogram. Area under the curves, calibration plots, decision curve and clinical impact analysis were used to assess the performance of the nomogram.Results: 4600 individuals and 3345 individuals were included in the development and validation cohort, of which 124 and 86 individuals were diagnosed with OLGIM III-IV, respectively. Parameters in the training validation cohort matched well and there was no significant difference between two cohorts. A nomogram model for predicting OLGIM Stage III-IV consisted of 4 significantly associated variables, including age, gender, PG I and G-17 (AUC 0.723 and 0.700 for the 2 cohorts). The nomogram demonstrated excellent performance in the calibration curve. Decision curve and clinical impact analysis suggested clinical benefit of the prediction model.Conclusions: This reliable individualized nomogram might contribute to more accurate management for patients with OLGIM III-IV. Therefore, we suggest that this study be used as an incentive to promote the application.

Cumulative evidence indicates the important role of Nur77 in organ fibrogenesis. However, the role of Nur77 in hepatitis B virus (HBV)‐related liver fibrosis (LF) remains unclear. Cells were transfected with the microRNA mimic miRNA‐506‐3p or inhibitor, and pcDNA3.1‐Nur77 or Nur77 guide RNA. Exosomes were isolated from HBV‐infected HepG2‐sodium taurocholate cotransporting polypeptide cells. The levels of miR‐506‐3p, Nur77, and LF‐related genes and proteins were detected by quantitative polymerase chain reaction (qPCR) and western blot analysis, respectively. The pathology of the liver from HBV‐infected patients was examined using hematoxylin‐eosin and Masson's staining. The expression of Nur77 in liver tissue was determined by immunohistochemistry, and the LF score was assessed using the METAVIR system. The relationship between miR‐506‐3p/Nur77 and LF score was analyzed by correlation analysis. HBV infection downregulated miR‐506‐3p expression and upregulated Nur77 levels in hepatocytes. Exosomes from HBV‐infected hepatocytes also displayed decreased gene expression of miR‐506‐3p and increased expressions of Nur77‐ and LF‐related genes in stellate cells compared with exosomes from hepatocytes with mock infection. These changes were reversed by Nur77 guide RNA. Nur77 expression in liver tissue was strongly correlated with LF, whereas serum miR‐506‐3p was strongly negatively correlated with LF. Exosomes from HBV‐infected hepatocytes activate stellate cells and aggravate LF through the miR‐506‐3p/Nur77 pathway. These exosomes may be the basis of a promising therapeutic strategy.