Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe conditions lacking specific pharmacological treatments. Endoplasmic reticulum (ER) stress plays a pivotal role in their pathophysiology, yet the precise regulatory mechanisms remain elusive. In this study, we identify the E3 ubiquitin ligase ring finger protein 5 (RNF5) as a critical driver of ALI/ARDS. RNF5 is markedly upregulated in response to ALI and significantly exacerbates lung injury by stabilizing HSPA5 (heat shock protein family A member 5), a master regulator of the unfolded protein response (UPR). Notably, in vivo Rnf5 ablation effectively attenuated pulmonary edema, inflammatory cell infiltration, and apoptosis, whereas lung-specific Rnf5 overexpression worsened inflammation and cell death in mice. Mechanistically, RNF5 interacts with HSPA5 and competitively blocks its binding to PERK, facilitating PERK release. Furthermore, RNF5 promotes the retro-translocation of HSPA5 from the ER lumen to the cytosol. In the cytosol, RNF5 mediates the K6- and K63-linked polyubiquitination of HSPA5, enhancing its thermal stability and preventing its re-entry into the ER. This spatial sequestration sustains the persistent dissociation of the PERK-HSPA5 complex, leading to the hyperactivation of the pro-apoptotic and pro-inflammatory PERK-eIF2α-CHOP signaling cascade. The ability of RNF5 to promote ALI is strictly dependent on its E3 ligase activity. In conclusion, our findings uncover a compartment-specific regulatory mechanism of HSPA5, suggesting that the RNF5-HSPA5-PERK axis represents a promising therapeutic target for ALI/ARDS.

Once regarded solely as an intermediate of the tricarboxylic acid (TCA) cycle involved in energy production, fumarate has now emerged as a pivotal immunometabolite with far-reaching effects on inflammatory signaling and immune cell fate. This review comprehensively delineates the dual nature of fumarate, which functions as a context-dependent rheostat of inflammation. Intracellular fumarate levels are tightly regulated by enzymatic activity, transport systems, and exogenous sources, including the pharmacological agent dimethyl fumarate (DMF). Fumarate can covalently modify critical cysteine residues in proteins through a process known as succination. Importantly, DMF acts at supraphysiological concentrations and may engage mechanisms distinct from those associated with endogenously accumulated fumarate. This unique post-translational modification enables fumarate to directly modulate key signaling pathways, including nuclear factor kappa B (NF-κB), nuclear factor erythroid 2-related factor 2 (NRF2), hypoxia-inducible factor 1-alpha (HIF-1α), Janus kinase/signal transducer and activator of transcription (JAK-STAT), and the NLR family pyrin domain-containing 3 (NLRP3) inflammasome, thereby orchestrating a broad anti-inflammatory program. We further examine how fumarate reshapes the functional phenotypes of macrophages, dendritic cells, T cells, and B cells, ultimately skewing immune responses toward tolerance and resolution. Crucially, this review distinguishes among the physiological roles of endogenous fumarate, the pathological consequences of fumarate accumulation resulting from fumarate hydratase (FH) deficiency, and the pharmacological actions of exogenous fumarate esters. Conversely, dysregulated fumarate metabolism, as observed in conditions such as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and systemic lupus erythematosus, can paradoxically promote pathological inflammation. The successful clinical translation of fumarate esters, particularly DMF, for the treatment of multiple sclerosis and psoriasis underscores their therapeutic potential. By synthesizing recent advances in fumarate biology, this review not only elucidates its role as a fundamental link between cellular metabolism and immunity but also highlights future directions for targeting fumarate-associated pathways in a broad spectrum of chronic inflammatory diseases.

Oral squamous cell carcinoma (OSCC) begins with pre-existing oral potential malignant diseases (OP-MDs), among which oral leukoplakia (OL) is the most common precancerous lesion. This study systematically explored the mechanism of N6-methyladenosine (m6A) RNA methylation in the occurrence and development of OSCC by integrating bioinformatics analysis and experimental verification. Based on the analysis of the GSE85195 dataset, we identified the key differentially expressed genes (DEGs) and m6A regulatory factors in the progression from OL to OSCC. Functional enrichment analysis revealed that these genes were significantly enriched in the extracellular matrix (ECM) signaling pathway. By constructing a protein-protein interaction network, we identified THBS1 as the core hub gene, and survival analysis revealed that the high expression of THBS1 was associated with a poor prognosis of OSCC patients. Bioinformatics analysis found that IGF2BP2 could regulate the expression of THBS1 through m6A. In vitro assays indicated that IGF2BP2 can regulate the expression of THBS1, and knockdown of IGF2BP2 can significantly inhibit the proliferation, migration, and invasion abilities of OSCC cells. Further analysis revealed that the risk score based on IGF2BP2, THBS1, and tumor stage was closely associated with tumor immune microenvironment characteristics. These evidences not only reveal a potential new mechanism by which m6A modification may mediate the IGF2BP2-THBS1 axis to promote the progression of OSCC, but also provide a new theoretical basis for understanding the remodeling of the immune microenvironment of OSCC.

BACKGROUND AND AIMS:Family with sequence similarity 216 member A (FAM216A) is overexpressed in several cancer tissues, but its prognostic value and pathological effect in hepatocellular carcinoma (HCC) have not been fully elucidated. MATERIALS AND METHODS:FAM216A expression in HCC specimens and cell lines was determined by real-time PCR and western blotting. FAM216A expression was knocked down in HCCLM3 and Huh7 cells, and overexpressed in Hep3B and PLC/PRF/5 cells. The proliferation, migration, and invasion of different HCC cell lines were assessed by colony formation and Transwell assays. The expression of epithelial-mesenchymal transition (EMT)-related proteins and the level of polo-like kinase 1/extracellular regulated protein kinase (PLK1/ERK) were determined. RESULTS:Increased FAM216A expression was observed in HCC tissues, a result that is consistent with outcomes obtained from an online database, and patient prognosis was negatively correlated with the FAM216A expression level. Additionally, FAM216A overexpression promoted the proliferation, migration, and invasion of HCC cells and activated EMT via the PLK1/ERK signaling pathway. CONCLUSIONS:FAM216A is overexpressed in HCC tissues and is associated with poor clinical outcomes. Mechanistically, FAM216A promotes aggressive tumor behavior by activating the PLK1/ERK signaling pathway.

Hepatocellular carcinoma (HCC) has a high mortality rate because of the limitations of conventional chemotherapies (e.g., doxorubicin, DOX), including poor tumor targeting, systemic toxicity, and chemoresistance. Bacterial outer membrane vesicles (OMVs) are promising drug carriers but have limitations like nonspecific phagocytosis and weak targeting. In this study, a dual-targeted nanosystem ((GPC3 + CD133)T-OMVs@DOX) was developed using GPC3/CD133 peptide-modified OMVs loaded with DOX to enhance HCC-specific targeting, optimize drug release, and reduce off-target toxicity. Compared with single-targeted or unmodified OMVs, dual-targeted (GPC3 + CD133)T-OMVs significantly increased binding/internalization in GPC3/CD133-coexpressing Huh-7 cells (p < 0.05). DOX loading yielded high LE (∼81%), with a pH-responsive release of 40% at pH 7.4 vs. 80% at pH 5.0 over 48 h. Sparstolonin B (SsnB), a TLR2/4 inhibitor, reduced macrophage phagocytosis by ∼60%, prolonging the duration of DOX-loaded OMVs in circulation. In vivo, the dual-targeted system inhibited tumor growth by 75%, outperforming free DOX (40%) and single-targeted OMVs-DOX (55%). Mice treated with the OMVs maintained a stable weight, whereas those given free DOX showed ∼15% weight loss. Histology revealed minimal organ damage in the dual-targeted group vs. severe cardiomyocyte injury with free DOX. In conclusion, the dual-targeted OMV system enhances tumor specificity via cooperative GPC3/CD133 recognition, optimizes pH-responsive release, and reduces nonspecific clearance by modulating macrophages. These features improve antitumor efficacy and mitigate toxicity, positioning OMV-based nanocarriers as promising platforms for precision HCC therapy.

Background Suicide in patients with digestive system tumors has been a concern, yet relevant studies remain limited. This study aimed to identify factors influencing suicide in patients with digestive system tumors using a large sample size from public databases and to develop a clinically applicable risk prediction model, thereby providing a reference for clinical interventions. Methods Data for 173,804 patients diagnosed with digestive system tumors between 1998 and 2015 were obtained from the Surveillance, Epidemiology, and End Results database. The standard mortality rate of suicide among digestive system tumor patients was compared with that of the general US population. Predictors of suicide in patients with digestive system tumors were identified using lasso regression and logistic regression, and subsequently visualized with a nomogram. Receiver operating characteristic curve analysis was used to determine the predictive accuracy of the nomogram. A calibration curve was plotted to assess the concordance between predicted and observed probabilities. Additionally, decision curve analysis and clinical influence curves were used to evaluate the clinical utility of the nomogram. Results A total of 131,354 patients from the Surveillance, Epidemiology, and End Results database were used to develop the model; 652 (0.5%) of those patients died by suicide. The cohort was followed for a cumulative duration of 1,277,281.75 person-years. Age, sex, tumor grade, staging, surgical intervention, chemotherapy, marital status, and place of residence were identified as independent predictors of suicide in patients with digestive system tumors. The nomogram constructed based on these predictors demonstrated high predictive accuracy, with an area under the receiver operating characteristic curve of 0.78. Additionally, the calibration curve indicated a strong concordance between the predicted and observed probabilities. The decision curve analysis and clinical influence curves further validated the clinical applicability of the nomogram. Conclusions We identified factors influencing suicide in patients with digestive system tumors and developed a robust prediction model to guide decision making.

OBJECTIVE:To explore the mechanism of Tangfukang formula (, TFK) in treating type 2 diabetes mellitus (T2DM). METHODS:We employed network pharmacology combined with experimental validation to explore the potential mechanism of TFK against T2DM. Initially, we filtered bioactive compounds with the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Symptom Mapping (SymMap), and gathered targets of TFK and T2DM. Subsequently, we constructed a protein-protein interaction (PPI) network, enriched core targets through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and adopted molecular docking to study the binding mode of compounds and the signaling pathway. Finally, we employed a KKAy mice model to investigate the effect and mechanism of TFK against T2DM. Biochemical assay, histology assay, and Western blot (WB) were used to assess the mechanism. RESULTS:There were 492 bioactive compounds of TFK screened, and 1226 overlapping targets of TFK against T2DM identified. A compound-T2DM-related target network with 997 nodes and 4439 edges was constructed. KEGG enrichment analysis identified some core pathways related to T2DM, including adenosine 5-monophosphate-activated protein kinase (AMPK) signaling pathway. Molecular docking study revealed that compounds of TFK, including citric acid, could bind to the active pocket of AMPK crystal structure with free binding energy of －4.8, －8 and －7.9, respectively. Animal experiments indicated that TFK decreased body weight, fasting blood glucose, fasting serum insulin, homeostasis model of insulin resistance, glycosylated serum protein, total cholesterol, triglyceride, and low-density lipoprotein cholesterol, and improve oral glucose tolerance test results. TFK reduced steatosis in liver tissue, and infiltration of inflammatory cells, and protected liver cells to a certain extent. WB analysis revealed that, TFK upregulated the phosphorylation of AMPK and branched-chain α-ketoacid dehydrogenase proteins. CONCLUSION:TFK has the potential to effectively manage T2DM, possibly by regulating the AMPK signaling pathway. The present study lays a new foundation for the therapeutic application of TFK in the treatment of T2DM.

BACKGROUND:Primary liver cancer is the sixth most common cancer globally and ranks third in cancer-related mortality. Patients with distant metastasis (PLCDM) have particularly low survival rates and are more difficult to treat. This study aims to identify risk factors associated with distant metastasis and overall survival (OS) in primary liver cancer and to determine the optimal predictive models using machine learning. METHODS:We extracted data from the SEER database (Incidence-SEER Research Data, 17 Registries, Nov 2022 Sub (2000-2020)) and identified risk factors for distant metastasis using logistic regression. Eight machine learning models were constructed using the "tidymodels" package in R and evaluated based on ROC curves, AUC, and accuracy. Cox regression was used to identify risk factors for OS, and Cox and Random Survival Forest (RSF) models were compared using time-dependent ROC curves. The best-performing model was interpreted using Shapley analysis. We also developed user-friendly web applications using the "shiny" package in R for clinical use. RESULTS:Multivariate analysis identified grade, T stage, N stage, tumor size, and surgery as independent risk factors for PLCDM. The Random Forest (RF) model showed the best performance with AUC values of 0.836, 0.817, and 0.846 in the training, internal validation, and external validation cohorts, respectively, and favorable Brier scores and accuracy. Shapley analysis ranked the risk factors by contribution as surgery, T stage, tumor size, N stage, and grade. Cox regression identified grade, surgery, and T stage as independent prognostic factors for OS. The Cox model outperformed the RSF model in time-dependent ROC analysis. Calibration and decision curve analysis (DCA) further confirmed its strong predictive performance and clinical utility. Shapley analysis ranked the risk factors as grade, surgery, and T stage. CONCLUSIONS:We successfully constructed and validated optimal models for predicting PLCDM and its prognosis. These models provide valuable tools to guide clinical decision-making for PLCDM.

Periareolar video-assisted thoracoscopic surgery (VATS) provides cosmetic advantages but poses technical challenges due to limited working space. The novel 2-mm needle-type intracorporeal assembly endoscopic forceps is designed to minimize incision size while retaining full surgical functionality. This study aimed to evaluate the feasibility, safety, and effectiveness of this novel endoscopic forceps in periareolar VATS. This single-center retrospective observational study included patients who underwent periareolar VATS using either the 2-mm forceps or a conventional 5-mm grasper between January and December 2024. Outcomes included operative time, complications, visual analog scale (VAS) pain scores at 1 week and 1 month, patient and observer scar assessment scale (POSAS) scores at 6 months, and surgeon feedback. Patients were stratified as follows: 2-mm group (n = 78; uniportal 45, biportal 33) and a historical 5-mm control (n = 37; all uniportal) from the same team under identical indications and perioperative protocols. Because the control contained only uniportal cases, all between-group comparisons were prespecified for the uniportal subset (2 mm: 45 vs. 5 mm: 37); 2-mm biportal cases were summarized descriptively. A total of 115 periareolar VATS procedures were completed without severe complications or perioperative mortality. Instrument assembly and disassembly required 100 ± 28 s and 25 ± 11 s, respectively. The needle-type puncture sites required no suturing and showed minimal-to-virtually no scarring at follow-up. In the uniportal subset, the 2-mm group had significantly lower POSAS totals and early VAS scores than the 5-mm group, with comparable operative time and surgeon-reported difficulty. Three minor mammary gland injuries occurred overall (two in the 2-mm group and one in the 5-mm group), with no lasting sensory impairment. The novel 2-mm intracorporeal forceps is safe and effective for periareolar VATS, significantly enhancing cosmetic outcomes and surgical efficiency, suggesting broad clinical application potential.

Pyruvate and branched-chain amino acid (BCAA) metabolism are pivotal pathways in tumor progression, yet the intricate interplay between them and its implications for tumor progression remain elusive. Our research reveals that dihydrolipoamide S-acetyltransferase (DLAT), a pyruvate metabolism enzyme, promotes leucine accumulation and sustains mammalian target of rapamycin (mTOR) complex activation in hepatocellular carcinoma (HCC). Mechanistically, DLAT directly acetylates the K109 residue of AU RNA-binding methylglutaconyl-coenzyme A (CoA) hydratase (AUH), a critical enzyme in leucine catabolism, inhibiting its activity and leading to leucine accumulation. Notably, DLAT upregulation correlates with poor prognosis in patients with HCC. Therefore, we developed an AUHK109R-mRNA lipid nanoparticles (LNPs) therapeutic strategy, which effectively inhibits tumor growth by restoring leucine catabolism and inhibiting mTOR activation in vivo. In summary, our findings uncover DLAT's unexpected role as an acetyltransferase for AUH, suppressing leucine catabolism. Restoring leucine catabolism with AUHK109R-mRNA LNP effectively inhibits HCC development, highlighting a novel direction for cancer research.

Pancreatic cancer (PC), known as the "king of cancers," is characterized by an exceptionally low five-year survival rate, posing a formidable challenge to global public health. N6-methyladenosine (m6A) methylation is prevalent across various stages of eukaryotic RNA expression, including splicing, maturation, stability, translation, and localization, and represents a pivotal mechanism of epigenetic regulation. m6A methylation influences tumor initiation and progression by modulating post-transcriptional processes, playing a critical role in sustaining cancer cell stemness, promoting cell proliferation, and mediating drug resistance. Extensive research underscores the substantial contribution of m6A modifications to PC development. However, the multiplicity of m6A regulators and their intricate mechanisms of action complicate the landscape. This review aims to deepen the understanding of m6A's role in PC by delineating its involvement in four key areas of tumorigenesis: the hypoxic tumor microenvironment, metabolic reprogramming, immune microenvironment, and resistance mechanisms. Additionally, the review addresses the emerging frontier of m6A interactions with non-coding RNAs (ncRNAs), offering insights into the potential therapeutic and prognostic applications of m6A in the treatment and prognosis prediction of PC.

BACKGROUND AND AIM:To study the corresponding strategies to control stomach cancer, a comprehensive assessment of the disease burden is required. Herein, we present long-term trends in the burden of stomach cancer in China over the past three decades, as well as its epidemiological features. METHODS:We characterized the burden of stomach cancer in China using the GBD 2021 methods and results, based on prevalence, incidence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life years (DALYs) estimated using the DisMod-MR 2-1. We also used joinpoint and age-period-cohort (APC) analysis methods to interpret the epidemiological characteristics of stomach cancer, project the disease burden of stomach cancer in China over the next decade, and compare these trends with global prevalence patterns. RESULTS:The age-standardized incidence (ASIR) and mortality rates (ASMR) in both sexes changed from 48.03 (40.21, 56.69) to 29.05 (22.42, 36.2) and from 46.05 (38.88, 54.43) to 21.51 (16.66, 26.61) per 100 000 people in China from 1990 to 2021. The age-standardized DALY rate in China decreased from 1181.61 (978.38, 1390.89) per 100 000 people in 1990 to 501.26 (387.29, 627.98) per 100 000 people in 2021. The average annual percentage change (AAPC) in age-standardized incidence, prevalence, and mortality rates for stomach cancer in China were -1.61 (95% CI: -1.73, -1.48), -0.50 (95% CI: -0.67, -0.32), and -2.44 (95% CI: -2.62, -2.26). The effects of age, period, and cohort on mortality rates differed. CONCLUSIONS:In the next decade, China's ASIR and ASMR for stomach cancer will continue to decline. However, despite the decrease in incidence, the overall burden of stomach cancer in China will remain significantly higher than the global average. The burden of stomach cancer in China will be a major public health challenge, given the country's large population base and aging population.

Background: Hepatocellular carcinoma (HCC) is a globally prevalent disease. Our article evaluates risk models based on autophagy- and HCC-related genes and their prognostic value by bioinformatics analytical methods to provide a scientific basis for clinical treatment. Methods: Prognostic genes were identified by univariate and multivariate Cox analyses, and risk scores were calculated. The value of risk models was analysed by receiver operating characteristic curve (ROC), immune microenvironment and drug sensitivity. Prognostic gene-related regulatory mechanisms based on network database. Results: We screened four prognosis-related genes (SQSTM1, GABARAPL1, CDKN2A, HSPB8) for model construction. The AUC for 1-, 2- and 3-year survival was higher than 0.6 in both the training and validation sets. The nomogram constructed based on risk scores, pathologic_T predicted the outcome better. There were differences in the tumour microenvironment between the high and low risk groups, as evidenced by differences in the distribution of immune cells and differences in the expression of immune checkpoints. Conclusion: Our results illustrate that models, nomograms and risk scores were valuable for tumour progression. Clinical trial number: Not applicable.

Background Myocardial fibrosis is an important pathological feature of dilated cardiomyopathy (DCM). The roles of SOCS2 in fibrosis of different organs are controversial. Herein, we investigated the function and potential mechanism of SOCS2 in myocardial fibrosis. Methods Bioinformatics, immunohistochemistry (IHC), immunofluorescence (IF), western blot (WB), real-time fluorescence quantitative PCR (qPCR), rat primary myocardial fibroblasts (rCFs) culture, doxorubicin (DOX) induced mouse dilated cardiomyopathy (DCM) model, and in vivo adeno-associated virus (AAV) infection were used to explore the role of SOCS2 in DCM. Results Bioinformatics analysis showed that SOCS2 was positively correlated with fibrosis related factors. SOCS2 was significantly upregulated in patients and mice with DCM. In vivo experiments showed that targeted inhibition of cardiac SOCS2 could improve mouse cardiac function and alleviate myocardial fibrosis. Further research demonstrated that SOCS2 promoted the transformation of myofibroblasts. Knockdown of SOCS2 reduced the nuclear localization of β-catenin, which inhibited the fibrogenic effect of Wnt/β-catenin pathway. In addition, bioinformatics analysis suggested that lymphoid enhancer binding factor 1 (LEF1) was significantly positively correlated with SOCS2. Finally, dual luciferase assays demonstrated that LEF1 could bind to the promoter region of SOCS2, thereby mediating its transcriptional activation. Conclusion SOCS2 could activate the Wnt/β-catenin by regulating the nuclear translocation of β-catenin, which induces the transcriptional activation of SOCS2. Overall, these results indicated a positive feedback activation phenomenon between SOCS2, β-catenin and LEF1 in DCM. These results suggested that inhibition of SOCS2 could effectively alleviate the progression of myocardial fibrosis and improve cardiac function.

Pancreatic cancer (PC) responds weakly to conventional immunotherapy. RNA N6-methyladenosine (m6A) modification has an essential role in the immune response, while its potential role in PC tumor microenvironment (TME) immune cell infiltration remains unknown. In this study, we thoroughly assessed the m6A modification patterns of 472 PC samples using 19 m6A regulators, and we systematically correlated these modification patterns with TME immune cell infiltration characteristics. We also created the m6Ascore and evaluated the m6A modification patterns of individual tumors, identified three different m6A modification patterns, and explored the role of the important m6A “writer” RBM15 in the regulation of macrophage function in PC. Two independent PC cohorts confirmed that patients with higher m6Ascore showed significant survival benefit. We verified that knockdown of RBM15 has the ability to inhibit PC growth and to promote macrophage infiltration and enhance phagocytosis of PC cells by macrophages. In conclusion, m6A modifications play a non-negligible role in the formation of TME diversity and complexity in PC. We reveal that inhibition of RBM15 suppresses PC development and modulates macrophage phagocytosis, and provide a more effective immunotherapeutic strategy for PC.

Exploring the role of novel cancer gene BZW1 in lung adenocarcinoma (LUAD) and unveiling associated signalling pathways. Firstly, we conducted a pan-cancer analysis of BZW1 using multiple databases. Subsequently, leveraging single-cell data from LUAD, we successfully uncovered potential oncological processes associated with BZW1 and further validated them through experimentation. Simultaneously, we continued to investigate the potential molecular mechanisms underlying the oncological processes mediated by BZW1. Additionally, we employed various machine learning algorithms to construct prognostic models concerning BZW1 and the epithelial-mesenchymal transition (EMT) process. Our research firstly demonstrated the elevated expression of BZW1 in various cancer cells. Leveraging single-cell data from LUAD, we identified that BZW1 regulates the occurrence of EMT in LUAD, a phenomenon validated across multiple LUAD cell lines. Moreover, we further discovered that BZW1 regulates LUAD's EMT process through the Wnt/β-catenin signalling pathway. Lastly, we successfully constructed prognostic models using BZW1-related genes and EMT genes.

PURPOSE:Pancreatic cancer (PC) is one of the most deadly human malignancies. Curcumin is a natural polyphenolic compound with wide-ranging pharmacological effects. Growing evidence suggests that curcumin has anticancer activity against PC, but the mechanism remains incompletely elucidated. This study aimed to investigate the effects and mechanisms of curcumin on the invasion and migration of PC cells.METHODS:Effect of curcumin on tissue factor pathway inhibitor (TFPI)-2 mRNA expression in PC cells was initially identified using qRT-PCR. Cytotoxicity of curcumin was assessed with MTT assays and IC50 was calculated. Involvement of ERK and JNK pathways, as well as protein expression of TFPI-2 and epithelial-mesenchymal transition (EMT)-related markers, were detected using immunoblotting. Invasion and migration of PC cells were examined using Transwell assays. TFPI-2 expression was manipulated by transfection with siRNA and shRNA. Rescue assays were used to validate the effect of curcumin on cell invasion and migration via TFPI-2.RESULTS:Curcumin increased the expression of TFPI-2 mRNA and protein in PC cells and attenuated cell invasion and migration. Curcumin also inhibited ERK and JNK pathways and EMT in PC cells. Knockdown of TFPI-2 partially reversed the inhibition of ERK and JNK pathways and EMT by curcumin. Mechanistically, curcumin upregulated TFPI-2, thereby inhibiting the ERK and JNK pathways, leading to the inhibition of EMT in PC cells.CONCLUSION:Collectively, curcumin inhibits ERK- and JNK-mediated EMT through upregulating TFPI-2, which in turn suppresses the migration and invasion of PC cells. These findings provide new insights into the antitumor mechanism of curcumin.

Background: Alpha/beta hydrolase domain-containing protein 17C (ABHD17C) is a depalmitoylation enzyme that removes the S-palmitoylation of targeted proteins. The hepatocellular carcinoma (HCC) cells SNU449 and Hep3B use ABHD17C as an oncogene; however, the exact mechanism of this action is yet unknown. Methods: The expression of ABHD17C in liver cancer tissues was analyzed by bioinformatics, and the expression of ABHD17C in clinical liver cancer tissues and adjacent normal tissues was detected. Then, the proliferative viability of HCC cells after overexpression or knockdown of ABHD17C was examined, and pyroptosis and apoptosis proteins were detected. Results: ABHD17C was overexpressed in human HCC tissues as well as numerous HCC cell lines. Depletion of ABHD17C caused reduced viability, cell cycle arrest, and defective invasion and migration in HCC cells, while overexpression of ABHD17C exhibited the opposite effect. Moreover, we discovered that the knockdown of ABHD17C resulted in enhanced apoptotic and pyroptotic phenotypes of HCC cells, whereas overexpression of ABHD17C attenuated such phenotypes. Conclusions: It suggests that ABHD17C contributes to HCC carcinogenesis, making it a promising target for medication treatment.

Background: While RACGAP1 is identified as a potential oncogene, its specific role in lung adenocarcinoma (LUAD) remains unclear. Methods: First, we conducted a comprehensive analysis of the role of RACGAP1 across 33 types of cancer. Subsequently, we investigated the expression levels of RACGAP1 and its impact on prognosis using data from The Cancer Genome Atlas (TCGA) database. We utilized single-cell sequencing data to explore the tumor-related processes of RACGAP1 in LUAD and validated our findings through experimental verification. Employing a consensus clustering (CC) approach, we subdivided LUAD patients into two subtypes based on RACGAP1 cell cycle-related genes (RrCCGs). These subtypes exhibited significant differences in tumor characteristics, lymph node metastasis, and recurrence. Furthermore, we evaluated the prognostic influence of RrCCGs using univariate Cox regression and least absolute shrinkage and selection operator regression models (LASSO), successfully establishing a prognostic model. Results: RACGAP1 is frequently overexpressed in various tumors and can impact the prognosis of patients with LUAD. Additionally, experimental evidence has demonstrated that low expression of RACGAP1 favors tumor cell apoptosis and restoration of the cell cycle, while high expression promotes invasion and metastasis. Through CC analysis of RrCCGs, patients were classified into two groups, with survival analysis revealing distinct prognoses and stages between the two groups. Furthermore, Cox and LASSO regression successfully constructed a prognostic model with robust predictive capability.