The carcinogenic role of FASN by regulating lipid metabolism reprogramming has been well-established in multiple tumors. However, whether mechanisms during intrahepatic cholangiocarcinoma (ICC) progression, such as circRNAs, regulate FASN expression remains unknown. Here we demonstrate a lipid metabolism-related circRNA, circMBOAT2 (hsa_circ_0007334 in circBase), frequently upregulated in ICC tissues, and positively correlated with ICC malignant features. CircMBOAT2 knockdown inhibits the growth and metastasis of ICC cells. Mechanistically, circMBOAT2 combines with PTBP1 and protects PTBP1 from ubiquitin/proteasome-dependent degradation, impairing the function of PTBP1 to transfer FASN mRNA from the nucleus to the cytoplasm. Moreover, circMBOAT2 and FASN have the same effect on fatty acid profile, unsaturated fatty acids instead of saturated fatty acids are primarily regulated and associated with malignant behaviors of ICC cells. The levels of lipid peroxidation and ROS were significantly higher when FASN was knocked down and recovered when circMBOAT2 was overexpressed. Our results identified that circMBOAT2 was upregulated in ICC and promoted progression by stabilizing PTBP1 to facilitate FASN mRNA cytoplasmic export, which altered lipid metabolic profile and regulated redox homeostasis in ICC, suggesting that circMBOAT2 may serve as an available therapeutic target for ICC with active lipid metabolism.

Circular RNAs (circRNAs) have recently been suggested as potential functional modulators of cellular physiology processes in gastric cancer (GC). In this study, we demonstrated that circFOXP1 was more highly expressed in GC tissues. High circFOXP1 expression was positively associated with tumor size, lymph node metastasis, TNM stage, and poor prognosis in patients with GC. Cox multivariate analysis revealed that higher circFOXP1 expression was an independent risk factor for disease-free survival (DFS) and overall survival (OS) in GC patients. Functional studies showed that increased circFOXP1 expression promoted cell proliferation, cell invasion, and cell cycle progression in GC in vitro. In vivo, the knockdown of circFOXP1 inhibited tumor growth. Mechanistically, we observed ALKBH5-mediated m6A modification of circFOXP1 and circFOXP1 promoted GC progression by regulating SOX4 expression and sponging miR-338-3p in GC cells. Thus, our findings highlight that circFOXP1 could serve as a novel diagnostic and prognostic biomarker and potential therapeutic target for GC.

Lipid metabolism plays an important role in the growth and development of tumors. However, the role of lipid metabolism in gallbladder cancer (GBC) has not been clearly clarified. Here, we demonstrated that fatty acid synthase (FASN), a key enzyme in de novo fatty acid biosynthesis, had upregulated expression in GBC samples both at protein and mRNA levels. Analysis of clinical data indicated the association between elevated FASN expression and poorer histology grades. Furthermore, FASN activity impairment through FASN knockdown or treatment with orlistat resulted in the inhibition of cell proliferation and migration, as well as increased sensitivity to gemcitabine. Both FASN knockdown and orlistat treatment induced cell apoptosis. Mechanistically, impairment of FASN activity suppressed the activation of the PI3K/AKT signaling pathway, which led to increased cell apoptosis and sensitivity to gemcitabine. These findings were also validated through nude mouse xenograft models, thus highlighting the potential of targeting FASN as a clinical treatment strategy. Collectively, the present study underscores the crucial role of FASN in the progression of gallbladder cancer via the PI3K/AKT pathway.

Background: Long non-coding RNAs (lncRNAs) are crucial factors affecting the occurrence, progression, and prognosis of gastric carcinoma (GC). The accumulation of disulfide bonds to excessive levels in cells expressing high SLC7A11 triggers disulfidptosis, which functions as a regulated form of cellular death. Research has demonstrated that upregulated SLC7A11 is common in human cancers, but the effect of disulfidptosis on GC remains unclear. Identifying lncRNAs associated with disulfidptosis (drlncRNAs) and establishing a prognostic risk profile holds considerable importance for advancing GC research and treatment. Methods: Clinical records and transcriptomic datasets from individuals with GC were acquired from The Cancer Genome Atlas (TCGA) repository. A three-drlncRNA risk model was built using three common regression analysis methods. Then we used receiver operating characteristic (ROC) curves, independent prognostic analysis, and additional statistical approaches to assess the precision of the model. This investigation additionally encompassed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, immune cell infiltration evaluation, and pharmacological sensitivity predictions. To further investigate immunotherapy response disparities between patient cohorts with elevated- and reduced-risk scores, analyses of tumor mutational burden (TMB), tumor immune dysfunction and exclusion (TIDE), and microsatellite instability (MSI) were implemented. Results: We constructed a unique model composed of three drlncRNAs (AC107021.2, AC016394.2, and AC129507.1). Its independent prognostic capability for GC patients was validated through both single-variable and multivariable Cox regression analyses. GO and KEGG pathway assessments revealed predominant enrichment within the elevated-risk cohort, particularly in pathways involving sulfur compound interactions, traditional Wnt signaling mechanisms, cell-substrate adherens junctions, and cAMP signaling cascades, among others. Tumor microenvironment (TME) evaluation demonstrated elevated ImmuneScores, StromalScores, and ESTIMATEScores within the high-risk patient population. Concurrently, this elevated-risk cohort exhibited enhanced immune cell infiltration patterns, whereas the reduced-risk group displayed superior expression of immune checkpoints (ICPs). Additional investigations revealed that patients categorized into the reduced-risk classification possessed greater tumor mutational burden, increased MSI-high proportions, and diminished tumor immune dysfunction and exclusion scores compared to their high-risk counterparts. Pharmacological sensitivity assessments confirmed the superior efficacy of several therapeutic agents, including gemcitabine and veliparib (ABT.888), in patients with lower risk classifications. Conclusions: Our established risk stratification system demonstrates independent prognostic predictive capacity while offering personalized clinical intervention guidance for individuals diagnosed with GC.

Background: Long non-coding RNAs (lncRNAs) are crucial factors affecting the occurrence, progression and prognosis of gastric cancer. Disulfidptosis, a type of programmed cell death, results from abnormal accumulation of disulfide bonds in high-SLC7A11 cells. Research have demonstrated that upregulated SLC7A11 is common in human cancers, but the effect of disulfidptosis on gastric cancer remains unclear. It is of great significance to recognize disulfidptosis -related lncRNAs (drlncRNAs) and develop a risk signature with prognostic value in gastric cancer. Methods: The transcriptome data and clinical information of gastric cancer patients were obtained from TCGA (the Cancer Genome Atlas) database. A 3 drlncRNAs risk model was built by three common regression analysis methods. Then we used ROC curves, independent prognostic analysis and other methods to assess the accuracy of the model. Furthermore, GO and KEGG enrichment analysis, immune infiltration analysis and drug sensitivity prediction were also performed in this study. Finally, TMB, MSI, and TIDE analyses were conducted to further explore the difference of high- and low- risk score group in immunotherapy response. Results: We constructed a prognostic model composed of 3 drlncRNAs (AC107021.2, AC016394.2 and AC129507.1). Univariate and multivariate Cox regression proved that the model was able to predict the prognosis of GC patients independently. GO and KEGG analyses suggested that the high-risk group mainly enriched in sulfur compound binding, canonical WNT signaling pathway, cell-substrate adherens junction, cAMP signaling pathway and so on. TME analysis indicated that ImmuneScores, StromalScores, and ESTIMATEScores were higher in the high-risk group. Meanwhile, the high-risk group showed higher levels of immune cell infiltration, while the low-risk group exhibited higher expression levels of immune checkpoints. Our research further revealed that, compared to patients in the high-risk group, patients in the low-risk group had higher tumor mutation burden, a higher proportion of MSI-H, and lower TIDE scores. Finally, gemcitabine, ABT.888 (veliparib) and other sensitive drugs were confirmed to be more effective in low-risk groups. Conclusion: The risk model we constructed can independently predict prognosis and provide precise and individual clinical treatment guidance for patients with GC.

Circular RNAs (circRNAs) have recently been found as potential functional modulators of the cellular physiology processes in gastric cancer (GC). However, the potential clinical significance and molecular mechanisms of circRNAs involved in the development of GC remain largely unknown. In the study, we demonstrated that circFOXP1 was highly expressed in GC tissues compared with adjacent normal tissues. Higher circFOXP1 expression positively associated with tumor size, lymph node metastasis, TNM stage and poor prognosis in patients with GC. Multivariate Cox analysis revealed that higher circFOXP1 expression was an independent risk for the disease-free survival (DFS) and overall survival (OS) of GC patients. Functional studies showed that higher circFOXP1 expression promoted cell proliferation, cell invasion, and cell cycle progression in GC in vitro. In vivo, knockdown of circFOXP1 inhibited tumor growth. Mechanistically, by double luciferase reporter, Methylated RNA immunoprecipitation (MeRIP), RNA binding protein immunoprecipitation assay and RNA pull-down assays, we clarified that circFOXP1 was under m6A-modification mediated by ALKBH5 in GC cells. Besides, circFOXP1 promoted GC progression by regulating SOX4 expression sponging miR-338-3p in GC cells. In conclusion, our findings highlight that circFOXP1 could serve as a novel diagnostic and prognostic biomarker and potential therapeutic target of GC treatment.