Trending Topics in Gastroenterology | GastroAGI

MOGAT2 influence colorectal cancer progression through ACSM1-mediated lipid metabolic reprogramming

Monoacylglycerol O-acyltransferase 2 (MOGAT2) plays a significant role in influencing colorectal cancer (CRC) progression by regulating lipid metabolism through ACSM1 (Acyl-CoA synthetase medium-chain family member 1). In a study investigating MOGAT2’s role, researchers found that its expression directly impacts tumor behavior. When MOGAT2 was suppressed, CRC cells exhibited aggressive characteristics, including increased proliferation, invasion, and colony formation, along with reduced apoptosis (cell death). These changes suggest a more malignant cancer phenotype. On the other hand, overexpressing MOGAT2 reversed these effects, reducing tumor growth and invasion, promoting apoptosis, and inhibiting epithelial-mesenchymal transition (EMT), a process critical for cancer metastasis. Mechanistically, MOGAT2 reprograms lipid metabolism in CRC cells. It reduces the accumulation of free fatty acids, regulates cholesterol transport, and suppresses the expression of lipid synthesis enzymes like GPAT2, GPAT3, and GAAT. This reprogramming helps restore metabolic balance in cancer cells, which is crucial for controlling their growth and spread. Further analysis identified ACSM1 as a key downstream mediator of MOGAT2’s tumor-suppressive effects. ACSM1 contributes to the metabolic changes induced by MOGAT2. When ACSM1 was silenced, the beneficial effects of MOGAT2 overexpression were lost, and cancer cells regained aggressive traits, reduced apoptosis, and experienced metabolic dysregulation. In summary, MOGAT2 acts as a tumor suppressor in CRC by modulating lipid metabolism through ACSM1. This pathway reduces tumor growth, promotes apoptosis, and inhibits invasion and EMT. Targeting the MOGAT2–ACSM1 axis may offer a promising therapeutic approach for managing CRC progression.

miR147 promotes mucosal integrity and intestinal inflammation

miR147 plays a crucial role in promoting mucosal integrity and regulating intestinal inflammation. As a protective microRNA, miR147 is specifically enriched in intestinal epithelial cells (IECs), particularly in differentiated enterocytes at the luminal surface of the colon. Its expression is intrinsic to epithelial differentiation and not dependent on microbial exposure, as demonstrated in germ-free mice. During inflammation, miR147 expression is upregulated in response to cytokine-driven signals, as observed in dextran sodium sulfate (DSS)-induced colitis models and inflammatory conditioned media experiments. Functionally, miR147 is vital for maintaining epithelial barrier integrity and promoting mucosal healing during inflammation. Global and epithelial-specific miR147 knockout mice exhibit severe colitis characterized by significant body weight loss, shortened colons, epithelial destruction, and increased intestinal permeability. Transcriptomic analysis revealed that miR147 suppresses proinflammatory and mitochondrial metabolism genes, particularly Ndufa4, a mitochondrial complex IV-associated gene. Ndufa4 was identified as a direct target of miR147, and its dysregulation in miR147-deficient tissues leads to disrupted metabolism and weakened barrier function. Mechanistic studies confirmed that the miR147–Ndufa4 axis is essential for epithelial homeostasis, as mice engineered to lack the miR147 binding site in Ndufa4 mirrored the severe inflammation seen in miR147 knockouts. Furthermore, miR147 supports robust type I interferon signaling in colonocytes, enhancing antiviral and anti-inflammatory defense while sustaining metabolic balance. The study suggests that miR147 mimics or Ndufa4-targeted therapies could restore mucosal healing and reduce inflammation, highlighting miR147 as a potential therapeutic target for inflammatory bowel disease (IBD) and colorectal cancer.

Salvigenin Inhibits Gastric Cancer Progression via EGFR/PI3K/AKT-Mediated Antitumor Signaling

Yes, salvigenin inhibits gastric cancer progression by targeting the EGFR/PI3K/AKT signaling pathway, which plays a critical role in tumor growth, survival, and aggressiveness. The study highlights the following key findings: 1. **Anticancer Properties of Salvigenin**: Salvigenin, a bioactive flavonoid, demonstrated significant anticancer effects in gastric cancer cells. It reduced cell proliferation, migration, and invasion while promoting apoptosis, effectively curbing the malignancy of gastric cancer. 2. **Mechanism of Action**: Mechanistic investigations using network pharmacology, molecular docking, and protein expression analyses revealed that salvigenin exerts its antitumor effects primarily by inhibiting the EGFR/PI3K/AKT signaling pathway. This pathway is well-known for its role in promoting tumor cell survival, proliferation, and metastasis. 3. **Validation of Mechanism**: - **Rescue Experiments**: When EGFR signaling was artificially activated using NSC 228155 or EGFR overexpression, the inhibitory effects of salvigenin on cancer cell malignancy were reversed. This strongly supports the conclusion that salvigenin's anticancer effects are mediated through the suppression of EGFR/PI3K/AKT signaling. - **In Vivo Evidence**: In xenograft mouse models, salvigenin effectively suppressed tumor growth, confirming its ability to block the EGFR/PI3K/AKT pathway and reduce tumor progression in a living organism. 4. **Therapeutic Potential**: Salvigenin's ability to target a key oncogenic pathway (EGFR/PI3K/AKT) positions it as a promising candidate for targeted therapy in gastric cancer management. By reducing tumor aggressiveness and enhancing apoptosis, salvigenin offers a potential approach for improving outcomes in gastric cancer patients. In summary, salvigenin's inhibition of the EGFR/PI3K/AKT signaling pathway is central to its anticancer effects, making it a potent agent for combating gastric cancer progression.

Interferon-gamma in driving crypt hyperplasia in celiac disease

Interferon-gamma plays a crucial role in driving crypt hyperplasia, a hallmark of celiac disease and other inflammatory intestinal disorders. Crypt hyperplasia refers to the abnormal elongation and proliferation of epithelial crypts in the intestinal lining, which is commonly observed in active celiac disease. Research using mass spectrometry-based tissue proteomics revealed strong interferon-gamma activity in the epithelial crypt zone of patients with active celiac disease. This was evidenced by increased expression of major histocompatibility complex (MHC) molecules and decreased levels of proteins involved in fatty acid metabolism, indicating significant molecular changes in the intestinal epithelium. To further investigate, experiments in wild-type mice demonstrated that administration of interferon-gamma reproduced the morphological and molecular features of crypt hyperplasia, confirming its role in driving this pathological process. Importantly, mice lacking interferon-gamma receptors specifically in gut epithelial cells did not develop crypt hyperplasia when exposed to interferon-gamma, providing direct evidence that interferon-gamma acts on epithelial cells to induce these changes. Overall, interferon-gamma is a direct driver of crypt hyperplasia in celiac disease, highlighting its critical role in the disease's pathogenesis. It may also play a similar role in other inflammatory intestinal disorders involving interferon-gamma signaling, making it a potential therapeutic target for these conditions.

Hesperetin, Liver Fibrosis, Gut Microbiota and Autophagy

Hesperetin, a naturally occurring flavonoid with notable anti-inflammatory and antioxidant properties, has shown promising effects in addressing liver fibrosis, a condition characterized by excessive scarring due to chronic liver injury. In a mouse model of carbon tetrachloride-induced liver fibrosis, hesperetin demonstrated significant antifibrotic potential. It reduced liver injury and fibrosis, improved liver tissue structure, and suppressed autophagy-related markers in hepatic stellate cells, which are key drivers of fibrosis. By inhibiting the activation of these cells, hesperetin effectively limited the progression of fibrosis and decreased inflammatory cell infiltration within the liver. Additionally, hesperetin influenced gut microbiota composition, an important factor in liver health. Using 16S rDNA sequencing, researchers observed that hesperetin increased the proportion of Firmicutes and boosted beneficial populations of lactic acid bacteria. These changes in gut microbial balance contributed to reduced liver inflammation and fibrosis, highlighting the gut-liver axis's role in disease modulation. The study concluded that hesperetin alleviates liver fibrosis through a multifaceted mechanism involving the suppression of hepatic stellate cell autophagy, reduction of inflammation, and restoration of healthy gut microbiota. These findings suggest hesperetin as a potential therapeutic candidate for managing liver fibrosis and improving overall liver health.

Hypoxia-Activated CAFs Promote Lymphatic Metastasis in Colorectal Cancer via CLEC11A/LGR5-Mediated WNT Signaling.

The title "Hypoxia-Activated CAFs Promote Lymphatic Metastasis in Colorectal Cancer via CLEC11A/LGR5-Mediated WNT Signaling" succinctly encapsulates the findings of the study. Here's an in-depth explanation of the key points: 1. **Hypoxia and Cancer-Associated Fibroblasts (CAFs):** - Hypoxia, a condition of low oxygen levels in the tumor microenvironment, plays a significant role in cancer progression and metastasis. - Under hypoxic conditions, normal fibroblasts are converted into cancer-associated fibroblasts (CAFs) by the activation of the transcription factor HIF1A (Hypoxia-Inducible Factor 1-alpha). - These hypoxia-activated CAFs exhibit altered behavior, including increased secretion of specific proteins that influence tumor progression. 2. **CLEC11A Secretion by Hypoxic CAFs:** - Hypoxic CAFs were found to secrete CLEC11A, a protein that plays a pivotal role in promoting cancer metastasis. - CLEC11A binds to the LGR5 receptor, which is present on colorectal cancer cells. 3. **CLEC11A/LGR5 Interaction and WNT Signaling:** - The interaction between CLEC11A and LGR5 activates the WNT/beta-catenin signaling pathway, a well-known pathway involved in cancer progression. - Activation of this pathway drives epithelial-mesenchymal transition (EMT), a process where cancer cells lose their epithelial characteristics and gain mesenchymal traits, making them more invasive and motile. - The WNT signaling pathway also promotes lymphangiogenesis, the formation of new lymphatic vessels, which facilitates the spread of cancer cells through the lymphatic system. 4. **Lymphatic Metastasis:** - The combined effects of EMT and lymphangiogenesis significantly enhance the ability of colorectal cancer cells to metastasize via the lymphatic system, contributing to disease progression and poor prognosis. 5. **Therapeutic Insights:** - Inhibiting CLEC11A secretion from CAFs was shown to significantly reduce lymphatic metastasis in both cell and animal models. - Blocking the LGR5 receptor or interfering with the WNT signaling pathway also reversed the metastatic effects, highlighting the therapeutic potential of targeting the CLEC11A-LGR5 axis. - These findings suggest that strategies aimed at disrupting this signaling axis could serve as effective treatments to prevent cancer spread in colorectal cancer patients. 6. **Clinical Implications:** - The study provides a deeper understanding of how the tumor microenvironment, specifically hypoxia and CAF activity, drives lymphatic metastasis in colorectal cancer. - Targeting the hypoxia-induced CLEC11A/LGR5-mediated WNT signaling pathway could offer a novel therapeutic approach to combat colorectal cancer metastasis and improve patient outcomes. In summary, the research underscores the critical role of hypoxia-activated CAFs in promoting lymphatic metastasis in colorectal cancer through the CLEC11A/LGR5-mediated activation of the WNT signaling pathway. This discovery not only elucidates a key mechanism of cancer progression but also identifies potential targets for therapeutic intervention.

Impact of HMOX1 + Macrophages on Tumor Immunity and Immunotherapy Response in HCC

HMOX1-positive (HMOX1+) macrophages have a profound impact on tumor immunity and the response to immunotherapy in hepatocellular carcinoma (HCC), as revealed by the study. Here is a detailed explanation of their role: ### 1. **HMOX1+ Macrophages and Tumor Immunity:** - **Immunosuppressive Role:** HMOX1+ macrophages are tumor-associated macrophages (TAMs) that play a central role in creating an immunosuppressive tumor microenvironment (TME). These macrophages are characterized by the high expression of heme oxygenase 1 (HMOX1), an enzyme involved in heme metabolism and cellular stress responses. - **Immune Cell Infiltration:** Tumors with elevated levels of HMOX1+ macrophages show increased infiltration of regulatory T cells (Tregs). Tregs are known to suppress anti-tumor immune responses, further contributing to immune evasion by the tumor. - **CD8+ T Cell Dysfunction:** In the presence of HMOX1+ macrophages, CD8+ T cells exhibit elevated expression of programmed cell death protein 1 (PD-1), a marker of T cell exhaustion. Exhausted CD8+ T cells are less effective in recognizing and killing cancer cells, which undermines the anti-tumor immune response. ### 2. **Impact on Immunotherapy Response:** - **Poor Prognosis and Reduced Responsiveness:** The study found that the presence of HMOX1+ macrophages in the TME is associated with poorer prognosis in HCC patients. Additionally, these macrophages correlate with reduced responsiveness to immunotherapy, particularly immune checkpoint inhibitors like anti-PD-1 therapy. - **Immune Resistance:** HMOX1+ macrophages contribute to an immune-resistant environment by promoting Treg infiltration and CD8+ T cell exhaustion, making the tumor less susceptible to immunotherapy. ### 3. **Therapeutic Implications – Targeting HMOX1:** - **Pharmacological Inhibition of HMOX1:** The study demonstrated that inhibiting HMOX1 pharmacologically using Znpp (Zinc protoporphyrin IX) improved the efficacy of anti-PD-1 therapy in preclinical mouse models of HCC. This suggests that targeting HMOX1+ macrophages can reverse the immunosuppressive state of the TME. - **Enhanced Immunotherapy Effectiveness:** By reducing the activity of HMOX1, the study observed improved anti-tumor immune responses, likely due to decreased Treg infiltration and reduced PD-1 expression on CD8+ T cells. This indicates that HMOX1 inhibition reactivates exhausted T cells and restores their ability to fight the tumor. ### 4. **Prognostic and Therapeutic Potential of HMOX1:** - **Prognostic Marker:** The expression of HMOX1 in tumor-associated macrophages could serve as a biomarker for predicting patient prognosis and their likely response to immunotherapy. - **Combination Therapy:** Combining HMOX1 inhibitors with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 therapies) could provide a synergistic effect, enhancing the overall success of immunotherapy in HCC patients. ### Conclusion: HMOX1+ macrophages play a critical role in promoting an immunosuppressive TME in HCC, leading to poor prognosis and reduced effectiveness of immunotherapy. Targeting HMOX1, either alone or in combination with existing immunotherapies, represents a promising strategy to overcome immune resistance and improve clinical outcomes for HCC patients. This approach could potentially transform the treatment landscape for this highly challenging cancer.

Lipid Metabolism Signature in NAFLD Revealed by Transcriptomic and Single-Cell RNA-Seq Analyses

The study identified key lipid metabolism-related genes (LMGs) associated with nonalcoholic fatty liver disease (NAFLD) using transcriptomic and single-cell RNA sequencing (scRNA-seq) analyses. Researchers analyzed multiple datasets (GSE48452, GSE63067, GSE89632, GSE72756) alongside scRNA-seq data (GSE159977). They identified 295 differentially expressed genes (DEGs) between NAFLD and controls, with 24 LMGs linked to fatty acid metabolism, bile acid metabolism, and inflammation. NAFLD patients were classified into two clusters based on these LMGs. Cluster 1 showed inhibited fatty acid metabolism but activated inflammatory and TNF signaling pathways, indicating disease heterogeneity. Using machine learning methods (LASSO, BSR, Boruta), three key LMGs—PRKAA2, KLF5, and ME1—were identified. ME1 and PRKAA2 were validated as core genes for diagnostic modeling, with ME1 showing stronger biological relevance. A two-gene diagnostic model integrating PRKAA2 and ME1 achieved high accuracy (AUC = 0.945). Immune analysis revealed significant associations of ME1 and PRKAA2 with immune cells, especially NK and T cells, highlighting immune-metabolic crosstalk in NAFLD. scRNA-seq identified six cell types, with NK cells strongly correlating with ME1 expression. NAFLD samples showed reduced T-cell proportions but elevated NK-cell infiltration, indicating immune imbalance. ME1 was found to drive lipid accumulation and influence NK-cell metabolic activity, while PRKAA2's role was context-dependent. Functional pathway analysis revealed that differential LMGs were involved in TNF, JAK–STAT, AMPK, and PPAR signaling, which regulate lipid metabolism and inflammation. The study underscores ME1’s potential as a biomarker and therapeutic target, linking lipid dysregulation and immune imbalance in NAFLD. Future studies should validate these findings and explore ME1’s therapeutic potential.

Lactylation-based gene signature and gastric adenocarcinoma

Gastric adenocarcinoma (STAD) is a type of stomach cancer that accounts for 95% of gastric cancers and has poor survival rates. A recent study focused on a biological process called "lactylation," where lactate molecules attach to proteins, influencing metabolism and gene expression in cancer. The study aimed to identify lactylation-related genes (LRGs) that could predict patient outcomes and immune system involvement in STAD. Researchers analyzed data from 375 STAD samples and 32 normal tissues, identifying 12 key LRGs. They built a six-gene model (including DHRS7, NOP2, CRABP2, CALD1, ALB, and RIMS1) to predict patient survival. Patients with higher risk scores had shorter survival times. Among these genes, DHRS7 was studied in-depth. DHRS7 levels were lower in cancer tissues but higher in advanced stages, correlating with worse outcomes. It was linked to immune cells like macrophages, particularly M2 macrophages, which promote an immunosuppressive tumor environment. DHRS7 also influenced key cancer pathways (e.g., PI3K-AKT and TGF-β) and processes like tumor growth, invasion, and immune escape. Interestingly, DHRS7 acted as a tumor suppressor in early stages but promoted cancer in later stages, similar to other proteins like TGF-β. This dual role makes it a potential target for personalized therapies. The study suggests that lactylation-based gene signatures, especially DHRS7, could serve as biomarkers for prognosis and guide immunotherapy or metabolism-focused treatments in STAD. However, further research is needed to validate these findings and explore DHRS7's mechanisms.

Leonurine Alleviates DSS-Induced Colitis in Mice

Leonurine, an active compound derived from *Leonurus japonicus*, has shown significant potential in alleviating DSS-induced ulcerative colitis (UC) in mice. The study utilized a 3% dextran sulfate sodium (DSS) solution to induce colitis, replicating symptoms of human UC, including inflammation and epithelial barrier damage. Oral administration of leonurine (30 mg/kg/day) for 7 days markedly reduced symptoms such as body weight loss, colon shortening, and disease activity index (DAI) scores. Histopathological analysis revealed reduced epithelial cell loss, crypt damage, and inflammatory infiltration, improving colon tissue structure. Leonurine enhanced intestinal barrier function by upregulating tight junction proteins claudin-1 and occludin, reducing permeability caused by DSS. ELISA tests demonstrated decreased serum levels of proinflammatory cytokines TNF-α and IL-1β, indicating its anti-inflammatory effects. Transmission electron microscopy confirmed preserved tight junction integrity, preventing structural damage caused by DSS. Transcriptomic analysis revealed 861 differentially expressed genes, with significant modulation of pathways related to leukocyte chemotaxis, extracellular matrix organization, and pancreatic secretion. Leonurine downregulated pancreatic protease genes *Cela2a* and *Cela3b*, implicated in gut inflammation and barrier disruption. Quantitative PCR validated these findings. Leonurine also modulated gut microbiota composition, reducing inflammatory bacterial genera such as *Rikenellaceae_RC9_gut_group*, *UBA1819*, *Enterococcus*, and *Oscillibacter*. It increased the abundance of anti-inflammatory Verrucomicrobia, promoting microbial balance. By regulating pancreatic enzymes and microbial composition, leonurine restored intestinal homeostasis, limited bacterial translocation, and protected gut barrier function. These findings highlight its therapeutic potential as a natural candidate for UC treatment, warranting further research into its mechanisms in pancreatic-gut axis regulation.