Additional file 1 of A novel role of secreted methionine adenosyltransferase α2 in colorectal liver metastases

Figshare · 2026-01-01

Supplementary Material 1

Correction: S-adenosylmethionine and methylthioadenosine inhibit cancer metastasis by targeting MicroRNA 34a/b-methionine adenosyltransferase 2A/2B axis

Oncotarget · 2026-01-06

Forkhead box protein M1 network induction and crosstalk drives the development of alcohol-associated liver disease

Hepatology · 2026-03-27

BACKGROUND AND AIMS: Forkhead Box Protein M1 (FOXM1) is an oncoprotein that plays an important role in liver inflammation and fibrosis. It is phosphorylated by multiple kinases at specific sites, leading to interaction with peptidyl-prolyl isomerase NIMA-interacting 1 (PIN1) for further activation. The role of FOXM1 in alcohol-associated liver disease (ALD) is unknown and investigated here. APPROACH AND RESULTS: We used the NIAAA ALD protocol in wild-type, flox, and albumin-Cre Foxm1 knockout ( Foxm1Hep-/- ) mice, ethanol (EtOH)-treated human and mouse hepatocytes, and human ALD specimens, and examined the effect of FDI-6, a small molecule inhibitor of FOXM1. We found FOXM1 was upregulated in murine and human ALD, particularly in hepatocytes. FOXM1-PIN1 interaction increased in both cytosol and nuclei, along with increased total and nuclear levels of FOXM1, FOXM1-pT600 (marker of activation), cyclin D1, pERK, and pPKC. Total PIN1 level was unchanged, but nuclear PIN1 content increased. Silencing PIN1, cyclin D1, or inhibiting MEK alone blunted the EtOH-mediated increase in nuclear FOXM1 expression/activity, but the combination inhibited completely. FDI-6-treated and Foxm1Hep-/- mice were protected from EtOH-induced liver injury, the increase in triglyceride and proinflammatory cytokines. RNA-Seq analysis, validated in Foxm1Hep-/- livers and human ALD, revealed multiple novel Foxm1 targets, including granulin (GRN), cathepsins L/E, and importin-α5, which enhanced the nuclear translocation of PIN1. CONCLUSIONS: Taken together, FOXM1 is activated in hepatocytes in response to EtOH through a mechanism that involves PKCε, MEK/ERK, cyclin D1-CDK4/6, PIN1, and GRN. Targeting this pathway may represent a novel therapeutic strategy for ALD.

1182 ALCOHOL-ASSOCIATED METABOLOMIC AND PROTEOMIC SIGNATURES PREDICTING INCIDENT CIRRHOSIS AND MRI-DEFINED LIVER STEATOSIS AND FIBROINFLAMATION IN THE UK BIOBANK COHORT

Gastroenterology · 2026-05-01

A novel role of secreted methionine adenosyltransferase α2 in colorectal liver metastases

Figshare · 2026-01-01

Abstract Background Colorectal liver metastasis (CRLM) occurs frequently in patients with colorectal cancer (CRC). Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine, the principal methyl donor. MAT1A (encodes MATα1) is expressed mainly in normal adult liver, whereas MAT2A (encodes MATα2) is expressed in all extrahepatic tissues. MAT1A is a major defense against CRLM as loss of Mat1a sensitizes the liver to CRLM. In contrast, MAT2A is overexpressed in CRC and promotes oncogenicity. Here, we sought to determine if CRCs secrete MATα2 and if this influences CRLM. Methods Our study included human hepatocytes, human CRC cells, extracellular vesicle (EV) isolation, chromatin immunoprecipitation (ChIP), ChIP-seq, promoter activity assays, proliferation, migration, and invasion assays, western blotting, immunohistochemistry and immunofluorescence. We confirmed some of the findings using human hepatocyte spheroids, CRLM and normal liver tissue array, and plasma samples. Results CRCs secrete MATα2 in free but truncated form (MATα2-t) and intact within EVs (EV-MATα2). EV-MATα2 can be internalized by human hepatocytes and CRCs, found within the nucleus, which then binds to MAT1A and MAT2A promoters on ChIP to lower and increase MAT1A and MAT2A promoter activities, respectively. In human CRLM samples, hepatocytes in nontumor regions express lower MATα1 but higher MATα2 as compared to normal liver. Treating RKO cells with EVs released from RKO cells overexpressing MAT2A promoted cell proliferation, migration, and invasion. MATα2-t was detected at a higher level in media from colon, pancreatic, and prostate cancer cell lines than corresponding normal epithelial cells as well as in the plasma of CRC patients as compared to healthy controls. RKO cells treated with MATα2-t activated focal adhesion kinase (FAK), an important kinase for cancer cell evasion of apoptosis. Conversely, treatment with MATα2 neutralizing antibody inhibited FAK and induced apoptosis. Conclusions CRC cells secrete both MATα2 within EVs and free MATα2-t. EV-MATα2 can be internalized and act as a transcription factor to lower hepatocytes’ MAT1A, the major defense against CRLM, while promoting CRC oncogenicity. Freely released MATα2-t acts as a ligand in an autocrine fashion to activate FAK, which is essential for CRC survival. Taken together, secreted MATα2 plays an essential role in promoting CRLM.

Loss of fungal sensing exacerbates liver injury in a murine model of MASLD

JCI Insight · 2026-03-10

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with limited interventions. While the role of gut bacteria in MASLD has been extensively studied, the contribution of gut fungi remains largely unexplored. This study investigates the impact of fungal dysbiosis and the role of CARD9, a key adaptor protein in fungal sensing on gut-liver axis dysfunction in MASLD. Patients with advanced liver fibrosis exhibited distinct mycobiota profiles. Using a Card9-deficient mouse model subjected to high-fat, high-glucose/-fructose feeding, we observed exacerbated liver injury and fibrosis accompanied by fungal dysbiosis, paralleling our findings in human patients. Beyond its established expression in myeloid cells, CARD9 was also detected in intestinal enterocytes where its expression was diminished under metabolic stress. Intestinal organoids with CARD9 inhibition had reduced expression of antimicrobial Reg3g, the tight junction protein ZO-1, and the antifungal enteroendocrine hormone PYY. These findings suggest that CARD9 maintains gut barrier integrity, preventing microbial translocation and subsequent liver injury and fibrosis. Our results provide insights into the interplay between fungal dysbiosis, gut barrier dysfunction, and MASLD, and identify CARD9 as a key protein within this axis.

1182 ALCOHOL-ASSOCIATED METABOLOMIC AND PROTEOMIC SIGNATURES PREDICTING INCIDENT CIRRHOSIS AND MRI-DEFINED LIVER STEATOSIS AND FIBROINFLAMATION IN THE UK BIOBANK COHORT

Gastrointestinal Endoscopy · 2026-05-01

A novel role of secreted methionine adenosyltransferase α2 in colorectal liver metastases

Figshare · 2026-01-01

Abstract Background Colorectal liver metastasis (CRLM) occurs frequently in patients with colorectal cancer (CRC). Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine, the principal methyl donor. MAT1A (encodes MATα1) is expressed mainly in normal adult liver, whereas MAT2A (encodes MATα2) is expressed in all extrahepatic tissues. MAT1A is a major defense against CRLM as loss of Mat1a sensitizes the liver to CRLM. In contrast, MAT2A is overexpressed in CRC and promotes oncogenicity. Here, we sought to determine if CRCs secrete MATα2 and if this influences CRLM. Methods Our study included human hepatocytes, human CRC cells, extracellular vesicle (EV) isolation, chromatin immunoprecipitation (ChIP), ChIP-seq, promoter activity assays, proliferation, migration, and invasion assays, western blotting, immunohistochemistry and immunofluorescence. We confirmed some of the findings using human hepatocyte spheroids, CRLM and normal liver tissue array, and plasma samples. Results CRCs secrete MATα2 in free but truncated form (MATα2-t) and intact within EVs (EV-MATα2). EV-MATα2 can be internalized by human hepatocytes and CRCs, found within the nucleus, which then binds to MAT1A and MAT2A promoters on ChIP to lower and increase MAT1A and MAT2A promoter activities, respectively. In human CRLM samples, hepatocytes in nontumor regions express lower MATα1 but higher MATα2 as compared to normal liver. Treating RKO cells with EVs released from RKO cells overexpressing MAT2A promoted cell proliferation, migration, and invasion. MATα2-t was detected at a higher level in media from colon, pancreatic, and prostate cancer cell lines than corresponding normal epithelial cells as well as in the plasma of CRC patients as compared to healthy controls. RKO cells treated with MATα2-t activated focal adhesion kinase (FAK), an important kinase for cancer cell evasion of apoptosis. Conversely, treatment with MATα2 neutralizing antibody inhibited FAK and induced apoptosis. Conclusions CRC cells secrete both MATα2 within EVs and free MATα2-t. EV-MATα2 can be internalized and act as a transcription factor to lower hepatocytes’ MAT1A, the major defense against CRLM, while promoting CRC oncogenicity. Freely released MATα2-t acts as a ligand in an autocrine fashion to activate FAK, which is essential for CRC survival. Taken together, secreted MATα2 plays an essential role in promoting CRLM.

Additional file 1 of A novel role of secreted methionine adenosyltransferase α2 in colorectal liver metastases

Open MIND · 2026-01-01

Supplementary Material 1

USP4-Mediated deubiquitination of A2AR suppresses autophagy-dependent ferroptosis in gastric cancer

Cellular and Molecular Life Sciences · 2025-10-06

Deubiquitinating enzymes (DUBs) are crucial for regulating the degradation of specific proteins and represent a novel therapeutic direction in cancer. In gastric cancer, USP4 levels are significantly elevated, though its therapeutic potential remains underexplored. Our study demonstrates that USP4 plays a pivotal role in gastric cancer cells via the autophagy-dependent ferroptosis pathway. Specifically, USP4 selectively removes Lys48-linked polyubiquitin chains through its deubiquitination activity at the C311 site, stabilizing the A2AR protein. This action precisely modulates autophagy and inhibits ferroptosis, thereby promoting gastric cancer progression. Additionally, our findings indicate that targeting USP4 or A2AR can activate autophagy and restore the ferroptosis process, which is essential for autophagy-dependent ferroptosis. Consequently, the USP4-A2AR signaling pathway is critically important for the survival of gastric cancer cells and represents a potential therapeutic target for gastric cancer.