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.

ARF GTPase protein 1 (GIT1) is a scaffold protein that is overexpressed in hepatocellular carcinoma (HCC) and colorectal cancer (CRC). GIT1 forms a complex with methionine adenosyltransferase 2B (MAT2B) that activates RAS-RAF-MEK-ERK signaling in HCC and CRC to enhance tumorigenicity. Here, we investigated in a proof-of-concept study whether a small molecule that disrupts GIT1-MAT2B interaction can be effective in HCC and CRC treatment. Since the GIT1 crystal structure is unavailable, we developed a molecular model and used computer-based drug discovery approach to screen for small molecules targeting the GIT1 ankyrin repeat domain, the region closest to where MAT2B interacts that is accessible. Of nine compounds tested, compound 3 (C3) selectively interacts with GIT1 and shows an anti-cancer effect in a GIT1-dependent manner. C3 is antiproliferative, induced apoptosis and G2/M cell cycle arrest while inhibiting colony formation and migration in liver and colon cancer cells. C3 lowered interaction between GIT1 and MAT2B, and with downstream effectors cRAF, MEK and ERK, lowering MEK activity and cyclin D1 expression. Unexpectedly, C3 stabilized GIT1 interaction with cyclin B1 while weakening cyclin B1’s interaction with components of the anaphase promoting complex, concomitant with sustained cyclin B1 expression and mitosis arrest. In mice, C3 administration was well tolerated and inhibited murine CRC growth and liver metastasis in immune competent mice and human CRC growth in the livers of nude mice. In conclusion, a small molecule inhibitor that disrupts GIT1’s normal interactome is a promising new approach to treating liver and colon cancers.

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.

BACKGROUND & AIMS:Corrected T1 (cT1), measured by liver MRI, enables non-invasive assessment of hepatic water content. Although a threshold of ≥800 ms has been proposed to identify individuals at risk of metabolic dysfunction-associated steatohepatitis (MASH) and adverse outcomes, it identifies only a small proportion of individuals (∼5%) and may fail to capture risk below this threshold. We aimed to evaluate whether cT1 values below 800 ms are associated with mortality and whether hepatic steatosis, assessed by MRI-derived proton density fat fraction (PDFF), modifies this association. METHODS:We analyzed 29,597 UK Biobank participants with liver MRI-derived cT1 measurements. Participants were categorized into three groups (<700, 700-799, and ≥800 ms) based on penalized spline analysis. Outcomes included all-cause mortality, cause-specific mortality, and liver-related events. Cox proportional hazards models were adjusted for demographic, lifestyle, and cardiometabolic factors. RESULTS:Approximately 40% of participants had cT1 values of 700-799 ms, and 5% had cT1 values ≥800 ms. Over a median follow-up of 5.3 years, participants with cT1 values of 700-799 ms had higher risks of all-cause mortality (adjusted hazard ratio [aHR] 1.21; 95% CI 1.02-1.43) and cardiovascular mortality (aHR 1.54; 95% CI 1.04-2.28) than those with cT1 values <700 ms. Risks were even higher among participants with cT1 values ≥800 ms. Clinically significant hepatic steatosis (PDFF ≥10%) significantly modified the association between cT1 and all-cause mortality (p for interaction <0.05). Higher cT1 was associated with increased all-cause mortality only among participants with PDFF <10% (aHR 1.25 [95% CI 1.06-1.49] for cT1 700-799 ms and 2.20 [95% CI 1.40-3.48] for cT1 ≥800 ms, compared with cT1 <700 ms), but not among those with PDFF ≥10%. CONCLUSION:cT1 values between 700 and 799 ms were independently associated with an increased risk of mortality. Notably, this association was modified by the presence of clinically significant hepatic steatosis as assessed by PDFF. IMPACT AND IMPLICATIONS:Using liver MRI to measure cT1, we demonstrated that cT1 values of 700-799 ms, below the conventional threshold of 800 ms, were independently associated with an increased risk of all-cause and cardiovascular mortality. We also found that this association was present only among participants with PDFF <10%, indicating that clinically significant hepatic steatosis modifies the relationship between cT1 and mortality. These findings suggest that lower cT1 thresholds may improve risk stratification and that the prognostic significance of cT1 should be interpreted in the context of hepatic steatosis.

BACKGROUND & AIMS:Coffee consumption has been linked to a reduced risk of liver disease, but large-scale prospective studies integrating imaging biomarkers, proteomics, and intake patterns remain limited. The effects of coffee type, additives, and metabolic modifiers are also unclear. METHODS:We analyzed 354,957 UK Biobank participants without baseline cirrhosis or hepatocellular carcinoma. Coffee consumption, type (caffeinated/decaffeinated), and additives (sugar/sweeteners) were assessed by questionnaire. Incident cirrhosis, hepatocellular carcinoma, and liver-related mortality were ascertained through linked records. In a subcohort (n = 28,961) undergoing magnetic resonance imaging, hepatic fat (proton density fat fraction), iron, and fibroinflammation (iron-corrected T1) were evaluated. Proteomic profiling (n = 44,633) used Olink assays. Models were adjusted for demographic, behavioral, metabolic, and genetic covariates. RESULTS:Over a median 13-year follow-up, higher coffee intake showed a graded reduction in liver outcomes, with ≥5 cups/day group having risk reductions of cirrhosis (hazard ratio, 0.68; 95% confidence interval, 0.58-0.79), hepatocellular carcinoma (hazard ratio, 0.53; 95% confidence interval, 0.34-0.83), and liver-related mortality (hazard ratio, 0.58; 95% confidence interval, 0.45-0.74). Protective associations were similar for caffeinated and decaffeinated coffee and persisted among those adding sugar or artificial sweeteners, although additive use correlated with modestly higher iron-corrected T1. Higher coffee intake corresponded to lower hepatic fat, iron, and fibroinflammation. Proteomic analysis revealed consistent patterns: higher levels of hepatocellular synthesis and complement proteins (transthyretin, selenoprotein P, complement factor H-related protein4/5) and lower levels of fibrogenic and macrophage-activation markers (microfibril-associated protein 4, colony stimulating factor 1 receptor, ectonucleotide pyrophosphatase/phosphodiesterase 2, transthyretin) with coffee drinking. CONCLUSIONS:Higher coffee intake was associated with favorable clinical, imaging, and proteomic indicators of liver health. These multidimensional findings support moderate unsweetened coffee as a simple strategy for liver disease prevention.

Primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), arise from the neoplastic transformation of hepatocytes and cholangiocytes, respectively. Loss or downregulation of PTEN, a tumor suppressor negatively regulating the PI3K/AKT pathway, is frequently observed in CCA and HCC. Notably, PTEN mutations are observed at nearly twice the frequency in combined CCA-HCC tumors than either HCC or CCA alone. Using lineage-specific liver-targeted PTEN-deficient mouse models, we demonstrate that PTEN loss drives cellular dedifferentiation and tumorigenesis, a process that is critically dependent on AKT2. Mechanistically, PTEN deficiency induces activation of NOTCH and upregulation of transcriptional factor SOX9, which plays a central role in tumor cell transformation. In parallel, PTEN loss increases SMAD4 expression and sensitizes the tumor cells to TGFβ signaling, with TGFβ treatment repressing SOX9 expression in tumor cells lacking PTEN. Together, our study defined a critical role for PTEN-AKT2 signaling in maintaining liver epithelial lineage fidelity and revealed how its disruption promotes the conversion of mature hepatocytes or cholangiocytes into liver cancer stem-like cells (LCSCs). Furthermore, we identify a PTEN-dependent crosstalk between NOTCH and TGFβ pathways that governs liver tumor development. Together, this work provides mechanistic insight into lineage plasticity in liver cancer with implications for pathway-directed therapy.

Hepatic deletion of methionine adenosyltransferase-1a (Mat1a) in mice reduces S-adenosylmethionine (SAMe), a key methyl donor essential for many biological processes, which promotes the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Hyperglycemia and reduced MAT1A expression, along with low SAMe levels, are common in MASLD patients. This study explores how Mat1a-knockout (KO) hepatocytes respond to prolonged high glucose conditions, focusing on glucose metabolism and lipid accumulation. Hepatocytes from methionine adenosyltransferase-1a-knockout (Mat1a-KO) mice were incubated in high glucose conditions overnight, allowing for analysis of key metabolic intermediates and gene expression related to glycolysis, gluconeogenesis, glyceroneogenesis, phospholipid synthesis, and very low density lipoprotein (VLDL) secretion. SAMe deficiency in Mat1a-KO hepatocytes led to reduced protein methyltransferase-1 activity, resulting in increased expression of glycolytic enzymes (glucokinase, phosphofructokinase, and pyruvate kinase) and decreased expression of gluconeogenic enzymes (phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and glucose-6-phosphatase). These alterations led to a reduction in dihydroxyacetone phosphate (DHAP), which subsequently inhibited mammalian target of rapamycin complex 1 (mTORC1) activity. This inhibition resulted in decreased phosphatidylcholine synthesis via the CDP-choline pathway and impaired VLDL secretion, ultimately causing lipid accumulation. Thus, under high glucose conditions, SAMe deficiency in hepatocytes depletes DHAP, inhibits mTORC1 activity, and promotes lipid buildup.

S-adenosylmethionine (SAMe) is a key methyl donor that plays a critical role in a variety of cellular processes, such as DNA, RNA and protein methylation, essential for maintaining genomic stability, regulating gene expression and maintaining cellular homeostasis. The involvement of SAMe in cancer pathogenesis is multifaceted, as through its multiple cellular functions, it can influence tumor initiation, progression and therapeutic resistance. In addition, the connection of SAMe with polyamine synthesis and oxidative stress management further underscores its importance in cancer biology. Recent studies have highlighted the potential of SAMe as a biomarker for cancer diagnosis and prognosis. Furthermore, the therapeutic implications of SAMe are promising, with evidence suggesting that SAMe supplementation or modulation could improve the efficacy of existing cancer treatments by restoring proper methylation patterns and mitigating oxidative damage and protect against damage induced by chemotherapeutic drugs. Moreover, targeting methionine cycle enzymes to both regulate SAMe availability and SAMe-independent regulatory effects, particularly in methionine-dependent cancers such as colorectal and lung cancer, presents a promising therapeutic approach. Additionally, exploring epitranscriptomic regulations, such as m6A modifications, and their interaction with non-coding RNAs could enhance our understanding of tumor progression and resistance mechanisms. Precision medicine approaches integrating patient subtyping and combination therapies with chemotherapeutics, such as decitabine or doxorubicin, together with SAMe, can enhance chemosensitivity and modulate epigenomics, showing promising results that may improve treatment outcomes. This review comprehensively examines the various roles of SAMe in cancer pathogenesis, its potential as a diagnostic and prognostic marker, and its emerging therapeutic applications. While SAMe modulation holds significant promise, challenges such as bioavailability, patient stratification and context-dependent effects must be addressed before clinical implementation. In addition, better validation of the obtained results into specific cancer animal models would also help to bridge the gap between research and clinical practice.

Objective Aldolases (ALDO) are sensors that regulate AMPK via binding to fructose 1,6-biphosphate (FBP), an intermediate of glucose and fructose metabolism. Fructose consumption is linked to metabolic dysfunction-associated steatotic liver disease (MASLD) progression but whether ALDO-AMPK signaling is involved is unknown. Methionine adenosyltransferase alpha 1 (Mat1a) knockout (KO) mice have low hepatic S-adenosylmethionine (SAMe) level and spontaneously develop steatohepatitis. ALDOB methylation has not been reported and here we investigated whether SAMe level regulates ALDOB and ALDOB-AMPK signaling and whether fructose feeding accelerates MASLD progression by disrupting ALDOB-AMPK signaling. Methods Mass spectrometry identified ALDOB methylation sites and recombinant in vitro approaches assessed how methylation at those sites affects ALDOB oligomerization and activity. Primary hepatocytes cultured with high/low glucose and/or fructose and wild type (WT) and Mat1a KO mice fed with a high-fructose diet examined AMPK-ALDOB signaling and MASLD progression. Results In Mat1a KO livers ALDOB R173 is hypomethylated while ALDOB activity is enhanced. Recombinant ALDOB is methylated at R173 and R304 by protein arginine methyltransferase 1. Low hepatic SAMe level results in hypomethylated ALDOB, which favors the tetrameric form that has higher enzymatic activity, and higher capacity to signal to activate AMPK. Fructose, independently of glucose levels, inhibited AMPK activity and induced lipid accumulation in hepatocytes. Mat1a KO mice have hyperactivated AMPK and fructose feeding inhibits it, enhancing the accumulation of fat in the liver and the progression of MASLD. Conclusion Hepatic SAMe levels regulate ALDOB oligomeric state and enzymatic activity impacting on AMPK signaling and fructose-induced MASLD progression.

Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity, mortality, and premature death worldwide. Its pathogenesis is complex and incompletely understood, with disrupted methionine metabolism as a key contributor. This pathway converts methionine into S-adenosylmethionine (SAM or SAMe), the principal methyl donor, a precursor of glutathione (GSH), and a critical regulator of hepatocellular function. Alterations in methionine metabolism are primarily driven by downregulation of methionine adenosyltransferase 1A (MAT1A), the liver-specific gene encoding the MATα1 subunit responsible for SAMe biosynthesis. Reduced MAT1A expression and activity lead to hepatic SAMe and GSH deficiency, resulting in global hypomethylation, mitochondrial dysfunction, impaired lipid metabolism, and progressive liver injury, hallmarks of ALD. Recent studies show that MATα1 also localizes to hepatocyte mitochondria, where its selective depletion contributes to mitochondrial dysfunction in ALD. Experimental models demonstrate that SAMe supplementation restores methylation capacity, replenishes GSH, reduces oxidative stress, and improves mitochondrial function and liver histology. Preservation of mitochondrial MATα1 also protects against ALD, underscoring its importance in hepatocellular health. Clinical exploration of SAMe in early-stage ALD suggests potential benefit and motivates continued investigation into treatment strategies that build on and extend beyond supplementation. This review summarizes current knowledge on the role of the MAT1A/SAMe axis in ALD pathophysiology, emphasizing molecular functions and critically evaluating preclinical and clinical evidence for potential therapy.

Prostate adenocarcinoma resistance to androgen receptor (AR) signaling inhibitor therapy is associated with elevated glutamine (L-Gln). Glutamine sensors, present in conserved riboswitches (glnA), control nitrogen metabolism in many organisms, such as cyanobacteria. Iterative in silico modifications of glnA found in Synechococcus elongatus and thermodynamic analysis of a 56mer aptamer resulted in high L-Gln specificity and affinity. The optimized aptamer depleted L-Gln from prostate adenocarcinoma cells by both L-Gln sequestration and extracellular glutaminase activation, serving as an allosteric activator. Glutamine depletion reduced FOXM1 transcriptional occupancy on the promoter of FGF8, a known mediator of prostate adenocarcinoma castration resistance. A point mutation in the binding pocket of the 56mer rendered the aptamer ineffective in L-Gln binding and FGF8 regulation. Accordingly, the L-Gln-depleting aptamer, with demonstrated serum stability, limited the proliferation and promoted cell death of castration-resistant prostate adenocarcinoma alone and in combination therapy with AR antagonists, enzalutamide and apalutamide, in subcutaneous and orthotopic mouse models. Further selective tumor targeting was achieved by functionalizing gold nanoparticles with either the optimized L-Gln aptamer or the point-mutant aptamer. Castration sensitivity was restored by the L-Gln-depleting aptamer but not by the point-mutant aptamer. The functionalized nanoparticle demonstrated superior antitumor efficacy in an orthotopic prostate adenocarcinoma model compared with the untargeted aptamer. The antitumor activity of the aptamer helped support L-Gln as an oncometabolite in prostate adenocarcinoma that can be targeted to sensitize tumors to hormone therapy.Significance: Depletion of glutamine, which can mediate hormone therapy resistance in prostate cancer patients, with a cyanobacteria-derived catalytic aptamer blocks FGF8 expression and sensitizes hormone refractive prostate tumors to androgen receptor inhibitors.

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. 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. 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. 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.

BACKGROUND:Nuclear magnetic resonance (NMR) spectroscopy enables the characterisation of lipoprotein sub-particles, providing a more detailed lipid profile than the conventional lipid measurements, with potential clinical relevance, particularly in cardiovascular disease (CVD), which remains the leading cause of mortality worldwide. Nonetheless, for clinical implementation, it is essential to first determine the normal variation of lipoprotein parameters by age and sex. METHODS:This cross-sectional study analysed a large dataset of 31,275 serum or plasma samples from five different countries using the B.I.LISA™ NMR-based platform, quantifying 112 lipoprotein parameters, including subclass size and concentration. Lipoprotein parameters from specific cohorts were fitted to a Quantile Generalised Additive Model (QGAM) to calculate the different percentiles as a function of age and sex. FINDINGS:A sub-cohort of individuals belonging to non-oriented cohorts (27,470 individuals) showed that lipoprotein parameters exhibit distinct sex- and age-dependent patterns, with inflection points observed around 44 and 60 years in women and around 60 years in men, aligning with known ageing acceleration models. The sub-cohort of 3021 individuals showing cardiometabolic risk factors was used to evaluate the effect of obesity, hypertension and diabetes in the lipoprotein distribution. Finally, we analysed the lipoprotein parameters that align with SCORE2 (a well-known CVD risk predictor) in an age- and sex-dependent manner. Many NMR-derived parameters effectively distinguish between low and high/very high CVD risk profiles, with very low-density (VLDL)-associated parameters demonstrating the highest sensitivity across a broad age range. INTERPRETATION:Our findings provide reference values for NMR-derived lipoprotein parameters by age and sex, enabling their accurate interpretation in the context of cardiovascular disease risk stratification. FUNDING:The specific funding of this article is provided in the acknowledgements section.

BACKGROUND & AIMS:FOLFOX, often used in patients with colorectal liver metastases, can cause sinusoidal obstruction syndrome (SOS) hindering subsequent treatment. S-adenosylmethionine (SAMe) is hepatoprotective and here we investigated whether it protects against FOLFOX-induced hepatotoxicity and defined the underlying mechanisms. METHODS:A murine model of FOLFOX-induced SOS examined the effect of SAMe and plasminogen-activating inhibitor-1 (PAI-1). In vitro studies included primary mouse and human hepatocytes, Kupffer cells, hepatic stellate cells, and liver sinusoidal endothelial cells. RESULTS:SAMe cotreatment completely blocked the induction of markers increased in FOLFOX-induced SOS and protected against liver injury. The most up-regulated gene was Serpine1, which encodes for PAI-1. SAMe blocked FOLFOX-induced expression and activation of nuclear factor (NF)-κB, which is known to activate SERPINE1/Serpine1 promoters. Interestingly, FOLFOX failed to activate hepatic NF-κB or cause liver injury in Serpine1 knockout male mice. Treatment of mouse hepatocytes with recombinant PAI-1 induced NF-κB activation; conditioned media from recombinant PAI-1 or interleukin-1β-treated hepatocytes, but not exosomes, increased the expression of proinflammatory cytokines and Cd31 in Kupffer cells and liver sinusoidal endothelial cells, respectively, which were blocked by SAMe. FOLFOX and interleukin-1β induced interaction between PAI-1 with urokinase plasminogen activator receptor in mouse liver and hepatocytes, respectively, which was blocked by SAMe. Recombinant PAI-1 requires interaction with uPA for full activation of NF-κB in hepatocytes. Neutralizing antibody against PAI-1 blocked interleukin-1β-mediated p65/PAI-1 activation in hepatocytes. CONCLUSIONS:FOLFOX treatment increased hepatocyte PAI-1 expression and liver injury, which were not observed in germline PAI-1 deficiency. Hepatocytes secrete PAI-1 to exert autocrine and paracrine effects to activate Kupffer cells and liver sinusoidal endothelial cells. SAMe protects against FOLFOX-mediated liver injury in part by inhibiting NF-κB activation and PAI-1 induction.

Steatotic liver enhances liver metastasis of colorectal cancer (CRC), but this process is not fully understood. Steatotic liver induced by a high-fat diet increases cancer-associated fibroblast (CAF) infiltration and collagen and hyaluronic acid (HA) production. We investigated the role of HA synthase 2 (HAS2) in the fibrotic tumor microenvironment in steatotic liver using Has2 Delta HSC mice, in which Has2 is deleted from hepatic stellate cells. Has2 Delta HSC mice had reduced steatotic liver-associated metastatic tumor growth of MC38 CRC cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found that low-molecular weight HA activates Yes-associated protein (YAP) in cancer cells, which then releases connective tissue growth factor to further activate CAFs for HAS2 expression. Single-cell analyses revealed a link between CAF-derived HAS2 and M2 macrophages and CRC cells through CD44; these cells were associated with exhausted CD8+ T cells via programmed death-ligand 1 and programmed cell death protein 1 (PD-1). HA synthesis inhibitors reduced steatotic liver-associated metastasis of CRC, YAP expression, and CAF and M2 macrophage infiltration, and improved response to anti-PD-1 antibody. In conclusion, steatotic liver modulates a fibrotic tumor microenvironment to enhance metastatic cancer activity through a bidirectional regulation between CAFs and metastatic tumors, enhancing the metastatic potential of CRC in the liver.

Background & Aims The liver is a common site of cancer metastasis, most commonly from colorectal cancer, and primary liver cancers that have metastasized are associated with poor outcomes. The underlying mechanisms by which the liver defends against these processes are largely unknown. Prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) are highly expressed in the liver. They positively regulate each other and their deletion results in primary liver cancer. Here we investigated their roles in primary and secondary liver cancer metastasis. Methods We identified common target genes of PHB1 and MAT1A using a metastasis array, and measured promoter activity and transcription factor binding using luciferase reporter assays and chromatin immunoprecipitation, respectively. We examined how PHB1 or MAT1A loss promotes liver cancer metastasis and whether their loss sensitizes to colorectal liver metastasis (CRLM). Results Matrix metalloproteinase-7 (MMP-7) is a common target of MAT1A and PHB1 and its induction is responsible for increased migration and invasion when MAT1A or PHB1 is silenced. Mechanistically, PHB1 and MAT1A negatively regulate MMP7 promoter activity via an AP-1 site by repressing the MAFG-FOSB complex. Loss of MAT1A or PHB1 also increased MMP-7 in extracellular vesicles, which were internalized by colon and pancreatic cancer cells to enhance their oncogenicity. Low hepatic MAT1A or PHB1 expression sensitized to CRLM, but not if endogenous hepatic MMP-7 was knocked down first, which lowered CD4+ T cells while increasing CD8+ T cells in the tumor microenvironment. Hepatocytes co-cultured with colorectal cancer cells express less MAT1A/PHB1 but more MMP-7. Consistently, CRLM raised distant hepatocytes' MMP-7 expression in mice and humans. Conclusion We have identified a PHB1/MAT1A-MAFG/FOSB-MMP-7 axis that controls primary liver cancer metastasis and sensitization to CRLM. Impact and implications Primary and secondary liver cancer metastasis is associated with poor outcomes but whether the liver has underlying defense mechanism(s) against metastasis is unknown. Here we examined the hypothesis that hepatic prohibitin 1 (PHB1) and methionine adenosyltransferase 1A (MAT1A) cooperate to defend the liver against metastasis. Our studies found PHB1 and MAT1A form a complex that suppresses matrix metalloproteinase-7 (MMP-7) at the transcriptional level and loss of either PHB1 or MAT1A sensitizes the liver to metastasis via MMP-7 induction. Strategies that target the PHB1/MAT1A-MMP-7 axis may be a promising approach for the treatment of primary and secondary liver cancer metastasis.

Abstract Background Metabolic syndrome (MetS) is a cluster of medical conditions and risk factors correlating with insulin resistance that increase the risk of developing cardiometabolic health problems. The specific criteria for diagnosing MetS vary among different medical organizations but are typically based on the evaluation of abdominal obesity, high blood pressure, hyperglycemia, and dyslipidemia. A unique, quantitative and independent estimation of the risk of MetS based only on quantitative biomarkers is highly desirable for the comparison between patients and to study the individual progression of the disease in a quantitative manner. Methods We used NMR-based metabolomics on a large cohort of donors (n = 21,323; 37.5% female) to investigate the diagnostic value of serum or serum combined with urine to estimate the MetS risk. Specifically, we have determined 41 circulating metabolites and 112 lipoprotein classes and subclasses in serum samples and this information has been integrated with metabolic profiles extracted from urine samples. Results We have developed MetSCORE, a metabolic model of MetS that combines serum lipoprotein and metabolite information. MetSCORE discriminate patients with MetS (independently identified using the WHO criterium) from general population, with an AUROC of 0.94 (95% CI 0.920–0.952, p < 0.001). MetSCORE is also able to discriminate the intermediate phenotypes, identifying the early risk of MetS in a quantitative way and ranking individuals according to their risk of undergoing MetS (for general population) or according to the severity of the syndrome (for MetS patients). Conclusions We believe that MetSCORE may be an insightful tool for early intervention and lifestyle modifications, potentially preventing the aggravation of metabolic syndrome.