This article addresses the current understanding of the bidirectional relationship between iron metabolism and the gut microbiota. Both iron deficiency and iron overload in the gut can negatively affect the composition and function of the intestinal microbiota. Conversely, beneficial members of the colonic microbiota play a key role in enhancing systemic iron absorption. Particular attention is given to the potential use of microbiota-modulating agents for the correction of colonic dysbiosis as part of a comprehensive therapeutic approach to iron deficiency/overload conditions. Therefore, these interventions, by supporting microbiota restoration and reduction of intestinal inflammation, may also offer novel therapeutic avenues for disorders of iron metabolism.
This article addresses the current understanding of the bidirectional relationship between iron metabolism and the gut microbiota. Both iron deficiency and iron overload in the gut can negatively affect the composition and function of the intestinal microbiota. Conversely, beneficial members of the colonic microbiota play a key role in enhancing systemic iron absorption. Particular attention is given to the potential use of microbiota-modulating agents for the correction of colonic dysbiosis as part of a comprehensive therapeutic approach to iron deficiency/overload conditions. Therefore, these interventions, by supporting microbiota restoration and reduction of intestinal inflammation, may also offer novel therapeutic avenues for disorders of iron metabolism.
DOI: https://doi.org/10.37349/edd.2025.100585
This article belongs to the special issue Gut Microbiota towards Personalized Medicine in Metabolic Disease
Celiac disease is an immune-mediated disorder with significant metabolic implications. Several factors have been proposed to explain the association between celiac disease in patients following a gluten-free diet and metabolic disorders, including metabolic syndrome. Growing evidence suggests a pivotal role of gut microbiome dysbiosis in the onset of celiac disease and its associated metabolic disturbances. The present narrative review examines (i) the connections between celiac disease and metabolism-related comorbidities, including metabolic syndrome and metabolic dysfunction-associated steatotic liver disease; (ii) the role of the gut microbiome in celiac disease, including the outcomes of gut microbiome dysbiosis in celiac children and adults; and (iii) the potential of microbial therapeutic strategies within the context of personalized medicine for patients with celiac disease and comorbid metabolic conditions. A synthesis of existing studies highlights several protective factors and interventions for future celiac disease prevention research. Adopting plant-based, health-promoting dietary patterns such as the Mediterranean or vegetarian diet within the first two years of life reduces celiac disease risk. These fiber- and phytochemical-rich diets support beneficial gut microbiota growth and short-chain fatty acid production, which maintain intestinal barrier integrity by enhancing mucus and tight junction proteins. Short-chain fatty acids also modulate immunity by inducing Tregs that secrete IL-10, suppressing pro-inflammatory Th1 responses and autoantibody production. Precision probiotics offer diverse therapeutic benefits in celiac disease by reducing inflammation, restoring beneficial microbes, and degrading immunogenic gliadin peptides. Postbiotics complement these effects by reinforcing barrier integrity and counteracting gliadin-induced inflammation. Thus, integrating clinical models with microbial biomarkers promises to improve celiac disease diagnosis and monitoring, enabling better risk stratification, earlier detection, and personalized management of this heterogeneous disease.
Celiac disease is an immune-mediated disorder with significant metabolic implications. Several factors have been proposed to explain the association between celiac disease in patients following a gluten-free diet and metabolic disorders, including metabolic syndrome. Growing evidence suggests a pivotal role of gut microbiome dysbiosis in the onset of celiac disease and its associated metabolic disturbances. The present narrative review examines (i) the connections between celiac disease and metabolism-related comorbidities, including metabolic syndrome and metabolic dysfunction-associated steatotic liver disease; (ii) the role of the gut microbiome in celiac disease, including the outcomes of gut microbiome dysbiosis in celiac children and adults; and (iii) the potential of microbial therapeutic strategies within the context of personalized medicine for patients with celiac disease and comorbid metabolic conditions. A synthesis of existing studies highlights several protective factors and interventions for future celiac disease prevention research. Adopting plant-based, health-promoting dietary patterns such as the Mediterranean or vegetarian diet within the first two years of life reduces celiac disease risk. These fiber- and phytochemical-rich diets support beneficial gut microbiota growth and short-chain fatty acid production, which maintain intestinal barrier integrity by enhancing mucus and tight junction proteins. Short-chain fatty acids also modulate immunity by inducing Tregs that secrete IL-10, suppressing pro-inflammatory Th1 responses and autoantibody production. Precision probiotics offer diverse therapeutic benefits in celiac disease by reducing inflammation, restoring beneficial microbes, and degrading immunogenic gliadin peptides. Postbiotics complement these effects by reinforcing barrier integrity and counteracting gliadin-induced inflammation. Thus, integrating clinical models with microbial biomarkers promises to improve celiac disease diagnosis and monitoring, enabling better risk stratification, earlier detection, and personalized management of this heterogeneous disease.
DOI: https://doi.org/10.37349/edd.2025.100584
This article belongs to the special issue Gut Microbiota towards Personalized Medicine in Metabolic Disease
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide. Its prevalence is increasing due to its close relationship with obesity, insulin resistance, and other metabolic disorders. In this context, the gut-liver axis has been identified as a fundamental regulator in the progression of MASLD, integrating metabolic, immunological, and inflammatory signals that influence hepatic homeostasis. This article reviews the interconnection between the intestine and the liver in the onset and progression of MASLD, highlighting the roles of cholesterol and its metabolism, intestinal barrier permeability, microbiota, and hepatic signaling pathways. We analyze how intestinal dysbiosis and alterations in the enterohepatic circulation of bile acids affect cholesterol absorption and metabolism. Furthermore, we address the influence of endotoxin translocation, activation of the innate immune system, and the interaction of key transcription factors on disease progression from steatosis to advanced fibrosis and hepatocellular carcinoma (HCC). Finally, therapeutic strategies, including pharmacological, dietary, and immunomodulation-based approaches, are discussed to regulate cholesterol metabolism, modulate the intestinal microbiota, and restore gut-liver axis homeostasis. Integrating this knowledge could open new perspectives for treating and preventing MASLD, addressing the disease from a broader and multidisciplinary viewpoint.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease worldwide. Its prevalence is increasing due to its close relationship with obesity, insulin resistance, and other metabolic disorders. In this context, the gut-liver axis has been identified as a fundamental regulator in the progression of MASLD, integrating metabolic, immunological, and inflammatory signals that influence hepatic homeostasis. This article reviews the interconnection between the intestine and the liver in the onset and progression of MASLD, highlighting the roles of cholesterol and its metabolism, intestinal barrier permeability, microbiota, and hepatic signaling pathways. We analyze how intestinal dysbiosis and alterations in the enterohepatic circulation of bile acids affect cholesterol absorption and metabolism. Furthermore, we address the influence of endotoxin translocation, activation of the innate immune system, and the interaction of key transcription factors on disease progression from steatosis to advanced fibrosis and hepatocellular carcinoma (HCC). Finally, therapeutic strategies, including pharmacological, dietary, and immunomodulation-based approaches, are discussed to regulate cholesterol metabolism, modulate the intestinal microbiota, and restore gut-liver axis homeostasis. Integrating this knowledge could open new perspectives for treating and preventing MASLD, addressing the disease from a broader and multidisciplinary viewpoint.
DOI: https://doi.org/10.37349/edd.2025.100583
This article belongs to the special issue The Role of Gut Microbiota in the Pathogenesis and Management of Metabolic-Associated Steatotic Liver Disease (MASLD)
Minimal hepatic encephalopathy (MHE) is often the least recognized form of hepatic encephalopathy, affecting up to 80% of people living with liver cirrhosis. While the signs can be quite subtle, MHE can seriously disrupt cognitive functions such as attention and memory. This disruption can impact daily life, potentially leading to an increased risk of accidents. Unfortunately, many health care providers might overlook the diagnosis because the symptoms can be vague, and identifying MHE usually requires specific tests like the psychometric hepatic encephalopathy score (PHES). Several factors contribute to MHE, including elevated ammonia levels, systemic inflammation, and issues with the gut-brain connection. It’s crucial to identify and treat MHE quickly, as it can progress to overt hepatic encephalopathy (OHE), which presents much more severe symptoms and is associated with higher mortality rates. Current treatment approaches often include medications like lactulose and rifaximin, along with cognitive rehabilitation and dietary changes. Emerging treatments that focus on gut health, such as probiotics, are showing potential in helping to lower ammonia levels. This review brings together the latest research on MHE, pointing out significant gaps in how we diagnose it and the potential of new therapies like synbiotics. By looking at recent multicenter studies, we aim to offer practical insights that could help prevent the progression to OHE, ultimately improving patient outcomes.
Minimal hepatic encephalopathy (MHE) is often the least recognized form of hepatic encephalopathy, affecting up to 80% of people living with liver cirrhosis. While the signs can be quite subtle, MHE can seriously disrupt cognitive functions such as attention and memory. This disruption can impact daily life, potentially leading to an increased risk of accidents. Unfortunately, many health care providers might overlook the diagnosis because the symptoms can be vague, and identifying MHE usually requires specific tests like the psychometric hepatic encephalopathy score (PHES). Several factors contribute to MHE, including elevated ammonia levels, systemic inflammation, and issues with the gut-brain connection. It’s crucial to identify and treat MHE quickly, as it can progress to overt hepatic encephalopathy (OHE), which presents much more severe symptoms and is associated with higher mortality rates. Current treatment approaches often include medications like lactulose and rifaximin, along with cognitive rehabilitation and dietary changes. Emerging treatments that focus on gut health, such as probiotics, are showing potential in helping to lower ammonia levels. This review brings together the latest research on MHE, pointing out significant gaps in how we diagnose it and the potential of new therapies like synbiotics. By looking at recent multicenter studies, we aim to offer practical insights that could help prevent the progression to OHE, ultimately improving patient outcomes.
DOI: https://doi.org/10.37349/edd.2025.100582
Aim:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread chronic liver condition associated with liver inflammation, fibrosis, and various metabolic disorders. Although cholic acid (CA), a primary bile acid (BA), is known to reduce steatosis when added to a high-fat diet, it may exacerbate hepatocellular injury by promoting oxidative stress and inflammation. Therefore, regulating BA-induced liver toxicity is crucial. Dimethyl fumarate (DMF) is an FDA-approved drug known to activate the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor that induces cytoprotective genes involved in cellular stress. The present study aimed to investigate whether DMF supplementation could attenuate CA-induced liver injury in high-fat diet-fed mice.
Methods:
To induce liver injury, high-fat diet with and without CA were compared for liver damage and liver fat gain. Following the establishment of the toxic but antisteatotic effect of CA, C57BL/6j mice were fed a high-fat diet supplemented with 0.5% CA (HFDCA) with or without DMF (0.3 mg/mL or 0.6 mg/mL), which was administered via drinking water for 7 weeks.
Results:
CA was found to be an accelerator of high-fat diet to induce liver damage, but prevented liver fat accumulation. HFDCA mice showed signs of liver damage, including elevated liver enzymes and liver enlargement. However, DMF treatment activated the Nrf2 pathway and partially mitigated the hepatotoxic effect of CA/high-fat diet, although some doses exhibited pro-oxidant effects.
Conclusions:
The findings suggest that DMF, as an activator of Nrf2, has potential as a therapeutic agent for liver diseases related to high-fat diets and BA-induced injury, though careful dosage management is crucial to maximize its benefits and mitigate BA toxicity.
Aim:
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a widespread chronic liver condition associated with liver inflammation, fibrosis, and various metabolic disorders. Although cholic acid (CA), a primary bile acid (BA), is known to reduce steatosis when added to a high-fat diet, it may exacerbate hepatocellular injury by promoting oxidative stress and inflammation. Therefore, regulating BA-induced liver toxicity is crucial. Dimethyl fumarate (DMF) is an FDA-approved drug known to activate the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), a transcription factor that induces cytoprotective genes involved in cellular stress. The present study aimed to investigate whether DMF supplementation could attenuate CA-induced liver injury in high-fat diet-fed mice.
Methods:
To induce liver injury, high-fat diet with and without CA were compared for liver damage and liver fat gain. Following the establishment of the toxic but antisteatotic effect of CA, C57BL/6j mice were fed a high-fat diet supplemented with 0.5% CA (HFDCA) with or without DMF (0.3 mg/mL or 0.6 mg/mL), which was administered via drinking water for 7 weeks.
Results:
CA was found to be an accelerator of high-fat diet to induce liver damage, but prevented liver fat accumulation. HFDCA mice showed signs of liver damage, including elevated liver enzymes and liver enlargement. However, DMF treatment activated the Nrf2 pathway and partially mitigated the hepatotoxic effect of CA/high-fat diet, although some doses exhibited pro-oxidant effects.
Conclusions:
The findings suggest that DMF, as an activator of Nrf2, has potential as a therapeutic agent for liver diseases related to high-fat diets and BA-induced injury, though careful dosage management is crucial to maximize its benefits and mitigate BA toxicity.
DOI: https://doi.org/10.37349/edd.2025.100581
This article belongs to the special issue Gastrointestinal Diseases, Cholesterol, Oxysterols, and Bile Acids
The liver operates as a highly coordinated microsystem, where various liver cell types engage in dynamic interactions to maintain homeostasis. This intercellular cooperation resembles sociological models of sustainable cooperation, encompassing mechanisms such as resource sharing, communication networks, and conflict resolution. However, both in biology and sociology, cooperation can break down due to external pressures and self-serving behaviors. In metabolic dysfunction-associated steatotic liver disease (MASLD), chronic metabolic stress disrupts this equilibrium, leading to endothelial dysfunction, immune overactivation, and fibrosis—akin to sociological models of systemic collapse. A common model in sociology, Hardin’s Tragedy of the Commons, describes how individuals overexploit shared resources when acting in self-interest, ultimately leading to resource depletion. Similarly, under metabolic stress, hepatic cells prioritize short-term survival by increasing lipid storage, inflammatory signaling, and extracellular matrix (ECM) production. This self-serving response, much like free-riding in societal systems, exacerbates dysfunction, reinforcing a cycle of fibrosis and organ failure. Moreover, the failure in MASLD extends beyond the liver itself. The liver’s cooperative role is integral to its participation in inter-organ axes, including those with the cardiovascular, gut, brain, and kidney systems. While the analogy has limitations—cells do not possess intent as humans do—the fundamental principle of cooperation breakdown leading to systemic instability holds across disciplines. An interdisciplinary approach integrating biological and sociological insights offers novel perspectives for therapeutic innovation. Sociological frameworks provide concepts such as incentive structures and collective action, which can be applied to cellular behavior. By restoring cooperative cellular networks, therapies like extracellular vesicle (EV) treatment, ECM remodeling, and receptor (ant)agonists mimic interventions in social systems that rebuild trust and sustainability. This review explores how biological and sociological models of cooperation breakdown align and how regenerative medicine can leverage these insights to develop strategies that restore cellular equilibrium and halt disease progression.
The liver operates as a highly coordinated microsystem, where various liver cell types engage in dynamic interactions to maintain homeostasis. This intercellular cooperation resembles sociological models of sustainable cooperation, encompassing mechanisms such as resource sharing, communication networks, and conflict resolution. However, both in biology and sociology, cooperation can break down due to external pressures and self-serving behaviors. In metabolic dysfunction-associated steatotic liver disease (MASLD), chronic metabolic stress disrupts this equilibrium, leading to endothelial dysfunction, immune overactivation, and fibrosis—akin to sociological models of systemic collapse. A common model in sociology, Hardin’s Tragedy of the Commons, describes how individuals overexploit shared resources when acting in self-interest, ultimately leading to resource depletion. Similarly, under metabolic stress, hepatic cells prioritize short-term survival by increasing lipid storage, inflammatory signaling, and extracellular matrix (ECM) production. This self-serving response, much like free-riding in societal systems, exacerbates dysfunction, reinforcing a cycle of fibrosis and organ failure. Moreover, the failure in MASLD extends beyond the liver itself. The liver’s cooperative role is integral to its participation in inter-organ axes, including those with the cardiovascular, gut, brain, and kidney systems. While the analogy has limitations—cells do not possess intent as humans do—the fundamental principle of cooperation breakdown leading to systemic instability holds across disciplines. An interdisciplinary approach integrating biological and sociological insights offers novel perspectives for therapeutic innovation. Sociological frameworks provide concepts such as incentive structures and collective action, which can be applied to cellular behavior. By restoring cooperative cellular networks, therapies like extracellular vesicle (EV) treatment, ECM remodeling, and receptor (ant)agonists mimic interventions in social systems that rebuild trust and sustainability. This review explores how biological and sociological models of cooperation breakdown align and how regenerative medicine can leverage these insights to develop strategies that restore cellular equilibrium and halt disease progression.
DOI: https://doi.org/10.37349/edd.2025.100580
As the most prevalent hepatic disorder worldwide, metabolic dysfunction-associated steatotic liver disease (MASLD) afflicts over one-third of the global population, representing a significant public health challenge. The multifactorial pathogenesis of this condition is principally rooted in metabolic dysregulation. It is notable that emerging evidence highlights a critical role for gut microbiota (GM) in disease initiation and progression. This comprehensive review elaborates some representative GM species that influence hepatic lipid metabolism and elucidates the mechanisms through which GM dysbiosis exacerbates MASLD pathogenesis. Importantly, the positive or negative effects of intestinal bacterial communities on MASLD are largely dependent on their special metabolites, such as short chain fatty acids, ethanol, and trimethylamine N-oxide. Current therapeutic strategies targeting GM modulation, including prebiotics, probiotics, fecal microbiota transplantation, specific medicines, and bacteriphages, demonstrate promising efficacy that partially restores microbial equilibrium and mitigates hepatic steatosis. Although limitations still persist in achieving sustained clinical remission, the expanding frontier of microbiome research continues to refine our understanding of host-microbiota crosstalk in MASLD. Future investigations integrating multiple approaches and longitudinal clinical data hold potential to unravel complex microbial networks, paving the way for innovative therapeutic breakthroughs in metabolic liver disease management.
As the most prevalent hepatic disorder worldwide, metabolic dysfunction-associated steatotic liver disease (MASLD) afflicts over one-third of the global population, representing a significant public health challenge. The multifactorial pathogenesis of this condition is principally rooted in metabolic dysregulation. It is notable that emerging evidence highlights a critical role for gut microbiota (GM) in disease initiation and progression. This comprehensive review elaborates some representative GM species that influence hepatic lipid metabolism and elucidates the mechanisms through which GM dysbiosis exacerbates MASLD pathogenesis. Importantly, the positive or negative effects of intestinal bacterial communities on MASLD are largely dependent on their special metabolites, such as short chain fatty acids, ethanol, and trimethylamine N-oxide. Current therapeutic strategies targeting GM modulation, including prebiotics, probiotics, fecal microbiota transplantation, specific medicines, and bacteriphages, demonstrate promising efficacy that partially restores microbial equilibrium and mitigates hepatic steatosis. Although limitations still persist in achieving sustained clinical remission, the expanding frontier of microbiome research continues to refine our understanding of host-microbiota crosstalk in MASLD. Future investigations integrating multiple approaches and longitudinal clinical data hold potential to unravel complex microbial networks, paving the way for innovative therapeutic breakthroughs in metabolic liver disease management.
DOI: https://doi.org/10.37349/edd.2025.100579
This article belongs to the special issue The Role of Gut Microbiota in the Pathogenesis and Management of Metabolic-Associated Steatotic Liver Disease (MASLD)
The changing management paradigm of acute complicated diverticulitis and the elective indications for surgery have evolved in the last decade based on reported evidence-based data. Recently, it has been demonstrated that randomized controlled trials (RCTs), the highest trial format in the hierarchy of evidence-based reporting, suffer from a ‘crisis of replicability’. The development of a fragility index (FI) quantitatively defines the robustness of an RCT by shifting the number of participants in a trial into a different binary group in an effort to influence reported statistical significance (the lower the FI the greater the study fragility). The only available report on FI in diverticular management showed that in an eclectic range of RCT’s comparing intervention and non-intervention, two-thirds of the studies had an FI ≤ 1 where statistical recalculation using Fisher’s Exact test rendered one-quarter of previously positive studies non-significant. Comparisons between studies and units are still dependent upon sample sizes and the numbers lost to follow-up even when some of the FI progeny (including a reverse FI, a fragility quotient dividing the FI by the sample size, or other incidence or generalized FI metrics) are utilized in assessment. Future analyses need to define all comparisons rather than cherry-picking examples where a p value approaches significance. Despite the fact that no FI value defines the strength of a RCT, its use attempts to link the reported p value with the sample size and the statistical power of the study. Positive findings in diverticular trials are then considered not so much definitive as rather provocateurs encouraging further similarly designed studies in different environments. Minimizing patient loss in treatment arms and reporting the reasons for drop-out, strictly adhering to randomization, consistent blinding, and group allocation concealment can all improve the logistical running of an RCT initially designed to evaluate some potentially important new treatment.
The changing management paradigm of acute complicated diverticulitis and the elective indications for surgery have evolved in the last decade based on reported evidence-based data. Recently, it has been demonstrated that randomized controlled trials (RCTs), the highest trial format in the hierarchy of evidence-based reporting, suffer from a ‘crisis of replicability’. The development of a fragility index (FI) quantitatively defines the robustness of an RCT by shifting the number of participants in a trial into a different binary group in an effort to influence reported statistical significance (the lower the FI the greater the study fragility). The only available report on FI in diverticular management showed that in an eclectic range of RCT’s comparing intervention and non-intervention, two-thirds of the studies had an FI ≤ 1 where statistical recalculation using Fisher’s Exact test rendered one-quarter of previously positive studies non-significant. Comparisons between studies and units are still dependent upon sample sizes and the numbers lost to follow-up even when some of the FI progeny (including a reverse FI, a fragility quotient dividing the FI by the sample size, or other incidence or generalized FI metrics) are utilized in assessment. Future analyses need to define all comparisons rather than cherry-picking examples where a p value approaches significance. Despite the fact that no FI value defines the strength of a RCT, its use attempts to link the reported p value with the sample size and the statistical power of the study. Positive findings in diverticular trials are then considered not so much definitive as rather provocateurs encouraging further similarly designed studies in different environments. Minimizing patient loss in treatment arms and reporting the reasons for drop-out, strictly adhering to randomization, consistent blinding, and group allocation concealment can all improve the logistical running of an RCT initially designed to evaluate some potentially important new treatment.
DOI: https://doi.org/10.37349/edd.2025.100578
This article belongs to the special issue Diverticulitis: Pathomechanism, Diagnosis and Treatment
Yu JW et al. (World J Gastroenterol. 2025;31:105188. DOI: 10.3748/wjg.v31.i16.105188) used male Sprague-Dawley rats fed a high-fat diet for 8 weeks to recapitulate metabolic dysfunction-associated steatotic liver disease (MASLD) experimentally. MASLD rats were randomized to receive either the duodenal mucosal ablation (DMA) using irreversible electroporation (IRE) during laparotomy or sham DMA. Data have shown that DMA was associated with duodenal thickening compared to the control group, crypts were narrower and shallower crypts and villi slimmer than sham DMA group. Moreover, the DMA group exhibited improved liver histology compared to the sham group though accompanied by inconsistent variations in blood lipid values and statistically non-significant variations in surrogate indices of MASLD. Thirdly, DMA rats had lower serum concentrations of gut hormones with crucial metabolic functions, lower lipopolysaccharide serum level, increased duodenal expression and immunofluorescence staining intensity of gut hormones expression, and higher expression of zonula occludens-1 and claudin than sham-rats. The study by Yu, et al. has innovative findings and is properly designed to illustrate the pathomechanisms underlying improved MASLD histology after DMA with IRE. However, this paper also has some methodological limitations that prompt additional studies in animal models and, ideally, in humans to be conducted as soon as safety and feasibility are demonstrated.
Yu JW et al. (World J Gastroenterol. 2025;31:105188. DOI: 10.3748/wjg.v31.i16.105188) used male Sprague-Dawley rats fed a high-fat diet for 8 weeks to recapitulate metabolic dysfunction-associated steatotic liver disease (MASLD) experimentally. MASLD rats were randomized to receive either the duodenal mucosal ablation (DMA) using irreversible electroporation (IRE) during laparotomy or sham DMA. Data have shown that DMA was associated with duodenal thickening compared to the control group, crypts were narrower and shallower crypts and villi slimmer than sham DMA group. Moreover, the DMA group exhibited improved liver histology compared to the sham group though accompanied by inconsistent variations in blood lipid values and statistically non-significant variations in surrogate indices of MASLD. Thirdly, DMA rats had lower serum concentrations of gut hormones with crucial metabolic functions, lower lipopolysaccharide serum level, increased duodenal expression and immunofluorescence staining intensity of gut hormones expression, and higher expression of zonula occludens-1 and claudin than sham-rats. The study by Yu, et al. has innovative findings and is properly designed to illustrate the pathomechanisms underlying improved MASLD histology after DMA with IRE. However, this paper also has some methodological limitations that prompt additional studies in animal models and, ideally, in humans to be conducted as soon as safety and feasibility are demonstrated.
DOI: https://doi.org/10.37349/edd.2025.100577
Background:
Esophageal varices (EV) and gastric varices (GV) are the most common portal hypertension complications in liver cirrhosis patients. Esophagogastroduodenoscopy (EGD) is the main standard procedure for variceal screening and treatment. Nonetheless, luminal evaluation sometimes cannot accurately evaluate the size of varices. Recently, endoscopic ultrasound (EUS) has been studied for EV and GV evaluation.
Methods:
Literature search was performed from PubMed, Scopus, and Cochrane Library databases until December 2022. Two independent reviewers (C.R.A.L. and T.P.) independently obtained and evaluated the selected studies according to pre-determined eligibility criteria.
Results:
Ten studies (four observational studies, three randomized controlled trials, and three retrospective reviews of case series) describing 593 patients met our eligibility criteria. Eight out of ten studies evaluated utilization of EUS for coil embolization and/or cyanoacrylate injection. All studies demonstrated excellent technical success rate of the procedure with good therapeutic efficacy, in terms of lowering the risk of recurrent bleeding. Significantly better findings were observed from groups treated with combination of coil and cyanoacrylate glue injection in comparison to monotherapy. One study also highlighted the higher possibility of developing pulmonary embolism in groups treated with conventional cyanoacrylate injection.
Discussion:
EUS-guided combination therapy appears to be a safe and effective modality for treating patients with gastric variceal bleeding with high number of complete obliteration and low risk of gastric variceal rebleeding. Further meta-analysis large-scale randomized clinical trials are still required to confirm these findings.
Background:
Esophageal varices (EV) and gastric varices (GV) are the most common portal hypertension complications in liver cirrhosis patients. Esophagogastroduodenoscopy (EGD) is the main standard procedure for variceal screening and treatment. Nonetheless, luminal evaluation sometimes cannot accurately evaluate the size of varices. Recently, endoscopic ultrasound (EUS) has been studied for EV and GV evaluation.
Methods:
Literature search was performed from PubMed, Scopus, and Cochrane Library databases until December 2022. Two independent reviewers (C.R.A.L. and T.P.) independently obtained and evaluated the selected studies according to pre-determined eligibility criteria.
Results:
Ten studies (four observational studies, three randomized controlled trials, and three retrospective reviews of case series) describing 593 patients met our eligibility criteria. Eight out of ten studies evaluated utilization of EUS for coil embolization and/or cyanoacrylate injection. All studies demonstrated excellent technical success rate of the procedure with good therapeutic efficacy, in terms of lowering the risk of recurrent bleeding. Significantly better findings were observed from groups treated with combination of coil and cyanoacrylate glue injection in comparison to monotherapy. One study also highlighted the higher possibility of developing pulmonary embolism in groups treated with conventional cyanoacrylate injection.
Discussion:
EUS-guided combination therapy appears to be a safe and effective modality for treating patients with gastric variceal bleeding with high number of complete obliteration and low risk of gastric variceal rebleeding. Further meta-analysis large-scale randomized clinical trials are still required to confirm these findings.
DOI: https://doi.org/10.37349/edd.2025.100576
Metabolic associated steatotic liver disease (MASLD) stands as the most common hepatic disorder in both developed and developing countries. The global increasing rates in obesity rates are fuelling an increase in MASLD cases. Fibroscan, a transient elastography device, is a research-based, noninvasive method for assessing liver fibrosis. Accurately measuring the extent of fibrosis presents difficulties in a cohort of individuals who are severely obese with a body mass index (BMI) ≥ 40 kg/m2, particularly regarding the reliability and applicability of the XL probe. This study’s objective is to evaluate the precision of fibroscan in morbidly obese individuals with a BMI ≥ 40 kg/m2. We explored Google, PubMed, and Medline to gather information on fibroscan and its application for measuring fibrosis levels in morbidly obese patients ≥ 40 kg/m2 who have MASLD. The fibrosis levels obtained from the fibroscan do not consistently correlate with the clinical or histopathological data, which are essential for accurately determining liver stiffness measurement (LSM) cutoff values and/or ranges for these patients with either significant or advanced fibrosis. Additional prospective multicenter studies are necessary to better establish LSM cutoff values and/or ranges for patients suffering from significant or advanced fibrosis due to morbid obesity.
Metabolic associated steatotic liver disease (MASLD) stands as the most common hepatic disorder in both developed and developing countries. The global increasing rates in obesity rates are fuelling an increase in MASLD cases. Fibroscan, a transient elastography device, is a research-based, noninvasive method for assessing liver fibrosis. Accurately measuring the extent of fibrosis presents difficulties in a cohort of individuals who are severely obese with a body mass index (BMI) ≥ 40 kg/m2, particularly regarding the reliability and applicability of the XL probe. This study’s objective is to evaluate the precision of fibroscan in morbidly obese individuals with a BMI ≥ 40 kg/m2. We explored Google, PubMed, and Medline to gather information on fibroscan and its application for measuring fibrosis levels in morbidly obese patients ≥ 40 kg/m2 who have MASLD. The fibrosis levels obtained from the fibroscan do not consistently correlate with the clinical or histopathological data, which are essential for accurately determining liver stiffness measurement (LSM) cutoff values and/or ranges for these patients with either significant or advanced fibrosis. Additional prospective multicenter studies are necessary to better establish LSM cutoff values and/or ranges for patients suffering from significant or advanced fibrosis due to morbid obesity.
DOI: https://doi.org/10.37349/edd.2025.100575
Aim:
Our previous study provided evidence that systemic zonula occludens (ZO) 1 levels are elevated in cirrhotic and hepatocellular carcinoma (HCC) patients. Here, we aimed to evaluate serum ZO-1 levels in patients with decompensated alcoholic cirrhosis (DCAC) with hepatorenal syndrome (HRS) and compare its diagnostic potential with the well-established HRS biomarker, cystatin C.
Methods:
A total of 36 DCAC patients with HRS and 40 healthy volunteers were recruited. Serum ZO-1, cystatin C, and clinical chemistry parameters were analysed.
Results:
Compared to control subjects, DCAC patients with HRS exhibited significantly higher ZO-1 levels (7.059 ± 0.29 vs. 0.788 ± 0.11; p < 0.0001) and cystatin C levels (2.97 ± 0.24 vs. 1.59 ± 0.04; p < 0.0001). Serum ZO-1 correlated positively with cystatin C (r = 0.561, p < 0.0001), serum creatinine (r = 0.779, p < 0.0001), and MELD-Na (r = 0.850, p < 0.0001). Moreover, ZO-1 demonstrated a higher area under the curve (AUC) than cystatin C, indicating a better diagnostic potential for HRS in DCAC patients.
Conclusions:
These findings suggest that ZO-1 may serve as a valuable biomarker for HRS in DCAC patients. However, further validation in a larger cohort is necessary to confirm its clinical utility.
Aim:
Our previous study provided evidence that systemic zonula occludens (ZO) 1 levels are elevated in cirrhotic and hepatocellular carcinoma (HCC) patients. Here, we aimed to evaluate serum ZO-1 levels in patients with decompensated alcoholic cirrhosis (DCAC) with hepatorenal syndrome (HRS) and compare its diagnostic potential with the well-established HRS biomarker, cystatin C.
Methods:
A total of 36 DCAC patients with HRS and 40 healthy volunteers were recruited. Serum ZO-1, cystatin C, and clinical chemistry parameters were analysed.
Results:
Compared to control subjects, DCAC patients with HRS exhibited significantly higher ZO-1 levels (7.059 ± 0.29 vs. 0.788 ± 0.11; p < 0.0001) and cystatin C levels (2.97 ± 0.24 vs. 1.59 ± 0.04; p < 0.0001). Serum ZO-1 correlated positively with cystatin C (r = 0.561, p < 0.0001), serum creatinine (r = 0.779, p < 0.0001), and MELD-Na (r = 0.850, p < 0.0001). Moreover, ZO-1 demonstrated a higher area under the curve (AUC) than cystatin C, indicating a better diagnostic potential for HRS in DCAC patients.
Conclusions:
These findings suggest that ZO-1 may serve as a valuable biomarker for HRS in DCAC patients. However, further validation in a larger cohort is necessary to confirm its clinical utility.
DOI: https://doi.org/10.37349/edd.2025.100574
This article belongs to the special issue Cirrhosis and Its Complications
Hepatitis D virus (HDV), a satellite virus requiring hepatitis B surface antigen (HBsAg) for propagation, is a hepatotropic virus implicated in acute and chronic viral hepatitis, with an accentuated risk of cirrhosis and hepatocellular carcinoma. The epidemiology of HDV infection is underestimated owing to underdiagnosis and low screening rates. Being inherently defective, HDV depends on HBsAg, the envelope protein of the hepatitis B virus (HBV), for hepatocyte entry and exit. However, viral replication is then HBV-independent but dependent on the host cell RNA polymerases. Infection can either be a coinfection with HBV or superinfection in individuals with pre-existing HBV, with the latter exhibiting a higher propensity for progression to chronicity. Clinical manifestations could range from acute hepatitis to acute flares in chronic hepatitis to rapidly progressive chronic liver disease. For decades, the treatment of HDV infection relied heavily on conventional and pegylated interferons (PEG-IFNs), which, despite limited efficacy and high relapse rates, continue to be a therapeutic option in patients with compensated liver disease. The past decade witnessed an advanced understanding of HDV virology and pathogenesis, which led to the development of multiple specific and targeted therapeutic agents, most notably the HDV viral entry inhibitor, bulevirtide, and the prenylation inhibitor, lonafarnib. In 2020, bulevirtide became the first drug approved in the European Union to treat chronic HDV with compensated liver disease. The emergence of lambda interferons, nucleic acid polymers, RNA silencers, and immune modulators further expands the therapeutic landscape. Combination regimens leveraging complementary mechanisms are promising but require further validation to optimize dosing and treatment durations. While novel therapies provide hope, significant unmet needs remain, especially for patients with decompensated cirrhosis. Future research must prioritize comprehensive strategies to enhance treatment efficacy and accessibility, offering a brighter prognosis for those affected by this devastating virus.
Hepatitis D virus (HDV), a satellite virus requiring hepatitis B surface antigen (HBsAg) for propagation, is a hepatotropic virus implicated in acute and chronic viral hepatitis, with an accentuated risk of cirrhosis and hepatocellular carcinoma. The epidemiology of HDV infection is underestimated owing to underdiagnosis and low screening rates. Being inherently defective, HDV depends on HBsAg, the envelope protein of the hepatitis B virus (HBV), for hepatocyte entry and exit. However, viral replication is then HBV-independent but dependent on the host cell RNA polymerases. Infection can either be a coinfection with HBV or superinfection in individuals with pre-existing HBV, with the latter exhibiting a higher propensity for progression to chronicity. Clinical manifestations could range from acute hepatitis to acute flares in chronic hepatitis to rapidly progressive chronic liver disease. For decades, the treatment of HDV infection relied heavily on conventional and pegylated interferons (PEG-IFNs), which, despite limited efficacy and high relapse rates, continue to be a therapeutic option in patients with compensated liver disease. The past decade witnessed an advanced understanding of HDV virology and pathogenesis, which led to the development of multiple specific and targeted therapeutic agents, most notably the HDV viral entry inhibitor, bulevirtide, and the prenylation inhibitor, lonafarnib. In 2020, bulevirtide became the first drug approved in the European Union to treat chronic HDV with compensated liver disease. The emergence of lambda interferons, nucleic acid polymers, RNA silencers, and immune modulators further expands the therapeutic landscape. Combination regimens leveraging complementary mechanisms are promising but require further validation to optimize dosing and treatment durations. While novel therapies provide hope, significant unmet needs remain, especially for patients with decompensated cirrhosis. Future research must prioritize comprehensive strategies to enhance treatment efficacy and accessibility, offering a brighter prognosis for those affected by this devastating virus.
DOI: https://doi.org/10.37349/edd.2025.100573
Aim:
Fructose is a highly lipogenic compound related to the onset of steatosis, its progression to steatohepatitis, and the eventual initiation of hepatocellular carcinoma (HCC). One of the cancer hallmarks is the metabolic adaptation to the environmental sources; however, this characteristic could be exploited to manipulate the HCC tumor’s response to therapies. Due to the high prevalence in the consumption of diets enriched with fructose and the unclear results in the literature, it is pertinent to characterize the effects of fructose on the biology of HCC as a possible beneficial player in the aggressiveness of this cancer. We focused on investigating the metabolic effect of fructose on the aggressiveness of liver cancer cells and chemotherapy response.
Methods:
We treated Huh-7 and HepG2 liver cancer cell lines with 1 mM fructose to address the metabolic reprogramming and its fructose-induced effects.
Results:
Cancer cells use fructose as an alternative fuel source in glucose-starved conditions, ensuring tumorigenic properties and cell survival in both cell lines. The metabolic effect differed depending on cell line origin and aggressiveness.
Conclusions:
HCC cells showed a metabolic adaptation under fructose treatment, enhancing the pentose phosphate pathway to fuel anabolism. Metabolic rewiring also improves the tumorigenic properties and chemoresistance of cancer cells in vitro and in vivo, contributing to chemotherapy failure and the aggressiveness of liver cancer cells.
Aim:
Fructose is a highly lipogenic compound related to the onset of steatosis, its progression to steatohepatitis, and the eventual initiation of hepatocellular carcinoma (HCC). One of the cancer hallmarks is the metabolic adaptation to the environmental sources; however, this characteristic could be exploited to manipulate the HCC tumor’s response to therapies. Due to the high prevalence in the consumption of diets enriched with fructose and the unclear results in the literature, it is pertinent to characterize the effects of fructose on the biology of HCC as a possible beneficial player in the aggressiveness of this cancer. We focused on investigating the metabolic effect of fructose on the aggressiveness of liver cancer cells and chemotherapy response.
Methods:
We treated Huh-7 and HepG2 liver cancer cell lines with 1 mM fructose to address the metabolic reprogramming and its fructose-induced effects.
Results:
Cancer cells use fructose as an alternative fuel source in glucose-starved conditions, ensuring tumorigenic properties and cell survival in both cell lines. The metabolic effect differed depending on cell line origin and aggressiveness.
Conclusions:
HCC cells showed a metabolic adaptation under fructose treatment, enhancing the pentose phosphate pathway to fuel anabolism. Metabolic rewiring also improves the tumorigenic properties and chemoresistance of cancer cells in vitro and in vivo, contributing to chemotherapy failure and the aggressiveness of liver cancer cells.
DOI: https://doi.org/10.37349/edd.2025.100572
Pancreatic cystic lesions are frequently found incidentally on cross-sectional imaging and are broadly classified into mucinous and non-mucinous cysts. While some exhibit benign behavior, others have a malignant potential and are considered noninvasive precursors of pancreatic ductal adenocarcinoma. Guidelines from various societies propose risk stratification based on morphologic features and cyst fluid analysis. Fluid analysis through EUS-guided fine needle aspiration contributes to improved classification and recently, targeted DNA or RNA-based next generation sequencing is emerging as a critical investigation tool for diagnostic confirmation and risk stratification of pancreatic cysts. Each of these modalities has specific strengths and limitations, highlighting the need for a multi-modal approach for comprehensive assessment to guide clinical decision making. In this perspective, we aim to provide a thorough clinicopathologic framework for diagnosing and risk stratifying pancreatic cysts encompassing imaging findings, cyst fluid analyses, and next generation sequencing.
Pancreatic cystic lesions are frequently found incidentally on cross-sectional imaging and are broadly classified into mucinous and non-mucinous cysts. While some exhibit benign behavior, others have a malignant potential and are considered noninvasive precursors of pancreatic ductal adenocarcinoma. Guidelines from various societies propose risk stratification based on morphologic features and cyst fluid analysis. Fluid analysis through EUS-guided fine needle aspiration contributes to improved classification and recently, targeted DNA or RNA-based next generation sequencing is emerging as a critical investigation tool for diagnostic confirmation and risk stratification of pancreatic cysts. Each of these modalities has specific strengths and limitations, highlighting the need for a multi-modal approach for comprehensive assessment to guide clinical decision making. In this perspective, we aim to provide a thorough clinicopathologic framework for diagnosing and risk stratifying pancreatic cysts encompassing imaging findings, cyst fluid analyses, and next generation sequencing.
DOI: https://doi.org/10.37349/edd.2025.100571
This article belongs to the special issue Advances in Hepato-gastroenterology: Diagnosis, Prognostication, and Disease Stratification
Diverticular disease of the colon is a very important digestive disease and its management depends on the characteristics of the disease and the patient and the resources available. There are benefits and harms of open and laparoscopic Hartmann’s procedure, laparoscopic peritoneal lavage, sigmoidectomy, and primary anastomosis. There are many gaps to be eliminated in the future, such as real risks, benefits, and cost-effectiveness in the application of each one. The decision to be made for each case of complicated diverticulitis often depends on the interaction and competence of the multidisciplinary team in charge.
Diverticular disease of the colon is a very important digestive disease and its management depends on the characteristics of the disease and the patient and the resources available. There are benefits and harms of open and laparoscopic Hartmann’s procedure, laparoscopic peritoneal lavage, sigmoidectomy, and primary anastomosis. There are many gaps to be eliminated in the future, such as real risks, benefits, and cost-effectiveness in the application of each one. The decision to be made for each case of complicated diverticulitis often depends on the interaction and competence of the multidisciplinary team in charge.
DOI: https://doi.org/10.37349/edd.2025.100570
This article belongs to the special issue Diverticulitis: Pathomechanism, Diagnosis and Treatment
Acetaminophen (APAP)-induced liver injury and acute liver failure is a significant clinical problem worldwide; in addition, APAP overdoses in animals or in cell culture are used as popular models to study drug-induced liver injury mechanisms and test therapeutic interventions. Early assumptions that APAP toxicity is caused by a single mechanism resulting in a defined mode of cell death in hepatocytes had to be questioned when over the years many different mechanisms and modes of cell death were reported. Although many of the contradictory results and conclusions reported over the years can be attributed to lack of understanding of established mechanisms, methodological problems, and misinterpretation of data, it is increasingly recognized that some of the reported differences in signaling mechanisms and even a switch in the mode of cell death can be caused by variations in the experimental conditions. In this review, examples will be discussed how experimental conditions (dose, solvent, etc.), the experimental system (species, strain, and substrain in vivo, cell type, and in vitro conditions), and also adaptive responses and off-target effects of genetic manipulations and chemical interventions, can impact the mechanisms of cell death. Given that the conditions will determine the results, it is therefore of critical importance to keep in mind the translational aspect of the experiments, i.e., the conditions relevant to the human pathophysiology. Only the full appreciation of these issues will lead to reproducible and clinically relevant results that advance our understanding of all facets of the human pathophysiology and identify clinically relevant therapeutic targets.
Acetaminophen (APAP)-induced liver injury and acute liver failure is a significant clinical problem worldwide; in addition, APAP overdoses in animals or in cell culture are used as popular models to study drug-induced liver injury mechanisms and test therapeutic interventions. Early assumptions that APAP toxicity is caused by a single mechanism resulting in a defined mode of cell death in hepatocytes had to be questioned when over the years many different mechanisms and modes of cell death were reported. Although many of the contradictory results and conclusions reported over the years can be attributed to lack of understanding of established mechanisms, methodological problems, and misinterpretation of data, it is increasingly recognized that some of the reported differences in signaling mechanisms and even a switch in the mode of cell death can be caused by variations in the experimental conditions. In this review, examples will be discussed how experimental conditions (dose, solvent, etc.), the experimental system (species, strain, and substrain in vivo, cell type, and in vitro conditions), and also adaptive responses and off-target effects of genetic manipulations and chemical interventions, can impact the mechanisms of cell death. Given that the conditions will determine the results, it is therefore of critical importance to keep in mind the translational aspect of the experiments, i.e., the conditions relevant to the human pathophysiology. Only the full appreciation of these issues will lead to reproducible and clinically relevant results that advance our understanding of all facets of the human pathophysiology and identify clinically relevant therapeutic targets.
DOI: https://doi.org/10.37349/edd.2025.100569
Aim:
Selecting patients for immunotherapy in metastatic gastric cancer (mGC) in second and subsequent lines remains challenging. The aim of our study is to assess the feasibility of anti-programmed death-ligand 1 (anti-PD-L1) inhibitors in pretreated patients with mGC, and to determine prognostic and predictive biomarkers.
Methods:
We retrospectively analyzed data of 122 patients treated in five oncology centers in Moscow between 2018 and 2023, who received nivolumab or pembrolizumab for advanced gastric cancer. The primary end-point of our study was 6-month progression-free survival (PFS). For multivariate analysis, variables with a value of p < 0.05 obtained in a univariate analysis were selected. The optimal threshold value of the neutrophil-lymphocyte ratio (NLR) as a predictor of the effectiveness of immunotherapy was determined using receiver operating characteristic (ROC) curve analysis.
Results:
Patients with mGC who received immune checkpoint inhibitors (ICIs) were included. 6-month PFS rate was 31.6%. The median PFS (mPFS) and overall survival (mOS) in patients in the high NLR group (NLR ≥ 1.8) were 2 and 4 months; mOS and mPFS in the low NLR group were not achieved (p < 0.001). The presence of ascites (p < 0.001), the administration of ICIs in III–IV lines (p = 0.004), and NLR ≥ 1.8 (p = 0.006) were independent prognostic factors, associated with decrease of OS. The median OS of patients in favorable and unfavorable prognostic groups were 13 months and 2 months, respectively (p < 0.001).
Conclusions:
Ascites, NLR level of ≥ 1.8, and administration of anti-PD-L1 inhibitors were associated with low efficacy of immunotherapy in patients with microsatellite stable mGC. Further research should be planned including patients who did not receive ICIs to determine the prognostic significance of our model.
Aim:
Selecting patients for immunotherapy in metastatic gastric cancer (mGC) in second and subsequent lines remains challenging. The aim of our study is to assess the feasibility of anti-programmed death-ligand 1 (anti-PD-L1) inhibitors in pretreated patients with mGC, and to determine prognostic and predictive biomarkers.
Methods:
We retrospectively analyzed data of 122 patients treated in five oncology centers in Moscow between 2018 and 2023, who received nivolumab or pembrolizumab for advanced gastric cancer. The primary end-point of our study was 6-month progression-free survival (PFS). For multivariate analysis, variables with a value of p < 0.05 obtained in a univariate analysis were selected. The optimal threshold value of the neutrophil-lymphocyte ratio (NLR) as a predictor of the effectiveness of immunotherapy was determined using receiver operating characteristic (ROC) curve analysis.
Results:
Patients with mGC who received immune checkpoint inhibitors (ICIs) were included. 6-month PFS rate was 31.6%. The median PFS (mPFS) and overall survival (mOS) in patients in the high NLR group (NLR ≥ 1.8) were 2 and 4 months; mOS and mPFS in the low NLR group were not achieved (p < 0.001). The presence of ascites (p < 0.001), the administration of ICIs in III–IV lines (p = 0.004), and NLR ≥ 1.8 (p = 0.006) were independent prognostic factors, associated with decrease of OS. The median OS of patients in favorable and unfavorable prognostic groups were 13 months and 2 months, respectively (p < 0.001).
Conclusions:
Ascites, NLR level of ≥ 1.8, and administration of anti-PD-L1 inhibitors were associated with low efficacy of immunotherapy in patients with microsatellite stable mGC. Further research should be planned including patients who did not receive ICIs to determine the prognostic significance of our model.
DOI: https://doi.org/10.37349/edd.2025.100568
This article belongs to the special issue Immunotherapy for Cancer of Digestive System
DOI: https://doi.org/10.37349/edd.2025.100567
The epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly growing worldwide. Thus, there is an urgent need for novel, non-invasive, and reliable biomarkers to replace liver biopsy for the diagnosis and prognosis of MASLD. Circulating peripheral blood mononuclear cells (PBMCs) are highly responsive to various stimuli and physiological changes. Beyond their immunomodulatory role, PBMC may act as metabolic sensors in several cardiometabolic disorders, including MASLD, with their metabolic programs shifting accordingly. Recent evidence suggests a link between impaired mitochondrial bioenergetics in PBMC and MASLD. Additionally, impaired mitochondrial respiration is intricately linked to the intracellular depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) in various cell types. Accumulating preclinical and clinical data show that NAD+-increasing strategies may protect against MASLD by restoring intracellular NAD+ pools and improving mitochondrial performance. This review will focus on [i] the relevance of mitochondrial dysfunction, including impaired bioenergetics, in PBMC as a marker for the diagnosis and prognosis of MASLD, and [ii] the potential benefits of NAD+ precursors in MAFLD and their relationship with improved mitochondrial respiration in blood immune cells.
The epidemic of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly growing worldwide. Thus, there is an urgent need for novel, non-invasive, and reliable biomarkers to replace liver biopsy for the diagnosis and prognosis of MASLD. Circulating peripheral blood mononuclear cells (PBMCs) are highly responsive to various stimuli and physiological changes. Beyond their immunomodulatory role, PBMC may act as metabolic sensors in several cardiometabolic disorders, including MASLD, with their metabolic programs shifting accordingly. Recent evidence suggests a link between impaired mitochondrial bioenergetics in PBMC and MASLD. Additionally, impaired mitochondrial respiration is intricately linked to the intracellular depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) in various cell types. Accumulating preclinical and clinical data show that NAD+-increasing strategies may protect against MASLD by restoring intracellular NAD+ pools and improving mitochondrial performance. This review will focus on [i] the relevance of mitochondrial dysfunction, including impaired bioenergetics, in PBMC as a marker for the diagnosis and prognosis of MASLD, and [ii] the potential benefits of NAD+ precursors in MAFLD and their relationship with improved mitochondrial respiration in blood immune cells.
DOI: https://doi.org/10.37349/edd.2025.100566
This article belongs to the special issue Mitochondria and Lipid Signalling in Liver Diseases
