Previous
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a multisystem disorder in which iron acts as both a metabolic “spark” and an accelerant of liver injury. This integrates emerging evidence that iron-driven oxidative stress and low-grade inflammation are mutually reinforcing processes in metabolic liver disease. In this perspective article, epidemiological evidence, molecular insights, and emerging clinical data are integrated to clarify how hyperferritinemia, often dismissed as a mere inflammatory marker, maps onto genuine iron redistribution and overload in the metabolic liver. Physiological iron homeostasis and its disruption by adiposity-related inflammation, hyperinsulinemia, sex hormones, and common HFE variants, creating a labile catalytic iron pool that fuels Fenton chemistry in lipid-laden hepatocytes. Population studies and expert-panel criteria are summarized that define “metabolic hyperferritinemia” and stratify dysmetabolic iron accumulation into three magnetic resonance imaging (MRI)-based grades, each linked to stepwise increases in steatosis, fibrosis, and clinical events. Mechanistically, excess Fe2+ triggers lipid peroxidation, mitochondrial dysfunction, ferroptosis, Kupffer cell activation, endoplasmic reticulum stress, and hepatic stellate cell sensitization to TGF-β, thereby accelerating the transition from steatosis to steatohepatitis and fibrosis. Finally, the diagnostic algorithms, iron-modulating therapies (phlebotomy, hepcidin agonists, diet), and prospective data supporting ferritin-based triage in clinics are discussed. Collectively, the outlined evidence positions iron not only as a biomarker but also as a modifiable driver of MASLD progression, underscoring the need for randomized trials that test whether targeted iron reduction improves hard hepatic outcomes.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a multisystem disorder in which iron acts as both a metabolic “spark” and an accelerant of liver injury. This integrates emerging evidence that iron-driven oxidative stress and low-grade inflammation are mutually reinforcing processes in metabolic liver disease. In this perspective article, epidemiological evidence, molecular insights, and emerging clinical data are integrated to clarify how hyperferritinemia, often dismissed as a mere inflammatory marker, maps onto genuine iron redistribution and overload in the metabolic liver. Physiological iron homeostasis and its disruption by adiposity-related inflammation, hyperinsulinemia, sex hormones, and common HFE variants, creating a labile catalytic iron pool that fuels Fenton chemistry in lipid-laden hepatocytes. Population studies and expert-panel criteria are summarized that define “metabolic hyperferritinemia” and stratify dysmetabolic iron accumulation into three magnetic resonance imaging (MRI)-based grades, each linked to stepwise increases in steatosis, fibrosis, and clinical events. Mechanistically, excess Fe2+ triggers lipid peroxidation, mitochondrial dysfunction, ferroptosis, Kupffer cell activation, endoplasmic reticulum stress, and hepatic stellate cell sensitization to TGF-β, thereby accelerating the transition from steatosis to steatohepatitis and fibrosis. Finally, the diagnostic algorithms, iron-modulating therapies (phlebotomy, hepcidin agonists, diet), and prospective data supporting ferritin-based triage in clinics are discussed. Collectively, the outlined evidence positions iron not only as a biomarker but also as a modifiable driver of MASLD progression, underscoring the need for randomized trials that test whether targeted iron reduction improves hard hepatic outcomes.
DOI: https://doi.org/10.37349/edd.2025.100599
This article belongs to the special issue Advances in Hepato-gastroenterology: Diagnosis, Prognostication, and Disease Stratification
This review explores recent advancements in the management of Helicobacter pylori infection, a widespread bacterial pathogen associated with various gastrointestinal disorders. The paper discusses improved diagnostic techniques, including molecular methods and non-invasive tests, which have enhanced detection accuracy and antibiotic resistance profiling. New treatment strategies, such as individualized therapy based on antimicrobial susceptibility testing (AST) and the use of probiotics as adjunctive therapy, are examined. The review also addresses the challenges of antibiotic resistance, highlighting the importance of surveillance and monitoring strategies. Novel antibiotic combinations and non-antibiotic therapies, including antibiofilm agents, are presented as potential solutions. The paper concludes by discussing post-treatment follow-up, management of persistent infections, and considerations for special patient populations. Future directions in Helicobacter pylori management, including emerging technologies and global eradication efforts, are briefly outlined.
This review explores recent advancements in the management of Helicobacter pylori infection, a widespread bacterial pathogen associated with various gastrointestinal disorders. The paper discusses improved diagnostic techniques, including molecular methods and non-invasive tests, which have enhanced detection accuracy and antibiotic resistance profiling. New treatment strategies, such as individualized therapy based on antimicrobial susceptibility testing (AST) and the use of probiotics as adjunctive therapy, are examined. The review also addresses the challenges of antibiotic resistance, highlighting the importance of surveillance and monitoring strategies. Novel antibiotic combinations and non-antibiotic therapies, including antibiofilm agents, are presented as potential solutions. The paper concludes by discussing post-treatment follow-up, management of persistent infections, and considerations for special patient populations. Future directions in Helicobacter pylori management, including emerging technologies and global eradication efforts, are briefly outlined.
DOI: https://doi.org/10.37349/edd.2025.100598
This article belongs to the special issue Helicobacter Pylori and Infection: Genomics, Diagnosis, Pathogenesis, Antibiotic Resistance, Microbiota, Cancer, Prevention and Therapeutics
Hepatic encephalopathy (HE) is a debilitating neuropsychiatric complication of liver dysfunction that spans a continuum from subtle cognitive impairment to deep coma. While historically attributed to hyperammonemia, current insights reveal a multifactorial pathogenesis involving systemic inflammation, astrocyte dysfunction, blood-brain barrier (BBB) disruption, and altered neurotransmission. Central to this complex network is the gut-liver axis—a bidirectional system that links the gut microbiota, intestinal barrier integrity, bile acid metabolism, and hepatic immune responses. In cirrhosis, dysbiosis and increased intestinal permeability facilitate the translocation of microbial products—such as endotoxins and ammonia—that trigger hepatic and systemic immune activation, amplifying neurotoxicity through the gut-liver-brain axis. Experimental and clinical evidence has shown that ammonia and bilirubin synergistically promote neuroinflammation, mitochondrial dysfunction, and glial activation. Multiomics data further support the role of the microbiota as an active modulator of liver-brain homeostasis. Microbiota-targeted therapies—including rifaximin, probiotics, synbiotics, and fecal microbiota transplantation (FMT)—demonstrate efficacy in reducing HE recurrence, improving cognition, and restoring microbial balance. Novel receptor-based strategies targeting the farnesoid X receptor (FXR), Takeda G-protein-coupled receptor 5 (TGR5), and aryl hydrocarbon receptor (AhR) show promise for modulating bile acid pathways and mitigating neuroinflammation. Emerging approaches also focus on dietary interventions, the reinforcement of epithelial barrier function, and artificial intelligence (AI)-driven tools for personalized monitoring. Despite these advances, challenges persist regarding FMT standardization, long-term safety, and the integration of digital diagnostics into routine care.
Hepatic encephalopathy (HE) is a debilitating neuropsychiatric complication of liver dysfunction that spans a continuum from subtle cognitive impairment to deep coma. While historically attributed to hyperammonemia, current insights reveal a multifactorial pathogenesis involving systemic inflammation, astrocyte dysfunction, blood-brain barrier (BBB) disruption, and altered neurotransmission. Central to this complex network is the gut-liver axis—a bidirectional system that links the gut microbiota, intestinal barrier integrity, bile acid metabolism, and hepatic immune responses. In cirrhosis, dysbiosis and increased intestinal permeability facilitate the translocation of microbial products—such as endotoxins and ammonia—that trigger hepatic and systemic immune activation, amplifying neurotoxicity through the gut-liver-brain axis. Experimental and clinical evidence has shown that ammonia and bilirubin synergistically promote neuroinflammation, mitochondrial dysfunction, and glial activation. Multiomics data further support the role of the microbiota as an active modulator of liver-brain homeostasis. Microbiota-targeted therapies—including rifaximin, probiotics, synbiotics, and fecal microbiota transplantation (FMT)—demonstrate efficacy in reducing HE recurrence, improving cognition, and restoring microbial balance. Novel receptor-based strategies targeting the farnesoid X receptor (FXR), Takeda G-protein-coupled receptor 5 (TGR5), and aryl hydrocarbon receptor (AhR) show promise for modulating bile acid pathways and mitigating neuroinflammation. Emerging approaches also focus on dietary interventions, the reinforcement of epithelial barrier function, and artificial intelligence (AI)-driven tools for personalized monitoring. Despite these advances, challenges persist regarding FMT standardization, long-term safety, and the integration of digital diagnostics into routine care.
DOI: https://doi.org/10.37349/edd.2025.100597
Aim:
Functional defecatory disorder (FDD) is associated with impaired defecation not only due to abnormalities in recto-anal coordination, but also due to abnormalities in anal tone and rectal sensation. This study aimed to characterize the spectrum of anorectal motor and sensory abnormalities in patients with FDD using the London classification.
Methods:
In this single-center prospective study, 100 consecutive patients fulfilling Rome IV criteria for FDD were included. Secondary causes of constipation were excluded. High-resolution anorectal manometry, rectal sensory testing, and a balloon expulsion test were performed as per the International Anorectal Physiology Working Group (IAPWG) protocol. Patients were classified using the London classification, which identifies multiple subtypes of anorectal dysfunction.
Results:
The median age was 34 years (range: 18–78), with 64% males and 36% females. Among the cohort, 85% had abnormal expulsion with dyssynergia, while 15% had abnormal expulsion with poor propulsion and dyssynergia. Anal hypotension with normal contractility was seen in 9%, while 4% had anal normotension with hypocontractility. Rectal hyposensitivity and borderline rectal hyposensitivity were noted in 4% and 5% of patients, respectively.
Conclusions:
This study highlights that dyssynergic defecation is frequently accompanied by additional anorectal dysfunctions. Applying the London classification enhances the recognition of coexisting abnormalities, which may have therapeutic implications. Future research should investigate whether addressing these additional dysfunctions improves treatment outcomes in FDD.
Aim:
Functional defecatory disorder (FDD) is associated with impaired defecation not only due to abnormalities in recto-anal coordination, but also due to abnormalities in anal tone and rectal sensation. This study aimed to characterize the spectrum of anorectal motor and sensory abnormalities in patients with FDD using the London classification.
Methods:
In this single-center prospective study, 100 consecutive patients fulfilling Rome IV criteria for FDD were included. Secondary causes of constipation were excluded. High-resolution anorectal manometry, rectal sensory testing, and a balloon expulsion test were performed as per the International Anorectal Physiology Working Group (IAPWG) protocol. Patients were classified using the London classification, which identifies multiple subtypes of anorectal dysfunction.
Results:
The median age was 34 years (range: 18–78), with 64% males and 36% females. Among the cohort, 85% had abnormal expulsion with dyssynergia, while 15% had abnormal expulsion with poor propulsion and dyssynergia. Anal hypotension with normal contractility was seen in 9%, while 4% had anal normotension with hypocontractility. Rectal hyposensitivity and borderline rectal hyposensitivity were noted in 4% and 5% of patients, respectively.
Conclusions:
This study highlights that dyssynergic defecation is frequently accompanied by additional anorectal dysfunctions. Applying the London classification enhances the recognition of coexisting abnormalities, which may have therapeutic implications. Future research should investigate whether addressing these additional dysfunctions improves treatment outcomes in FDD.
DOI: https://doi.org/10.37349/edd.2025.100596
Primary liver cancer, particularly hepatocellular carcinoma, remains a major global health challenge due to its multifactorial etiology, late-stage detection, and high mortality. This review proposes a precision prevention framework that (i) categorizes risk factors into biological (e.g., HBV/HCV, aflatoxins), environmental (e.g., air pollution, occupational/waterborne toxins), and host-related domains (e.g., obesity, diabetes, genetic susceptibility); and (ii) aligns interventions to three complementary strategies: elimination of dominant risk (HBV vaccination, aflatoxin control, alcohol/tobacco reduction), early warning and targeted management (life-course immunization, MAFLD screening and control, metformin in diabetics), and chemoprevention (e.g., oltipraz, chlorophyllin, sulforaphane). We further articulate “green” prevention as a scalable, diet-centered approach that can be tailored to risk tiers and local food systems. Advances in multi-omics, microbiome science, and AI-enabled risk models—together with cohort evidence from East Asia, sub-Saharan Africa, and Western populations—support stratified surveillance and earlier interventions. Finally, we discuss generalizability and implementation challenges (regional dietary diversity, resource access) and outline pragmatic solutions to improve uptake across diverse settings.
Primary liver cancer, particularly hepatocellular carcinoma, remains a major global health challenge due to its multifactorial etiology, late-stage detection, and high mortality. This review proposes a precision prevention framework that (i) categorizes risk factors into biological (e.g., HBV/HCV, aflatoxins), environmental (e.g., air pollution, occupational/waterborne toxins), and host-related domains (e.g., obesity, diabetes, genetic susceptibility); and (ii) aligns interventions to three complementary strategies: elimination of dominant risk (HBV vaccination, aflatoxin control, alcohol/tobacco reduction), early warning and targeted management (life-course immunization, MAFLD screening and control, metformin in diabetics), and chemoprevention (e.g., oltipraz, chlorophyllin, sulforaphane). We further articulate “green” prevention as a scalable, diet-centered approach that can be tailored to risk tiers and local food systems. Advances in multi-omics, microbiome science, and AI-enabled risk models—together with cohort evidence from East Asia, sub-Saharan Africa, and Western populations—support stratified surveillance and earlier interventions. Finally, we discuss generalizability and implementation challenges (regional dietary diversity, resource access) and outline pragmatic solutions to improve uptake across diverse settings.
DOI: https://doi.org/10.37349/edd.2025.100595
This article belongs to the special issue Prevention, Screening and Diagnosis for Primary Liver Cancer
Aim:
Hepatocellular carcinoma (HCC) poses a significant global health threat. The pregnane X receptor (PXR) is a central regulator of xenobiotic metabolism and plays a key role in mediating cellular resistance to anti-tumor drugs in HCC. Indeed, the precise role of PXR in HCC pathogenesis remains unclear. This study aimed to investigate blood and hepatic PXR levels and their association with inflammation in HCC patients. Additionally, we assessed the diagnostic potential of PXR in HCC patients compared to control subjects.
Methods:
Following approval by the Institute Ethical Committee, 40 HCC patients and 40 healthy volunteers were enrolled in this study. Baseline patient characteristics, serum alpha-fetoprotein (AFP), and biochemical parameters were analyzed. Serum levels of PXR, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-1β were measured using ELISA. The hepatic expression of phosphorylated nuclear factor kappa B (NFκB) and PXR proteins was analyzed by western blotting.
Results:
When compared to control subjects, serum PXR levels were increased in HCC cases (1.34 ± 0.16 vs. 4.09 ± 0.33; P < 0.0001). Similarly, hepatic PXR expression was increased in HCC tissues. Moreover, HCC patients exhibited elevated inflammatory cytokines and a deranged hepatobiliary profile compared to controls.
Conclusions:
Elevated serum PXR levels in HCC patients were positively correlated with inflammation. Notably, serum PXR demonstrated greater sensitivity and specificity in diagnosing HCC. These findings suggest that PXR may serve as a plausible biomarker in the diagnosis of HCC.
Aim:
Hepatocellular carcinoma (HCC) poses a significant global health threat. The pregnane X receptor (PXR) is a central regulator of xenobiotic metabolism and plays a key role in mediating cellular resistance to anti-tumor drugs in HCC. Indeed, the precise role of PXR in HCC pathogenesis remains unclear. This study aimed to investigate blood and hepatic PXR levels and their association with inflammation in HCC patients. Additionally, we assessed the diagnostic potential of PXR in HCC patients compared to control subjects.
Methods:
Following approval by the Institute Ethical Committee, 40 HCC patients and 40 healthy volunteers were enrolled in this study. Baseline patient characteristics, serum alpha-fetoprotein (AFP), and biochemical parameters were analyzed. Serum levels of PXR, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-1β were measured using ELISA. The hepatic expression of phosphorylated nuclear factor kappa B (NFκB) and PXR proteins was analyzed by western blotting.
Results:
When compared to control subjects, serum PXR levels were increased in HCC cases (1.34 ± 0.16 vs. 4.09 ± 0.33; P < 0.0001). Similarly, hepatic PXR expression was increased in HCC tissues. Moreover, HCC patients exhibited elevated inflammatory cytokines and a deranged hepatobiliary profile compared to controls.
Conclusions:
Elevated serum PXR levels in HCC patients were positively correlated with inflammation. Notably, serum PXR demonstrated greater sensitivity and specificity in diagnosing HCC. These findings suggest that PXR may serve as a plausible biomarker in the diagnosis of HCC.
DOI: https://doi.org/10.37349/edd.2025.100594
This article belongs to the special issue Prevention, Screening and Diagnosis for Primary Liver Cancer
Hepatitis A virus (HAV) is a spherical, non-enveloped, linear-positive single-stranded RNA virus that belongs to the Picornaviridae family. The virus attacks the liver, which leads to inflammation and the onset of jaundice. It represents a disease of the pediatric population and, in most cases, it causes an acute self-limited illness, but rarely a fulminant condition. HAV spreads from person to person through the fecal-oral route and ingestion of contaminated food or drink. It is highly endemic in large geographical areas of the world, including the Indian subcontinent, where most of the population is exposed to the virus in childhood. Most of the viral infections at this age cause asymptomatic disease that provides lifelong protection against HAV. However, our recent study showed an increased incidence of HAV infection in the adult population. This signifies a change in the pattern of age-specific seroprevalence of antibodies for hepatitis A and a huge number of non-immune susceptible individuals. Molecular epidemiological studies define various aspects of viral infection and transmission. Sequence characterization based on the VP1/P2A junction region confirmed IIIA and IA as the predominant genotypes circulating in the Indian subcontinent. The duration of the viremia is dependent on the host, and viral genotypes have no role in the severity of the disease. A mutational study confirmed the lack of genetic variations among Indian strains. Due to the high endemicity of this disease in the Indian subcontinent, vaccination is not recommended. However, individuals who are susceptible and seronegative for HAV-IgG should be targeted for vaccination. It will be a rational and cost-effective approach.
Hepatitis A virus (HAV) is a spherical, non-enveloped, linear-positive single-stranded RNA virus that belongs to the Picornaviridae family. The virus attacks the liver, which leads to inflammation and the onset of jaundice. It represents a disease of the pediatric population and, in most cases, it causes an acute self-limited illness, but rarely a fulminant condition. HAV spreads from person to person through the fecal-oral route and ingestion of contaminated food or drink. It is highly endemic in large geographical areas of the world, including the Indian subcontinent, where most of the population is exposed to the virus in childhood. Most of the viral infections at this age cause asymptomatic disease that provides lifelong protection against HAV. However, our recent study showed an increased incidence of HAV infection in the adult population. This signifies a change in the pattern of age-specific seroprevalence of antibodies for hepatitis A and a huge number of non-immune susceptible individuals. Molecular epidemiological studies define various aspects of viral infection and transmission. Sequence characterization based on the VP1/P2A junction region confirmed IIIA and IA as the predominant genotypes circulating in the Indian subcontinent. The duration of the viremia is dependent on the host, and viral genotypes have no role in the severity of the disease. A mutational study confirmed the lack of genetic variations among Indian strains. Due to the high endemicity of this disease in the Indian subcontinent, vaccination is not recommended. However, individuals who are susceptible and seronegative for HAV-IgG should be targeted for vaccination. It will be a rational and cost-effective approach.
DOI: https://doi.org/10.37349/edd.2025.100593
This article belongs to the special issue Viral Hepatitis
This article evaluates contemporary and evolving surgical techniques in diverticulitis management. A comprehensive literature search was conducted using PubMed on guidelines for articles on surgical interventions for diverticulitis. The relevant data were extracted and synthesized to identify trends, advancements, and gaps in the current understanding of surgical interventions for diverticulitis. Many patients with uncomplicated diverticulitis can achieve favourable outcomes through conservative management strategies. Surgical interventions are increasingly tailored based on individual risk profiles and disease severity. Recent methods for managing diverticulitis highlight the significance of personalized treatment, which can lead to faster recovery times and better overall quality of life. More patients are now considered appropriate candidates for primary anastomosis, with or without a stoma in place of Hartmann’s procedure, where reversal is often tricky. Additionally, minimally invasive surgical techniques are being employed more frequently.
This article evaluates contemporary and evolving surgical techniques in diverticulitis management. A comprehensive literature search was conducted using PubMed on guidelines for articles on surgical interventions for diverticulitis. The relevant data were extracted and synthesized to identify trends, advancements, and gaps in the current understanding of surgical interventions for diverticulitis. Many patients with uncomplicated diverticulitis can achieve favourable outcomes through conservative management strategies. Surgical interventions are increasingly tailored based on individual risk profiles and disease severity. Recent methods for managing diverticulitis highlight the significance of personalized treatment, which can lead to faster recovery times and better overall quality of life. More patients are now considered appropriate candidates for primary anastomosis, with or without a stoma in place of Hartmann’s procedure, where reversal is often tricky. Additionally, minimally invasive surgical techniques are being employed more frequently.
DOI: https://doi.org/10.37349/edd.2025.100592
This article belongs to the special issue Diverticulitis: Pathomechanism, Diagnosis and Treatment
Aim:
The current state of the problem of stomach and duodenal diseases presupposes a mandatory examination of patients for the presence of Helicobacter pylori infection. Highly specific and sensitive diagnostic methods are known and applied, however, the problem of removal from clinical laboratories, isolation, including during a pandemic, dictates the search for new solutions.
Methods:
Mobile diagnostic solutions based on portable devices with highly sensitive quartz piezoelectric sensors were investigated using a variety of devices (1–8 sensor elements) and data processing algorithms.
Results:
A three-year volunteer monitoring study demonstrated that sensor arrays are informative for exhaled air and volatile skin compound analysis, enabling both point diagnostics and long-term tracking.
Conclusions:
The study demonstrates the significant potential of sensor libraries in non-invasive diagnostics, particularly through the innovative application of facial skin projection for volatile marker detection. Three diagnostic approaches have been presented for assessing stomach and esophageal conditions via non-invasive monitoring of exhaled air composition and volatile skin compounds. The authors’ extensive experience in breath urease testing for both adults and children enabled purposeful modifications of diagnostic devices and data processing algorithms. A three-year volunteer monitoring study during anti-Helicobacter therapy and dietary interventions revealed high stability and informativeness of the urease test utilizing chemical sensor arrays. Notably, this research represents the first demonstration of facial organ projection as a method for stomach condition assessment and volatile molecule monitoring without sample collection, showcasing promising prospects for future diagnostic applications.
Aim:
The current state of the problem of stomach and duodenal diseases presupposes a mandatory examination of patients for the presence of Helicobacter pylori infection. Highly specific and sensitive diagnostic methods are known and applied, however, the problem of removal from clinical laboratories, isolation, including during a pandemic, dictates the search for new solutions.
Methods:
Mobile diagnostic solutions based on portable devices with highly sensitive quartz piezoelectric sensors were investigated using a variety of devices (1–8 sensor elements) and data processing algorithms.
Results:
A three-year volunteer monitoring study demonstrated that sensor arrays are informative for exhaled air and volatile skin compound analysis, enabling both point diagnostics and long-term tracking.
Conclusions:
The study demonstrates the significant potential of sensor libraries in non-invasive diagnostics, particularly through the innovative application of facial skin projection for volatile marker detection. Three diagnostic approaches have been presented for assessing stomach and esophageal conditions via non-invasive monitoring of exhaled air composition and volatile skin compounds. The authors’ extensive experience in breath urease testing for both adults and children enabled purposeful modifications of diagnostic devices and data processing algorithms. A three-year volunteer monitoring study during anti-Helicobacter therapy and dietary interventions revealed high stability and informativeness of the urease test utilizing chemical sensor arrays. Notably, this research represents the first demonstration of facial organ projection as a method for stomach condition assessment and volatile molecule monitoring without sample collection, showcasing promising prospects for future diagnostic applications.
DOI: https://doi.org/10.37349/edd.2025.100591
This article belongs to the special issue Helicobacter Pylori and Infection: Genomics, Diagnosis, Pathogenesis, Antibiotic Resistance, Microbiota, Cancer, Prevention and Therapeutics
Peroxisome proliferator-activated receptors (PPARs) comprise three isoforms: PPARα, PPARβ/δ, and PPARγ, which regulate the expression of genes involved in fatty acid uptake, β-oxidation, adipogenesis, gluconeogenesis, and insulin sensitivity. Type 2 diabetes (T2D), often accompanied by other features of metabolic syndrome, contributes to vasculopathy, end-stage organ failure, and cancer. Metabolic dysfunction-associated steatotic liver disease (MASLD) refers to steatotic liver disease in the presence of cardiometabolic risk factor(s) and without excessive alcohol consumption. MASLD is prevalent among adults with T2D and carries a high risk of liver fibrosis, metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis and incident T2D. In MASLD, the liver becomes a hub of lipid toxicity, oxidative stress, and fibrotic signalling whenever T2D disrupts hormonal and adipokine signalling, increases free fatty acid flux, and promotes chronic inflammation. MASLD, therefore, results from an impairment of the protection physiologically offered by PPARs through fatty acid oxidation, lipid storage in the adipose tissue, and mitigation of insulin resistance and pro-inflammatory cascades. By examining the molecular mechanisms of PPARα, PPARβ/δ, and PPARγ, as well as their interactions with cofactors like PGC-1α, and their crosstalk with pathways like sterol regulatory element-binding protein (SREBP), NF-κB, AMP-activated protein kinase (AMPK), and adipokines, researchers and clinicians can better understand how T2D-related MASLD can be prevented or treated. Single PPAR agonists, such as fibrates and glitazones, have limited clinical efficacy in achieving hard liver histology endpoints like MASH resolution and fibrosis regression in humans. However, the Pan-PPAR agonist Lanifibranor at the highest doses shows promise in ameliorating these outcomes in subjects with non-cirrhotic MASH. This suggests that activating all three PPAR isoforms together enhances their therapeutic effects on various cells and target organs, restoring insulin resistance, improving gluco-lipidic homeostasis, while inhibiting pro-inflammatory and pro-fibrogenic pathways. Analysis of unresolved issues should dictate the research agenda.
Peroxisome proliferator-activated receptors (PPARs) comprise three isoforms: PPARα, PPARβ/δ, and PPARγ, which regulate the expression of genes involved in fatty acid uptake, β-oxidation, adipogenesis, gluconeogenesis, and insulin sensitivity. Type 2 diabetes (T2D), often accompanied by other features of metabolic syndrome, contributes to vasculopathy, end-stage organ failure, and cancer. Metabolic dysfunction-associated steatotic liver disease (MASLD) refers to steatotic liver disease in the presence of cardiometabolic risk factor(s) and without excessive alcohol consumption. MASLD is prevalent among adults with T2D and carries a high risk of liver fibrosis, metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis and incident T2D. In MASLD, the liver becomes a hub of lipid toxicity, oxidative stress, and fibrotic signalling whenever T2D disrupts hormonal and adipokine signalling, increases free fatty acid flux, and promotes chronic inflammation. MASLD, therefore, results from an impairment of the protection physiologically offered by PPARs through fatty acid oxidation, lipid storage in the adipose tissue, and mitigation of insulin resistance and pro-inflammatory cascades. By examining the molecular mechanisms of PPARα, PPARβ/δ, and PPARγ, as well as their interactions with cofactors like PGC-1α, and their crosstalk with pathways like sterol regulatory element-binding protein (SREBP), NF-κB, AMP-activated protein kinase (AMPK), and adipokines, researchers and clinicians can better understand how T2D-related MASLD can be prevented or treated. Single PPAR agonists, such as fibrates and glitazones, have limited clinical efficacy in achieving hard liver histology endpoints like MASH resolution and fibrosis regression in humans. However, the Pan-PPAR agonist Lanifibranor at the highest doses shows promise in ameliorating these outcomes in subjects with non-cirrhotic MASH. This suggests that activating all three PPAR isoforms together enhances their therapeutic effects on various cells and target organs, restoring insulin resistance, improving gluco-lipidic homeostasis, while inhibiting pro-inflammatory and pro-fibrogenic pathways. Analysis of unresolved issues should dictate the research agenda.
DOI: https://doi.org/10.37349/edd.2025.100590
This article belongs to the special issue Nuclear Receptors and the Digestive Tract: from Molecular Physiology to Clinics via Pharmacology
Amyloidosis is a rare disease, corresponding to a deposition of proteins in various tissues. Amyloid light-chain (AL) amyloidosis can involve the liver in 17% to 45% of patients. Diagnosis of liver disease is based on specific criteria, coupling alkaline phosphatases and hepatomegaly. Liver stiffness is altered in cases of heart involvement, and overall, in cases of liver involvement. Liver biopsy is generally avoided due to an important bleeding risk. Treatment is essentially based on stem cell transplantation and chemotherapy, with large progress during the last decade. Liver involvement recovery is generally diagnosed with a reduction in alkaline phosphatases and in liver size.
Amyloidosis is a rare disease, corresponding to a deposition of proteins in various tissues. Amyloid light-chain (AL) amyloidosis can involve the liver in 17% to 45% of patients. Diagnosis of liver disease is based on specific criteria, coupling alkaline phosphatases and hepatomegaly. Liver stiffness is altered in cases of heart involvement, and overall, in cases of liver involvement. Liver biopsy is generally avoided due to an important bleeding risk. Treatment is essentially based on stem cell transplantation and chemotherapy, with large progress during the last decade. Liver involvement recovery is generally diagnosed with a reduction in alkaline phosphatases and in liver size.
DOI: https://doi.org/10.37349/edd.2025.100589
Hepatocellular carcinoma (HCC) ranks as the sixth most diagnosed cancer and the third most common cancer-related death globally. The underlying precise molecular mechanisms for its progression remain poorly understood. Interestingly, approximately 90% of HCC-related deaths are not due to the primary tumor itself but rather to its difficult-to-treat metastatic spread. Despite sorafenib being the first-line therapy for HCC, challenges such as drug resistance, frequent recurrence, and metastasis contribute to poor prognosis. In this context, alternative therapeutic strategies are urgently needed. A broad spectrum of phytochemicals, including polyphenolic derivatives, flavonoids, carotenoids, alkaloids, terpenes, lignans, and saponins, has shown considerable promise as potential anti-cancer agents, both in vitro and in vivo. These natural plant-derived compounds exhibit distinct and overlapping mechanisms of action, characterized by their antioxidant, anti-inflammatory, and anti-cancer properties, offering a novel approach to HCC treatment. An extensive literature search was conducted from 2010 to 2024 using reputable electronic databases such as MEDLINE, Embase, Google Scholar, Science Direct, and other reliable sources using different keywords, including HCC, medicinal plants in HCC, HCC metastasis, and mechanism of action of medicinal plants in HCC, among others. This comprehensive review aims to summarize the potential role of plant-based bioactive components in combating HCC through various cellular mechanisms, highlighting their therapeutic potential in the management of both primary and metastatic disease.
Hepatocellular carcinoma (HCC) ranks as the sixth most diagnosed cancer and the third most common cancer-related death globally. The underlying precise molecular mechanisms for its progression remain poorly understood. Interestingly, approximately 90% of HCC-related deaths are not due to the primary tumor itself but rather to its difficult-to-treat metastatic spread. Despite sorafenib being the first-line therapy for HCC, challenges such as drug resistance, frequent recurrence, and metastasis contribute to poor prognosis. In this context, alternative therapeutic strategies are urgently needed. A broad spectrum of phytochemicals, including polyphenolic derivatives, flavonoids, carotenoids, alkaloids, terpenes, lignans, and saponins, has shown considerable promise as potential anti-cancer agents, both in vitro and in vivo. These natural plant-derived compounds exhibit distinct and overlapping mechanisms of action, characterized by their antioxidant, anti-inflammatory, and anti-cancer properties, offering a novel approach to HCC treatment. An extensive literature search was conducted from 2010 to 2024 using reputable electronic databases such as MEDLINE, Embase, Google Scholar, Science Direct, and other reliable sources using different keywords, including HCC, medicinal plants in HCC, HCC metastasis, and mechanism of action of medicinal plants in HCC, among others. This comprehensive review aims to summarize the potential role of plant-based bioactive components in combating HCC through various cellular mechanisms, highlighting their therapeutic potential in the management of both primary and metastatic disease.
DOI: https://doi.org/10.37349/edd.2025.100588
Brazil ranks second globally in absolute liver transplants and leads pediatric transplantation in Latin America. This scoping review aims to map the results and perspectives of pediatric liver transplantation in Brazil from 2000 to 2022. A scoping review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews Checklist (PRISMA-ScR) guidelines, using PubMed, Virtual Health Library (VHL), and ScienceDirect. From 293 records, 26 studies were included based on predefined criteria. The review focused on clinical indications, techniques, outcomes, and regional disparities. Results: Of the 26 included studies, 10 (38%) reported survival rates, showing 1-, 5-, and 10-year survival of 89.3%, 78.1%, and 68.5% for deceased donors and 93.1%, 85.7%, and 67.5% for living donors, respectively. Eleven studies (42%) discussed living donor liver transplantation (LDLT), which accounts for 53.4% of pediatric transplants. Eight studies (31%) detailed postoperative complications, such as vascular (up to 19%) and biliary (15.7%) issues, rejection (~ 50%), and infections. The COVID-19 pandemic led to a 20.6% reduction in transplant activity and increased waiting list mortality from 8.4% to 11.9%. Despite Brazil’s leadership in pediatric liver transplants, challenges persist, including donor shortages, diagnostic delays, geographic concentration in São Paulo (66%), and limited data systematization. These factors hinder equitable access and optimal outcomes across the country. To improve pediatric liver transplantation in Brazil, actions are needed to strengthen donor registration systems, decentralize services, enhance team training, and adopt techniques like split liver transplantation. Expanding national databases and prognostic tools will help address disparities and improve care.
Brazil ranks second globally in absolute liver transplants and leads pediatric transplantation in Latin America. This scoping review aims to map the results and perspectives of pediatric liver transplantation in Brazil from 2000 to 2022. A scoping review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews Checklist (PRISMA-ScR) guidelines, using PubMed, Virtual Health Library (VHL), and ScienceDirect. From 293 records, 26 studies were included based on predefined criteria. The review focused on clinical indications, techniques, outcomes, and regional disparities. Results: Of the 26 included studies, 10 (38%) reported survival rates, showing 1-, 5-, and 10-year survival of 89.3%, 78.1%, and 68.5% for deceased donors and 93.1%, 85.7%, and 67.5% for living donors, respectively. Eleven studies (42%) discussed living donor liver transplantation (LDLT), which accounts for 53.4% of pediatric transplants. Eight studies (31%) detailed postoperative complications, such as vascular (up to 19%) and biliary (15.7%) issues, rejection (~ 50%), and infections. The COVID-19 pandemic led to a 20.6% reduction in transplant activity and increased waiting list mortality from 8.4% to 11.9%. Despite Brazil’s leadership in pediatric liver transplants, challenges persist, including donor shortages, diagnostic delays, geographic concentration in São Paulo (66%), and limited data systematization. These factors hinder equitable access and optimal outcomes across the country. To improve pediatric liver transplantation in Brazil, actions are needed to strengthen donor registration systems, decentralize services, enhance team training, and adopt techniques like split liver transplantation. Expanding national databases and prognostic tools will help address disparities and improve care.
DOI: https://doi.org/10.37349/edd.2025.100587
Here, the history of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis nomenclatures is summarized. Metabolic dysfunction-associated fatty liver disease (MAFLD) was coined in 2020, and metabolic dysfunction-associated steatotic liver disease (MASLD) was proposed in 2023. With this backset, the present article aims at reviewing the similarities and differences between MAFLD and MASLD through a systematic analysis of published comparative studies. MAFLD and MASLD have a complex disease spectrum comprising, further to all-cause mortality, hepatic (fibrosis, cirrhosis, and primary liver cancer) and extrahepatic outcomes (major adverse cardiovascular events, chronic kidney disease, extrahepatic cancers, type 2 diabetes, and vascular dementia). Comparative studies document that—due to its superior ability to identify liver fibrosis—MAFLD better captures mortality owing to all-causes, hepatic and extrahepatic outcomes, which are strongly associated with the severity of liver fibrosis. Moreover, MASLD is inappropriate in pediatric care, lacks specificity, tends to overdiagnosis, does not consider coexistent viral hepatitis or lean subjects, and amplifies disease heterogeneity. Collectively, the evidence presented in this narrative review supports an urgent need for the development of evidence-based guideline statements. This novel developmental process should involve not only a systematic review of the evidence, with equal contribution from all the world’s regions of stakeholders and clinical panelists, but also should use quantitative data to identify an objective-level consensus to guarantee wide adoption of the process outcomes.
Here, the history of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis nomenclatures is summarized. Metabolic dysfunction-associated fatty liver disease (MAFLD) was coined in 2020, and metabolic dysfunction-associated steatotic liver disease (MASLD) was proposed in 2023. With this backset, the present article aims at reviewing the similarities and differences between MAFLD and MASLD through a systematic analysis of published comparative studies. MAFLD and MASLD have a complex disease spectrum comprising, further to all-cause mortality, hepatic (fibrosis, cirrhosis, and primary liver cancer) and extrahepatic outcomes (major adverse cardiovascular events, chronic kidney disease, extrahepatic cancers, type 2 diabetes, and vascular dementia). Comparative studies document that—due to its superior ability to identify liver fibrosis—MAFLD better captures mortality owing to all-causes, hepatic and extrahepatic outcomes, which are strongly associated with the severity of liver fibrosis. Moreover, MASLD is inappropriate in pediatric care, lacks specificity, tends to overdiagnosis, does not consider coexistent viral hepatitis or lean subjects, and amplifies disease heterogeneity. Collectively, the evidence presented in this narrative review supports an urgent need for the development of evidence-based guideline statements. This novel developmental process should involve not only a systematic review of the evidence, with equal contribution from all the world’s regions of stakeholders and clinical panelists, but also should use quantitative data to identify an objective-level consensus to guarantee wide adoption of the process outcomes.
DOI: https://doi.org/10.37349/edd.2025.100586
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
