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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
Hepatitis B virus (HBV) infection is a major risk factor of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Pathogenesis of HBV-induced cirrhosis and HCC involves viral factors and virus-triggered local inflammatory and immune responses, the latter leading to progressive fibrosis, cirrhosis and carcinogenesis. Antiviral therapeutics suppress HBV replication and reduce the risks of cirrhosis and HCC. We discuss the current knowledge on the pathogenesis of HBV-induced cirrhosis and HCC, focusing on mechanisms of current and emerging antiviral therapeutics.
Hepatitis B virus (HBV) infection is a major risk factor of cirrhosis and hepatocellular carcinoma (HCC) worldwide. Pathogenesis of HBV-induced cirrhosis and HCC involves viral factors and virus-triggered local inflammatory and immune responses, the latter leading to progressive fibrosis, cirrhosis and carcinogenesis. Antiviral therapeutics suppress HBV replication and reduce the risks of cirrhosis and HCC. We discuss the current knowledge on the pathogenesis of HBV-induced cirrhosis and HCC, focusing on mechanisms of current and emerging antiviral therapeutics.
DOI: https://doi.org/10.37349/edd.2025.100565
This article belongs to the special issue Viral Hepatitis
Microsatellite unstable (MSI) colorectal cancer (CRC) tumors have a high mutational load (particularly frame-shift mutations) that creates numerous neoantigens that are presented to major histocompatibility complex molecules and recognized by T cells. Consequently, MSI tumors have a higher presence of tumor-infiltrating lymphocytes than mismatch repair-proficient tumors. Colorectal cancer patients with MSI constitute a rare group of immune checkpoint inhibitor (ICI)-responsive patients. Nonetheless, complete radiological responders comprise between 3% and 16% of MSI advanced CRC patients, which compares poorly with the 45% to 87% rate of pathological complete response in early MSI CRC patients treated with ICIs. In this review, we address the efficacy of current ICIs and the biological differences between early and advanced MSI CRC to potentially increase the efficacy of ICIs in both settings.
Microsatellite unstable (MSI) colorectal cancer (CRC) tumors have a high mutational load (particularly frame-shift mutations) that creates numerous neoantigens that are presented to major histocompatibility complex molecules and recognized by T cells. Consequently, MSI tumors have a higher presence of tumor-infiltrating lymphocytes than mismatch repair-proficient tumors. Colorectal cancer patients with MSI constitute a rare group of immune checkpoint inhibitor (ICI)-responsive patients. Nonetheless, complete radiological responders comprise between 3% and 16% of MSI advanced CRC patients, which compares poorly with the 45% to 87% rate of pathological complete response in early MSI CRC patients treated with ICIs. In this review, we address the efficacy of current ICIs and the biological differences between early and advanced MSI CRC to potentially increase the efficacy of ICIs in both settings.
DOI: https://doi.org/10.37349/edd.2025.100564
This article belongs to the special issue Immunotherapy for Cancer of Digestive System
Liver inflammation, injury, and hepatic cell death are caused by external agents (viruses, bacteria, drugs, alcohol, etc.) along with the genetic susceptibility of an individual. Persistent activation of the fibrogenic response in cells leads to liver fibrosis which in turn progresses to cirrhosis and cancer. The dysregulation of the immune system generates reactive oxygen species which in turn induce necrosis of hepatocytes. This process activates hepatic stellate cells and myofibroblasts to produce a huge quantity of collagens, alpha-smooth muscle actin, and extracellular matrix deposition in liver parenchyma. Due to the multifactorial nature of this disease, conventional therapies increasingly attempted combinatorial therapy or polytherapy to target multiple mechanistic sites in order to prevent entry into further complicated irreversible stages. Despite advancements in conventional therapy, several cases aggravate fibrosis (grade 3 to 4) and cirrhosis. The inconsistency in treatment outcomes and limited organ donors for liver transplantation have led to an ever-increasing and challenging demand for alternative therapies. In this review, we analyze the mechanism and causative factors of liver diseases, conventional mode, and alternative therapeutic options. The central to liver diseases are immune dysregulation, hence bioactive agents with immunomodulatory properties should be searched and exploited to meet therapeutic needs. Mesenchymal stem cells (MSCs) with their specialized anti-inflammatory and immunomodulatory properties could be utilized as an effective alternative therapeutic candidate in treating inflammatory liver diseases. MSC-derived exosome further provides an additional immunomodulatory option that could work in tandem with MSC in a synergistic form. In this series, we have reviewed preconditioned and genetically edited MSCs to augment homing, proliferation, and differentiation. Importantly, all the clinical challenges should be noted and addressed before stem cell cytotherapy should be considered safe and effective for patients with liver diseases. Published literature indicated that MSC therapy has the potential to substitute conventional options in the treatment of high-grade fibrosis and cirrhosis.
Liver inflammation, injury, and hepatic cell death are caused by external agents (viruses, bacteria, drugs, alcohol, etc.) along with the genetic susceptibility of an individual. Persistent activation of the fibrogenic response in cells leads to liver fibrosis which in turn progresses to cirrhosis and cancer. The dysregulation of the immune system generates reactive oxygen species which in turn induce necrosis of hepatocytes. This process activates hepatic stellate cells and myofibroblasts to produce a huge quantity of collagens, alpha-smooth muscle actin, and extracellular matrix deposition in liver parenchyma. Due to the multifactorial nature of this disease, conventional therapies increasingly attempted combinatorial therapy or polytherapy to target multiple mechanistic sites in order to prevent entry into further complicated irreversible stages. Despite advancements in conventional therapy, several cases aggravate fibrosis (grade 3 to 4) and cirrhosis. The inconsistency in treatment outcomes and limited organ donors for liver transplantation have led to an ever-increasing and challenging demand for alternative therapies. In this review, we analyze the mechanism and causative factors of liver diseases, conventional mode, and alternative therapeutic options. The central to liver diseases are immune dysregulation, hence bioactive agents with immunomodulatory properties should be searched and exploited to meet therapeutic needs. Mesenchymal stem cells (MSCs) with their specialized anti-inflammatory and immunomodulatory properties could be utilized as an effective alternative therapeutic candidate in treating inflammatory liver diseases. MSC-derived exosome further provides an additional immunomodulatory option that could work in tandem with MSC in a synergistic form. In this series, we have reviewed preconditioned and genetically edited MSCs to augment homing, proliferation, and differentiation. Importantly, all the clinical challenges should be noted and addressed before stem cell cytotherapy should be considered safe and effective for patients with liver diseases. Published literature indicated that MSC therapy has the potential to substitute conventional options in the treatment of high-grade fibrosis and cirrhosis.
DOI: https://doi.org/10.37349/edd.2025.100563
Mitochondria are essential organelles responsible for intracellular energy production and play crucial roles in cellular metabolism, inflammation, and apoptosis. Reactive oxygen species (ROS) are primarily produced in the mitochondria and endoplasmic reticulum of hepatocytes due to the activity of cytochrome P450 enzymes. Under ideal conditions, cells have specific molecular mechanisms that manage oxidative stress levels, thus ensuring a balance between oxidants and antioxidants. The interplay between ROS-induced mitochondrial dysfunction and the activation of the NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome in the context of liver diseases has been extensively studied. However, the exact mechanisms by which mitochondria promote the activation of the NLRP3 inflammasome and contribute to the onset of liver disease remain unclear. This review aims to elucidate the recently discovered mitochondrial regulation of the NLRP3 inflammasome in liver disorders, including alcohol-related liver disease (ALD), metabolic-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). Finally, it summarizes various natural and pharmaceutical agents that can mitigate liver damage by modulating the activation of the NLRP3 inflammasome through mitochondrial pathways. This work serves as an important resource for identifying new therapeutic approaches and provides further support for advancing the understanding of liver diseases.
Mitochondria are essential organelles responsible for intracellular energy production and play crucial roles in cellular metabolism, inflammation, and apoptosis. Reactive oxygen species (ROS) are primarily produced in the mitochondria and endoplasmic reticulum of hepatocytes due to the activity of cytochrome P450 enzymes. Under ideal conditions, cells have specific molecular mechanisms that manage oxidative stress levels, thus ensuring a balance between oxidants and antioxidants. The interplay between ROS-induced mitochondrial dysfunction and the activation of the NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome in the context of liver diseases has been extensively studied. However, the exact mechanisms by which mitochondria promote the activation of the NLRP3 inflammasome and contribute to the onset of liver disease remain unclear. This review aims to elucidate the recently discovered mitochondrial regulation of the NLRP3 inflammasome in liver disorders, including alcohol-related liver disease (ALD), metabolic-associated steatotic liver disease (MASLD), and hepatocellular carcinoma (HCC). Finally, it summarizes various natural and pharmaceutical agents that can mitigate liver damage by modulating the activation of the NLRP3 inflammasome through mitochondrial pathways. This work serves as an important resource for identifying new therapeutic approaches and provides further support for advancing the understanding of liver diseases.
DOI: https://doi.org/10.37349/edd.2024.00062
This article belongs to the special issue Mitochondria and Lipid Signalling in Liver Diseases
Steatotic liver disease (SLD) has been known for a long time, but our understanding of this disease has remained poor until the past decade. Despite extensive research, our ability to comprehend the etiopathogenesis and natural course of SLD is far from the desired level of comprehension. This is required to develop a universally effective novel therapeutic agent. This review aims to concisely elaborate the conceptual approach and advancement in the understanding of global disease burden and etiopathogenic process, identifying the gaps and the pathophysiologic mechanism behind developing novel therapeutic agents. We searched two major databases, PubMed and Google Scholar, to identify publications related to the abovementioned topics. All publications, including original papers, reviews, and commentaries, were reviewed. Findings: Metabolic dysfunction-associated steatotic liver disease (MASLD) is not limited to obese individuals, rather, it may develop in any individual independent of weight. Visceral adiposity is strongly associated with MASLD and subsequent risks of cirrhosis, hepatocellular carcinoma, and cardiovascular disease. MASLD is associated with diabetes mellitus independent of underlying pathogenic mechanisms, and there is a bidirectional connection between MASLD and diabetes mellitus, making the situation quite challenging. Not all patients with MASLD exhibit atherogenic dyslipidemia and thus do not have a higher risk of cardiovascular disease. The overlap of these metabolic risk factors is not straightforward. There is a differential contribution of these risk factors based on age, gender, race, ethnicity, alcohol consumption, and microbiota composition. Poor dietary habits and lifestyle directly affect the microbiota, modulators, and mediators, thereby affecting the final biochemical processes leading to steatosis, steatohepatitis, fibrosis, and oncogenesis. In conclusion, MASLD is a complex and pathogenically heterogeneous disease with significant interpatient variation in the natural course and outcome. Understanding the precise mechanism of variability is the key gap and a limiting factor in the development of a novel therapeutic agent.
Steatotic liver disease (SLD) has been known for a long time, but our understanding of this disease has remained poor until the past decade. Despite extensive research, our ability to comprehend the etiopathogenesis and natural course of SLD is far from the desired level of comprehension. This is required to develop a universally effective novel therapeutic agent. This review aims to concisely elaborate the conceptual approach and advancement in the understanding of global disease burden and etiopathogenic process, identifying the gaps and the pathophysiologic mechanism behind developing novel therapeutic agents. We searched two major databases, PubMed and Google Scholar, to identify publications related to the abovementioned topics. All publications, including original papers, reviews, and commentaries, were reviewed. Findings: Metabolic dysfunction-associated steatotic liver disease (MASLD) is not limited to obese individuals, rather, it may develop in any individual independent of weight. Visceral adiposity is strongly associated with MASLD and subsequent risks of cirrhosis, hepatocellular carcinoma, and cardiovascular disease. MASLD is associated with diabetes mellitus independent of underlying pathogenic mechanisms, and there is a bidirectional connection between MASLD and diabetes mellitus, making the situation quite challenging. Not all patients with MASLD exhibit atherogenic dyslipidemia and thus do not have a higher risk of cardiovascular disease. The overlap of these metabolic risk factors is not straightforward. There is a differential contribution of these risk factors based on age, gender, race, ethnicity, alcohol consumption, and microbiota composition. Poor dietary habits and lifestyle directly affect the microbiota, modulators, and mediators, thereby affecting the final biochemical processes leading to steatosis, steatohepatitis, fibrosis, and oncogenesis. In conclusion, MASLD is a complex and pathogenically heterogeneous disease with significant interpatient variation in the natural course and outcome. Understanding the precise mechanism of variability is the key gap and a limiting factor in the development of a novel therapeutic agent.
DOI: https://doi.org/10.37349/edd.2024.00061
