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Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity, insulin resistance, and increased cardiovascular risk. Male hypogonadism has emerged as a potentially modifiable risk factor, and testosterone replacement therapy (TRT) has been proposed as a potential adjunctive treatment for MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in hypogonadal men. Cross-sectional and longitudinal studies demonstrate a consistent inverse association between serum testosterone and MASLD prevalence and severity. Interventional evidence from randomized controlled trials (RCTs) and observational cohorts suggests TRT is associated with reductions in hepatic steatosis and improvements in liver-related biomarkers. In selected hypogonadal men, particularly those with metabolically active disease, TRT may contribute to MASH resolution and fibrosis improvement, although histological data remain limited. The most consistent response is observed in men with concurrent type 2 diabetes (T2D), obesity, or obstructive sleep apnea (OSA) and significant baseline steatosis. Preclinical data support convergent mechanisms involving the androgen receptor (AR), adenosine monophosphate-activated protein kinase (AMPK), and antifibrotic pathways. While recently approved therapies such as resmetirom and semaglutide represent significant advances in MASH treatment, their distinct mechanisms suggest that complementary roles alongside TRT are biologically plausible, though this remains entirely hypothetical in the absence of combination trial data. Taken together, TRT may represent a promising adjunctive therapy for reducing hepatic steatosis and improving the histopathological features of MASH in selected hypogonadal men with MASLD, particularly those with obesity or T2D and significant baseline steatosis; however, routine clinical use will require large, well-powered Phase 3 RCTs featuring standardized histological endpoints, extended follow-up, and rigorous cardiovascular and oncologic safety data.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is strongly associated with obesity, insulin resistance, and increased cardiovascular risk. Male hypogonadism has emerged as a potentially modifiable risk factor, and testosterone replacement therapy (TRT) has been proposed as a potential adjunctive treatment for MASLD and metabolic dysfunction-associated steatohepatitis (MASH) in hypogonadal men. Cross-sectional and longitudinal studies demonstrate a consistent inverse association between serum testosterone and MASLD prevalence and severity. Interventional evidence from randomized controlled trials (RCTs) and observational cohorts suggests TRT is associated with reductions in hepatic steatosis and improvements in liver-related biomarkers. In selected hypogonadal men, particularly those with metabolically active disease, TRT may contribute to MASH resolution and fibrosis improvement, although histological data remain limited. The most consistent response is observed in men with concurrent type 2 diabetes (T2D), obesity, or obstructive sleep apnea (OSA) and significant baseline steatosis. Preclinical data support convergent mechanisms involving the androgen receptor (AR), adenosine monophosphate-activated protein kinase (AMPK), and antifibrotic pathways. While recently approved therapies such as resmetirom and semaglutide represent significant advances in MASH treatment, their distinct mechanisms suggest that complementary roles alongside TRT are biologically plausible, though this remains entirely hypothetical in the absence of combination trial data. Taken together, TRT may represent a promising adjunctive therapy for reducing hepatic steatosis and improving the histopathological features of MASH in selected hypogonadal men with MASLD, particularly those with obesity or T2D and significant baseline steatosis; however, routine clinical use will require large, well-powered Phase 3 RCTs featuring standardized histological endpoints, extended follow-up, and rigorous cardiovascular and oncologic safety data.
DOI: https://doi.org/10.37349/edd.2026.1005135
This article belongs to the special issue Fibrosis and Hepatobiliary Cancer
Crimean-Congo hemorrhagic fever virus (CCHFV) is a globally distributed, highconsequence zoonotic pathogen whose clinical spectrum extends far beyond hemorrhagic diathesis. Over recent years, mounting evidence has illuminated the central role of hepatic involvement in shaping both acute disease outcomes and potential postinfectious sequelae. The liver functions as a complex immunological organ, critically integrating viral replication dynamics with host innate and adaptive responses. This review synthesizes current knowledge on the hepatic immunopathogenesis of CCHFV, delineating the contributions of direct cytopathic effects and virusinduced inflammatory circuits orchestrated by hepatocytes, Kupffer cells, and liver sinusoidal endothelial cells. We further dissect how viral determinants, particularly genomic diversity within the nucleoprotein and other structural elements, modulate host sensing, immune evasion, and the intensity of liver injury. The potential for long-term hepatic consequences, including the hypothesis-driven risk of hepatocellular carcinoma (HCC), is examined through the lens of chronic inflammation, altered tissue remodeling, and emerging parallels with other viral hepatitides. Despite these advances, critical gaps persist in mapping cell-type-specific viral tropism, mechanistic genotype-phenotype correlations, and the interplay between acute hepatic injury and long-term liver health. We highlight future research priorities that include the application of single-cell and spatial omics, advanced humanized models, and integrated immunovirological surveillance, all poised to resolve outstanding questions and facilitate the rational design of vaccines and therapeutics that provide robust protection while averting immunopathological liver injury. Collectively, this review reframes CCHFV from an acute hemorrhagic threat to a major disruptor of hepatic immune homeostasis, underscoring the need for multidisciplinary approaches to mitigate both immediate and chronic consequences of infection.
Crimean-Congo hemorrhagic fever virus (CCHFV) is a globally distributed, highconsequence zoonotic pathogen whose clinical spectrum extends far beyond hemorrhagic diathesis. Over recent years, mounting evidence has illuminated the central role of hepatic involvement in shaping both acute disease outcomes and potential postinfectious sequelae. The liver functions as a complex immunological organ, critically integrating viral replication dynamics with host innate and adaptive responses. This review synthesizes current knowledge on the hepatic immunopathogenesis of CCHFV, delineating the contributions of direct cytopathic effects and virusinduced inflammatory circuits orchestrated by hepatocytes, Kupffer cells, and liver sinusoidal endothelial cells. We further dissect how viral determinants, particularly genomic diversity within the nucleoprotein and other structural elements, modulate host sensing, immune evasion, and the intensity of liver injury. The potential for long-term hepatic consequences, including the hypothesis-driven risk of hepatocellular carcinoma (HCC), is examined through the lens of chronic inflammation, altered tissue remodeling, and emerging parallels with other viral hepatitides. Despite these advances, critical gaps persist in mapping cell-type-specific viral tropism, mechanistic genotype-phenotype correlations, and the interplay between acute hepatic injury and long-term liver health. We highlight future research priorities that include the application of single-cell and spatial omics, advanced humanized models, and integrated immunovirological surveillance, all poised to resolve outstanding questions and facilitate the rational design of vaccines and therapeutics that provide robust protection while averting immunopathological liver injury. Collectively, this review reframes CCHFV from an acute hemorrhagic threat to a major disruptor of hepatic immune homeostasis, underscoring the need for multidisciplinary approaches to mitigate both immediate and chronic consequences of infection.
DOI: https://doi.org/10.37349/edd.2026.1005134
Primary sclerosing cholangitis (PSC) is a rare chronic cholangiopathy that is strongly associated with inflammatory bowel disease, particularly ulcerative colitis. It is characterized by multifocal biliary strictures, typically producing the classic “beads-on-a-string” appearance on magnetic resonance cholangiopancreatography, and by the histological finding of periductal concentric fibrosis (“onion-skin” fibrosis). Its pathogenesis is multifactorial and involves genetic susceptibility, immune dysregulation, environmental influences, and perturbations of the gut-liver axis. In this context, toxic bile acids and other luminal mediators originating from inflamed bowel mucosa may contribute to cholangiocyte injury. Phosphatidylcholine (PC) plays a central role in membrane integrity, cellular signaling, and inflammatory regulation, and its deficiency may predispose to hepatobiliary damage. Kindlin proteins are key modulators of integrin-mediated functions; notably, kindlin-2 contributes to the stabilization of intercellular junctions, and its loss impairs smooth muscle and intestinal development. Mice with biliary-specific deletion of kindlin-2 develop onion-skin fibrosis in the absence of overt cholestatic abnormalities, thereby supporting the concept of a gut-liver pathogenic axis. Nevertheless, further investigation is required to determine the extent to which this model reproduces human PSC, particularly regarding PC availability and cholangiocyte junctional integrity. Disruption of tight junctions may reduce PC delivery to the biliary mucosa, thereby promoting hepatic injury. Although these findings support the rationale for exploring PC supplementation as a potential therapeutic strategy in PSC, additional studies are required before translation to clinical trials can be justified.
Primary sclerosing cholangitis (PSC) is a rare chronic cholangiopathy that is strongly associated with inflammatory bowel disease, particularly ulcerative colitis. It is characterized by multifocal biliary strictures, typically producing the classic “beads-on-a-string” appearance on magnetic resonance cholangiopancreatography, and by the histological finding of periductal concentric fibrosis (“onion-skin” fibrosis). Its pathogenesis is multifactorial and involves genetic susceptibility, immune dysregulation, environmental influences, and perturbations of the gut-liver axis. In this context, toxic bile acids and other luminal mediators originating from inflamed bowel mucosa may contribute to cholangiocyte injury. Phosphatidylcholine (PC) plays a central role in membrane integrity, cellular signaling, and inflammatory regulation, and its deficiency may predispose to hepatobiliary damage. Kindlin proteins are key modulators of integrin-mediated functions; notably, kindlin-2 contributes to the stabilization of intercellular junctions, and its loss impairs smooth muscle and intestinal development. Mice with biliary-specific deletion of kindlin-2 develop onion-skin fibrosis in the absence of overt cholestatic abnormalities, thereby supporting the concept of a gut-liver pathogenic axis. Nevertheless, further investigation is required to determine the extent to which this model reproduces human PSC, particularly regarding PC availability and cholangiocyte junctional integrity. Disruption of tight junctions may reduce PC delivery to the biliary mucosa, thereby promoting hepatic injury. Although these findings support the rationale for exploring PC supplementation as a potential therapeutic strategy in PSC, additional studies are required before translation to clinical trials can be justified.
DOI: https://doi.org/10.37349/edd.2026.1005133
Gastric cancer is one of the most prevalent malignancies of the gastrointestinal tract. Worldwide, it ranks as the fourth most commonly diagnosed cancer and the third leading cause of cancer-related mortality. A variety of diagnostic approaches are used for the detection of gastric cancer. Early diagnosis of gastric cancer is crucial, as timely treatment can significantly improve patient prognosis. Detection and monitoring of circulating tumor DNA (ctDNA) provide valuable clinical information while minimizing the need for invasive procedures, such as tissue biopsy. These ctDNAs have been identified as reliable and accurate biomarkers for gastric cancer. The application of ctDNA in gastric cancer plays a significant role in the early diagnosis, detection, and monitoring of minimal residual disease, as well as in the clinical management of advanced-stage disease.
Gastric cancer is one of the most prevalent malignancies of the gastrointestinal tract. Worldwide, it ranks as the fourth most commonly diagnosed cancer and the third leading cause of cancer-related mortality. A variety of diagnostic approaches are used for the detection of gastric cancer. Early diagnosis of gastric cancer is crucial, as timely treatment can significantly improve patient prognosis. Detection and monitoring of circulating tumor DNA (ctDNA) provide valuable clinical information while minimizing the need for invasive procedures, such as tissue biopsy. These ctDNAs have been identified as reliable and accurate biomarkers for gastric cancer. The application of ctDNA in gastric cancer plays a significant role in the early diagnosis, detection, and monitoring of minimal residual disease, as well as in the clinical management of advanced-stage disease.
DOI: https://doi.org/10.37349/edd.2026.1005132
Climate change (CC) affects our health in ways especially when it comes to liver diseases. Rising temperatures and changing weather patterns are altering the spread and severity of liver diseases. CC can affect health, especially liver diseases, in direct and indirect ways. Hepatic infections such as viral hepatitis and schistosomiasis, metabolic dysfunction-associated steatotic liver disease (MASLD), hepatocellular carcinoma, and acute on chronic liver failure (ACLF) are examples. The movement of infected individuals from areas where diseases are endemic, prompted by ecological disasters, introduces these diseases to previously unexposed regions. CC serves as an early warning for shifts and the necessity to re-evaluate hepatic diseases, which is crucial for health policymakers. Ambient temperature and its variability have a major influence on the pathogenesis of MASLD, demonstrating nonlinear exposure–response relationships. Long-term temperature exposure follows a reverse J-shaped pattern, while temperature variability shows a U-shaped association, with both extremes independently increasing disease susceptibility. Prolonged exposure to cold and fluctuations in temperature could worsen various liver diseases. Gaining a deeper insight into these CC-related risks for our patients and practice is essential to optimize their care both now and in the warmer temperatures ahead. Incorporating climate resilience into public health initiatives may aid in alleviating the growing prevalence of liver diseases linked to CC. Aside from increasing awareness, which should take precedence, there is a pressing need to investigate innovative ways to frame the educational message and eliminate financial incentives that contribute to environmental damage. Common climate strategies for healthcare systems include reducing and managing waste, utilizing cleaner and less energy, offering and endorsing planet-friendly food options, and addressing transportation issues related to accessing healthcare facilities, such as transitioning in-person appointments to virtual consultations when possible, encouraging green-endoscopy practices, and participating in conferences virtually can be beneficial.
Climate change (CC) affects our health in ways especially when it comes to liver diseases. Rising temperatures and changing weather patterns are altering the spread and severity of liver diseases. CC can affect health, especially liver diseases, in direct and indirect ways. Hepatic infections such as viral hepatitis and schistosomiasis, metabolic dysfunction-associated steatotic liver disease (MASLD), hepatocellular carcinoma, and acute on chronic liver failure (ACLF) are examples. The movement of infected individuals from areas where diseases are endemic, prompted by ecological disasters, introduces these diseases to previously unexposed regions. CC serves as an early warning for shifts and the necessity to re-evaluate hepatic diseases, which is crucial for health policymakers. Ambient temperature and its variability have a major influence on the pathogenesis of MASLD, demonstrating nonlinear exposure–response relationships. Long-term temperature exposure follows a reverse J-shaped pattern, while temperature variability shows a U-shaped association, with both extremes independently increasing disease susceptibility. Prolonged exposure to cold and fluctuations in temperature could worsen various liver diseases. Gaining a deeper insight into these CC-related risks for our patients and practice is essential to optimize their care both now and in the warmer temperatures ahead. Incorporating climate resilience into public health initiatives may aid in alleviating the growing prevalence of liver diseases linked to CC. Aside from increasing awareness, which should take precedence, there is a pressing need to investigate innovative ways to frame the educational message and eliminate financial incentives that contribute to environmental damage. Common climate strategies for healthcare systems include reducing and managing waste, utilizing cleaner and less energy, offering and endorsing planet-friendly food options, and addressing transportation issues related to accessing healthcare facilities, such as transitioning in-person appointments to virtual consultations when possible, encouraging green-endoscopy practices, and participating in conferences virtually can be beneficial.
DOI: https://doi.org/10.37349/edd.2026.1005131
Obesity is a rapidly growing global health concern. The pathogenesis is complex and cannot be fully explained by lifestyle factors alone. The increasing attention towards this concern has finally been directed towards environmental contributors which may influence metabolic regulation. Microplastics and nano-plastics (MNPs) are ubiquitous environmental pollutants that have recently been detected in food, drinking water, air, and human biological samples, raising concerns about their potential role in metabolic disorders, including obesity. Chronic exposure to MNPs may interfere with metabolic homeostasis through multiple biological pathways. Emerging evidence, including both experimental and animal studies, reports alterations in lipid metabolism, body weight, insulin sensitivity, and inflammatory responses following MNPs exposure. This review synthesizes current evidence linking MNPs to obesity, highlighting key exposure pathways, mechanistic insights, and gaps in existing research. Understanding the metabolic implications of MNPs exposure is essential for advancing obesity research and informing future public health strategies. Further well-designed human studies are needed to clarify causal relationships and guide preventive interventions.
Obesity is a rapidly growing global health concern. The pathogenesis is complex and cannot be fully explained by lifestyle factors alone. The increasing attention towards this concern has finally been directed towards environmental contributors which may influence metabolic regulation. Microplastics and nano-plastics (MNPs) are ubiquitous environmental pollutants that have recently been detected in food, drinking water, air, and human biological samples, raising concerns about their potential role in metabolic disorders, including obesity. Chronic exposure to MNPs may interfere with metabolic homeostasis through multiple biological pathways. Emerging evidence, including both experimental and animal studies, reports alterations in lipid metabolism, body weight, insulin sensitivity, and inflammatory responses following MNPs exposure. This review synthesizes current evidence linking MNPs to obesity, highlighting key exposure pathways, mechanistic insights, and gaps in existing research. Understanding the metabolic implications of MNPs exposure is essential for advancing obesity research and informing future public health strategies. Further well-designed human studies are needed to clarify causal relationships and guide preventive interventions.
DOI: https://doi.org/10.37349/edd.2026.1005130
Aim:
To evaluate whether estrogen exposure is associated with pancreatic ductal adenocarcinoma (PDAC) risk and to determine whether estrogen signaling influences tumor biology, integrating population-based incidence, pharmacovigilance, and transcriptomic data.
Methods:
We conducted a multi-modal analysis using four complementary data sources. Population-based incidence was assessed using Surveillance, Epidemiology, and End Results (SEER) multiple-primary standardized incidence ratio (MP-SIR) methodology among female breast cancer survivors, with latency stratification. Pharmacovigilance disproportionality analysis of estradiol-associated pancreatic cancer reports was performed using OpenVigil access to the Food and Drug Administration Adverse Event Reporting System (FAERS), calculating proportional reporting ratios (PRRs), reporting odds ratios (RORs), and χ2 statistics. A prospective UK Biobank cohort analysis evaluated self-reported ever use of hormone replacement therapy (HRT) and incident registry-confirmed PDAC using a 5-year landmark and multivariable Cox proportional hazards regression. Tumor transcriptomic associations between estrogen receptor 1 (ESR1) signaling and stromal programs were examined in The Cancer Genome Atlas Pancreatic Adenocarcinoma (TCGA-PAAD) using Spearman correlation and nonparametric group comparisons.
Results:
In SEER, pancreatic cancer incidence among breast cancer survivors was comparable to the general population (SIR 1.03, 95% CI 1.00–1.07), with no elevation in early or late latency periods. In contrast, pharmacovigilance analysis demonstrated a strong inverse association between estradiol exposure and pancreatic cancer reporting (PRR and ROR 0.095; χ2 = 76.674). In the UK Biobank, 265,572 women contributed 705 incident PDAC events after the 5-year landmark. Ever use of HRT was not significantly associated with PDAC after adjustment for age, body mass index, smoking status, type 2 diabetes, and socioeconomic deprivation (HR 1.16, 95% CI 0.99–1.36; p = 0.059). TCGA analyses revealed a significant positive association between ESR1 expression and inflammatory, tumor-restraining cancer-associated fibroblast programs (p < 1 × 10–6).
Conclusions:
Estrogen exposure was not associated with a statistically significant reduction in PDAC incidence. Pharmacovigilance and transcriptomic findings support a possible tumor-modifying role for estrogen signaling, whereas the UK Biobank results do not demonstrate a protective association between broadly defined HRT use and PDAC incidence.
Aim:
To evaluate whether estrogen exposure is associated with pancreatic ductal adenocarcinoma (PDAC) risk and to determine whether estrogen signaling influences tumor biology, integrating population-based incidence, pharmacovigilance, and transcriptomic data.
Methods:
We conducted a multi-modal analysis using four complementary data sources. Population-based incidence was assessed using Surveillance, Epidemiology, and End Results (SEER) multiple-primary standardized incidence ratio (MP-SIR) methodology among female breast cancer survivors, with latency stratification. Pharmacovigilance disproportionality analysis of estradiol-associated pancreatic cancer reports was performed using OpenVigil access to the Food and Drug Administration Adverse Event Reporting System (FAERS), calculating proportional reporting ratios (PRRs), reporting odds ratios (RORs), and χ2 statistics. A prospective UK Biobank cohort analysis evaluated self-reported ever use of hormone replacement therapy (HRT) and incident registry-confirmed PDAC using a 5-year landmark and multivariable Cox proportional hazards regression. Tumor transcriptomic associations between estrogen receptor 1 (ESR1) signaling and stromal programs were examined in The Cancer Genome Atlas Pancreatic Adenocarcinoma (TCGA-PAAD) using Spearman correlation and nonparametric group comparisons.
Results:
In SEER, pancreatic cancer incidence among breast cancer survivors was comparable to the general population (SIR 1.03, 95% CI 1.00–1.07), with no elevation in early or late latency periods. In contrast, pharmacovigilance analysis demonstrated a strong inverse association between estradiol exposure and pancreatic cancer reporting (PRR and ROR 0.095; χ2 = 76.674). In the UK Biobank, 265,572 women contributed 705 incident PDAC events after the 5-year landmark. Ever use of HRT was not significantly associated with PDAC after adjustment for age, body mass index, smoking status, type 2 diabetes, and socioeconomic deprivation (HR 1.16, 95% CI 0.99–1.36; p = 0.059). TCGA analyses revealed a significant positive association between ESR1 expression and inflammatory, tumor-restraining cancer-associated fibroblast programs (p < 1 × 10–6).
Conclusions:
Estrogen exposure was not associated with a statistically significant reduction in PDAC incidence. Pharmacovigilance and transcriptomic findings support a possible tumor-modifying role for estrogen signaling, whereas the UK Biobank results do not demonstrate a protective association between broadly defined HRT use and PDAC incidence.
DOI: https://doi.org/10.37349/edd.2026.1005129
This article belongs to the special issue Diagnostic and Prognostic Biomarkers in Pancreatic Cancer
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma represents a distinctive low-grade non-Hodgkin B-cell malignancy and one of the clearest examples of infection-associated carcinogenesis. Accounting for 7–9% of all B-cell lymphomas, this disease demonstrates a unique therapeutic paradigm, as early-stage gastric MALT lymphoma achieves complete remission in approximately 60–90% of patients following Helicobacter pylori eradication alone. This response reflects the tumor’s dependence on chronic antigenic stimulation, though disease progression and treatment resistance are driven by genetic alterations, such as the t(11;18) translocation, that confer antigen-independent growth. This review synthesizes current knowledge on clinical presentation, diagnostic evaluation, immunopathogenesis, prognostic factors, and evidence-based management of gastric MALT lymphoma. This review discusses the molecular mechanisms underlying the transition from antigen-dependent to antigen-independent disease, emerging therapeutic strategies, including targeted molecular therapies and BTK inhibitors, and addresses ongoing challenges in diagnosis, treatment resistance, and surveillance. Additionally, the broader implications of gastric MALT lymphoma to better understand how chronic infection drives lymphomagenesis and how pathogen eradication can lead to regression of antigen-dependent lymphoma, with the aim of providing insights for other microbe-associated malignancies, have been discussed.
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma represents a distinctive low-grade non-Hodgkin B-cell malignancy and one of the clearest examples of infection-associated carcinogenesis. Accounting for 7–9% of all B-cell lymphomas, this disease demonstrates a unique therapeutic paradigm, as early-stage gastric MALT lymphoma achieves complete remission in approximately 60–90% of patients following Helicobacter pylori eradication alone. This response reflects the tumor’s dependence on chronic antigenic stimulation, though disease progression and treatment resistance are driven by genetic alterations, such as the t(11;18) translocation, that confer antigen-independent growth. This review synthesizes current knowledge on clinical presentation, diagnostic evaluation, immunopathogenesis, prognostic factors, and evidence-based management of gastric MALT lymphoma. This review discusses the molecular mechanisms underlying the transition from antigen-dependent to antigen-independent disease, emerging therapeutic strategies, including targeted molecular therapies and BTK inhibitors, and addresses ongoing challenges in diagnosis, treatment resistance, and surveillance. Additionally, the broader implications of gastric MALT lymphoma to better understand how chronic infection drives lymphomagenesis and how pathogen eradication can lead to regression of antigen-dependent lymphoma, with the aim of providing insights for other microbe-associated malignancies, have been discussed.
DOI: https://doi.org/10.37349/edd.2026.1005128
This article belongs to the special issue Helicobacter Pylori and Infection: Genomics, Diagnosis, Pathogenesis, Antibiotic Resistance, Microbiota, Cancer, Prevention and Therapeutics
Hepatitis E virus (HEV) is a major global health concern, evolving from a self-limited enteric infection to a complex systemic disease with an expanding burden. This narrative review synthesizes current evidence on HEV virology, epidemiology, zoonotic transmission, and clinical manifestations to inform clinicians, researchers, and policymakers. Despite substantial morbidity among pregnant women and immunosuppressed patients, HEV awareness remains limited, and therapeutic options are constrained. Four genotypes (1–4) show distinct epidemiological patterns; chronic infection occurs primarily in immunocompromised hosts, while extrahepatic manifestations, including neurological and renal complications, are increasingly recognized. Treatment remains limited to ribavirin with variable efficacy and contraindications. The HEV-239 vaccine demonstrates sustained efficacy but requires broader implementation. This review integrates recent advances across virology, clinical practice, and public health, offering a unified framework for understanding HEV as a systemic disease requiring enhanced surveillance, targeted antiviral development, and expanded vaccine deployment within a “One Health” framework.
Hepatitis E virus (HEV) is a major global health concern, evolving from a self-limited enteric infection to a complex systemic disease with an expanding burden. This narrative review synthesizes current evidence on HEV virology, epidemiology, zoonotic transmission, and clinical manifestations to inform clinicians, researchers, and policymakers. Despite substantial morbidity among pregnant women and immunosuppressed patients, HEV awareness remains limited, and therapeutic options are constrained. Four genotypes (1–4) show distinct epidemiological patterns; chronic infection occurs primarily in immunocompromised hosts, while extrahepatic manifestations, including neurological and renal complications, are increasingly recognized. Treatment remains limited to ribavirin with variable efficacy and contraindications. The HEV-239 vaccine demonstrates sustained efficacy but requires broader implementation. This review integrates recent advances across virology, clinical practice, and public health, offering a unified framework for understanding HEV as a systemic disease requiring enhanced surveillance, targeted antiviral development, and expanded vaccine deployment within a “One Health” framework.
DOI: https://doi.org/10.37349/edd.2026.1005127
This article belongs to the special issue Viral Hepatitis
The brain–gut axis, first described in the 19th century, refers to the complex bidirectional communication network between the central nervous system and the gastrointestinal tract. This dynamic system operates through neuronal, endocrine, and immune pathways. It has since expanded to include the influence of gut microbiota, given its significant role in gut motility disorders and neurological diseases. The intricate relationship involves multiple signaling mechanisms, including toll-like receptors, nuclear factor-kappa B, α-synuclein, the hypothalamic–pituitary–adrenal axis, and vagal signaling. Dysregulation of the brain–gut axis has been implicated in numerous neurological conditions, including Parkinson’s disease, stroke, multiple sclerosis, autism spectrum disorder, spinal cord injury, and peripheral neuropathies, many of which present with well-recognized gastrointestinal manifestations. Conversely, neurological sequelae are frequently associated with primary gastrointestinal disorders such as inflammatory bowel disease, celiac disease, and hepatic failure. This narrative literature review aims to examine the epidemiology, clinical presentation, and pathogenesis of common neurological and gastrointestinal diseases through the lens of the brain–gut axis. By highlighting the interconnected metabolic, immune, and physiological mechanisms underlying these conditions, this review seeks to promote a more integrated understanding of disease processes and to support improved diagnostic strategies, therapeutic approaches, and long-term patient outcomes.
The brain–gut axis, first described in the 19th century, refers to the complex bidirectional communication network between the central nervous system and the gastrointestinal tract. This dynamic system operates through neuronal, endocrine, and immune pathways. It has since expanded to include the influence of gut microbiota, given its significant role in gut motility disorders and neurological diseases. The intricate relationship involves multiple signaling mechanisms, including toll-like receptors, nuclear factor-kappa B, α-synuclein, the hypothalamic–pituitary–adrenal axis, and vagal signaling. Dysregulation of the brain–gut axis has been implicated in numerous neurological conditions, including Parkinson’s disease, stroke, multiple sclerosis, autism spectrum disorder, spinal cord injury, and peripheral neuropathies, many of which present with well-recognized gastrointestinal manifestations. Conversely, neurological sequelae are frequently associated with primary gastrointestinal disorders such as inflammatory bowel disease, celiac disease, and hepatic failure. This narrative literature review aims to examine the epidemiology, clinical presentation, and pathogenesis of common neurological and gastrointestinal diseases through the lens of the brain–gut axis. By highlighting the interconnected metabolic, immune, and physiological mechanisms underlying these conditions, this review seeks to promote a more integrated understanding of disease processes and to support improved diagnostic strategies, therapeutic approaches, and long-term patient outcomes.
DOI: https://doi.org/10.37349/edd.2026.1005126
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent extranodal B-cell lymphoma that arises in close association with chronic Helicobacter pylori (H. pylori) infection and represents a unique paradigm of infection-driven oncogenesis. Persistent H. pylori colonization induces organized lymphoid tissue within the normally lymphoid-poor gastric mucosa, promoting sustained antigen-dependent T-cell-mediated B-cell proliferation and eventual clonal transformation. In contrast to many other lymphoid malignancies, early-stage gastric MALT lymphoma often regresses following microbial eradication, highlighting the central role of antigenic stimulation in disease pathogenesis. This review provides a contemporary overview of H. pylori-associated gastric MALT lymphoma, integrating epidemiology, molecular and immunologic mechanisms of lymphomagenesis, diagnostic evaluation, and modern management strategies. This review gives particular attention to molecular determinants of treatment response, including the t(11;18)(q21;q21)/API2-MALT1 translocation and other NF-κB-activating alterations that promote antigen-independent growth and resistance to eradication therapy. Current therapeutic approaches are reviewed, including antibiotic eradication regimens, radiotherapy, immunotherapy, and systemic treatment strategies for refractory or disseminated disease. By integrating mechanistic insights with clinical practice, this review highlights a precision-based framework for the diagnosis, risk stratification, and management of gastric MALT lymphoma in the modern era.
Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent extranodal B-cell lymphoma that arises in close association with chronic Helicobacter pylori (H. pylori) infection and represents a unique paradigm of infection-driven oncogenesis. Persistent H. pylori colonization induces organized lymphoid tissue within the normally lymphoid-poor gastric mucosa, promoting sustained antigen-dependent T-cell-mediated B-cell proliferation and eventual clonal transformation. In contrast to many other lymphoid malignancies, early-stage gastric MALT lymphoma often regresses following microbial eradication, highlighting the central role of antigenic stimulation in disease pathogenesis. This review provides a contemporary overview of H. pylori-associated gastric MALT lymphoma, integrating epidemiology, molecular and immunologic mechanisms of lymphomagenesis, diagnostic evaluation, and modern management strategies. This review gives particular attention to molecular determinants of treatment response, including the t(11;18)(q21;q21)/API2-MALT1 translocation and other NF-κB-activating alterations that promote antigen-independent growth and resistance to eradication therapy. Current therapeutic approaches are reviewed, including antibiotic eradication regimens, radiotherapy, immunotherapy, and systemic treatment strategies for refractory or disseminated disease. By integrating mechanistic insights with clinical practice, this review highlights a precision-based framework for the diagnosis, risk stratification, and management of gastric MALT lymphoma in the modern era.
DOI: https://doi.org/10.37349/edd.2026.1005125
This article belongs to the special issue Helicobacter Pylori and Infection: Genomics, Diagnosis, Pathogenesis, Antibiotic Resistance, Microbiota, Cancer, Prevention and Therapeutics
Immunotherapy is a promising treatment strategy for treating colorectal cancer (CRC). Despite significant advances in this field, resistance and low efficacy of immunotherapy remain a principal problem. One of the most important factors affecting the response to immunotherapy is the tumor microenvironment (TME). Among the components of the TME, tumor-associated macrophages (TAMs) are key immune cells involved in cancer progression by stimulating tumor cell proliferation, angiogenesis, epithelial-mesenchymal transition, metastasis, and tumor immune evasion. This review presents currently investigated combination therapy based on the immune checkpoint inhibitors and inhibitors of diverse components of the TME, including TAMs, that can potentially increase the effectiveness of CRC treatment. Therapeutic efficacy, together with the functional activity of TAMs, is estimated in multiple preclinical data obtained with diverse in vitro and in vivo models. Ongoing clinical trials demonstrated the association of treatment effectiveness with TAM phenotypes and functions.
Immunotherapy is a promising treatment strategy for treating colorectal cancer (CRC). Despite significant advances in this field, resistance and low efficacy of immunotherapy remain a principal problem. One of the most important factors affecting the response to immunotherapy is the tumor microenvironment (TME). Among the components of the TME, tumor-associated macrophages (TAMs) are key immune cells involved in cancer progression by stimulating tumor cell proliferation, angiogenesis, epithelial-mesenchymal transition, metastasis, and tumor immune evasion. This review presents currently investigated combination therapy based on the immune checkpoint inhibitors and inhibitors of diverse components of the TME, including TAMs, that can potentially increase the effectiveness of CRC treatment. Therapeutic efficacy, together with the functional activity of TAMs, is estimated in multiple preclinical data obtained with diverse in vitro and in vivo models. Ongoing clinical trials demonstrated the association of treatment effectiveness with TAM phenotypes and functions.
DOI: https://doi.org/10.37349/edd.2026.1005124
This article belongs to the special issue Immunotherapy for Cancer of Digestive System
Aim:
Recent studies suggest an association between sleep patterns and metabolic dysfunction-associated steatotic liver disease (MASLD) among American adults. Despite established sex-specific disparities in MASLD prevalence, the potential influence of sex on the sleep-MASLD relationship is not well defined. Our research aims to elucidate the sex-specific associations of sleep with MASLD by utilizing a nationally representative cohort from the United States.
Methods:
Data from United States adults aged 20 and older in the 2017–2020 NHANES were analyzed in this cross-sectional study. Sleep parameters were assessed via interviewer-administered questionnaires, while MASLD was defined using vibration-controlled transient elastography (VCTE). Sex-specific associations were investigated with sex-stratified multivariable logistic regression models, and their robustness was tested through subgroup and sensitivity analyses.
Results:
This study included 5,243 participants (51.2% female). A significant association was observed between sleep disorders and a greater likelihood of MASLD among male participants (OR = 1.50; 95% CI: 1.08–2.10). After full adjustment for covariates, the association remained significant in females (OR = 1.51; 95% CI: 1.06–2.16). Conversely, high sleep debt remained significantly associated with MASLD in both sexes (males: OR = 1.64; 95% CI: 1.14–2.37; females: OR = 1.51; 95% CI: 1.06–2.15). Subgroup analyses confirmed that sex did not modify these relationships.
Conclusions:
Sleep disorders and sleep debt were significantly associated with MASLD in both sexes. These findings suggest that sleep health may represent an important modifiable target in MASLD prevention strategies.
Aim:
Recent studies suggest an association between sleep patterns and metabolic dysfunction-associated steatotic liver disease (MASLD) among American adults. Despite established sex-specific disparities in MASLD prevalence, the potential influence of sex on the sleep-MASLD relationship is not well defined. Our research aims to elucidate the sex-specific associations of sleep with MASLD by utilizing a nationally representative cohort from the United States.
Methods:
Data from United States adults aged 20 and older in the 2017–2020 NHANES were analyzed in this cross-sectional study. Sleep parameters were assessed via interviewer-administered questionnaires, while MASLD was defined using vibration-controlled transient elastography (VCTE). Sex-specific associations were investigated with sex-stratified multivariable logistic regression models, and their robustness was tested through subgroup and sensitivity analyses.
Results:
This study included 5,243 participants (51.2% female). A significant association was observed between sleep disorders and a greater likelihood of MASLD among male participants (OR = 1.50; 95% CI: 1.08–2.10). After full adjustment for covariates, the association remained significant in females (OR = 1.51; 95% CI: 1.06–2.16). Conversely, high sleep debt remained significantly associated with MASLD in both sexes (males: OR = 1.64; 95% CI: 1.14–2.37; females: OR = 1.51; 95% CI: 1.06–2.15). Subgroup analyses confirmed that sex did not modify these relationships.
Conclusions:
Sleep disorders and sleep debt were significantly associated with MASLD in both sexes. These findings suggest that sleep health may represent an important modifiable target in MASLD prevention strategies.
DOI: https://doi.org/10.37349/edd.2026.1005123
Aim:
Chronic liver disease (CLD) is characterized by progressive impairment of hepatic function and frequent lipid metabolism abnormalities, with reductions in high-density lipoprotein cholesterol (HDL-C) and other lipoprotein fractions shown to parallel worsening liver dysfunction and predict adverse clinical outcomes such as decompensation and mortality. Established prognostic scores like Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) capture aspects of disease severity, but composite lipid indices such as the non-HDL/HDL-C ratio (NHHR), which balance atherogenic and protective lipoproteins, have emerged as potentially informative biomarkers in metabolic and liver disorders. This study evaluated the association of NHHR with clinical decompensation in CLD.
Methods:
This cross-sectional study included 220 adults with CLD of mixed etiologies. Baseline demographics, liver disease severity scores, and fasting lipid profiles were obtained. NHHR was calculated, and patients were categorized into tertiles. Spearman correlation coefficients were calculated to examine relationships between NHHR and clinical severity markers. Multivariable logistic regression was used to evaluate the association between NHHR and clinical decompensation. Model performance was compared using receiver operating characteristic curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI).
Results:
Among 220 patients with CLD (mean age 54.5 ± 11.9 years, 63% male), 96 (43.6%) had decompensated disease. Higher NHHR tertiles were associated with increasing MELD-3.0 scores (P = 0.028) and lower serum albumin (P < 0.001). NHHR correlated positively with MELD-3.0, bilirubin, and international normalized ratio (INR) and inversely with albumin and platelet count. Decompensation prevalence rose across NHHR tertiles (31.1% to 53.4%, P < 0.001). NHHR was independently associated with decompensation (adjusted OR 1.55, 95% CI 1.21–1.98, P < 0.001) and improved model discrimination (AUC 0.79 vs. 0.73).
Conclusions:
NHHR is independently associated with clinical decompensation in CLD and provides incremental prognostic value beyond traditional predictors, suggesting its potential utility in clinical risk assessment and stratification.
Aim:
Chronic liver disease (CLD) is characterized by progressive impairment of hepatic function and frequent lipid metabolism abnormalities, with reductions in high-density lipoprotein cholesterol (HDL-C) and other lipoprotein fractions shown to parallel worsening liver dysfunction and predict adverse clinical outcomes such as decompensation and mortality. Established prognostic scores like Model for End-Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) capture aspects of disease severity, but composite lipid indices such as the non-HDL/HDL-C ratio (NHHR), which balance atherogenic and protective lipoproteins, have emerged as potentially informative biomarkers in metabolic and liver disorders. This study evaluated the association of NHHR with clinical decompensation in CLD.
Methods:
This cross-sectional study included 220 adults with CLD of mixed etiologies. Baseline demographics, liver disease severity scores, and fasting lipid profiles were obtained. NHHR was calculated, and patients were categorized into tertiles. Spearman correlation coefficients were calculated to examine relationships between NHHR and clinical severity markers. Multivariable logistic regression was used to evaluate the association between NHHR and clinical decompensation. Model performance was compared using receiver operating characteristic curves, net reclassification improvement (NRI), and integrated discrimination improvement (IDI).
Results:
Among 220 patients with CLD (mean age 54.5 ± 11.9 years, 63% male), 96 (43.6%) had decompensated disease. Higher NHHR tertiles were associated with increasing MELD-3.0 scores (P = 0.028) and lower serum albumin (P < 0.001). NHHR correlated positively with MELD-3.0, bilirubin, and international normalized ratio (INR) and inversely with albumin and platelet count. Decompensation prevalence rose across NHHR tertiles (31.1% to 53.4%, P < 0.001). NHHR was independently associated with decompensation (adjusted OR 1.55, 95% CI 1.21–1.98, P < 0.001) and improved model discrimination (AUC 0.79 vs. 0.73).
Conclusions:
NHHR is independently associated with clinical decompensation in CLD and provides incremental prognostic value beyond traditional predictors, suggesting its potential utility in clinical risk assessment and stratification.
DOI: https://doi.org/10.37349/edd.2026.1005121
This article belongs to the special issue Gastrointestinal Diseases, Cholesterol, Oxysterols, and Bile Acids
Janus kinase (JAK) inhibitors represent a major advancement in the management of immune-mediated inflammatory diseases. A balanced approach that carefully weighs therapeutic benefits against potential risks is essential. Through appropriate patient selection, close monitoring, and open physician–patient communication, the clinical potential of JAK inhibitors can be optimized while minimizing adverse outcomes. Nine JAK inhibitors have demonstrated utility in hepatogastrointestinal disorders; however, only two have FDA approval. JAK inhibitors are classified into reversible (competitive) and irreversible (covalent) inhibitors according to their chemical binding with amino acids. This review discusses the safety profile, adverse effects, and molecular selectivity of JAK inhibitors, and highlights their therapeutic roles in hepatogastrointestinal diseases, including inflammatory bowel disease, hepatic fibrosis, hepatocellular carcinoma, autoimmune diseases associated with cancer therapy in post-transplant patients, eosinophilic esophagitis, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease, and acute graft-versus-host disease following liver transplantation.
Janus kinase (JAK) inhibitors represent a major advancement in the management of immune-mediated inflammatory diseases. A balanced approach that carefully weighs therapeutic benefits against potential risks is essential. Through appropriate patient selection, close monitoring, and open physician–patient communication, the clinical potential of JAK inhibitors can be optimized while minimizing adverse outcomes. Nine JAK inhibitors have demonstrated utility in hepatogastrointestinal disorders; however, only two have FDA approval. JAK inhibitors are classified into reversible (competitive) and irreversible (covalent) inhibitors according to their chemical binding with amino acids. This review discusses the safety profile, adverse effects, and molecular selectivity of JAK inhibitors, and highlights their therapeutic roles in hepatogastrointestinal diseases, including inflammatory bowel disease, hepatic fibrosis, hepatocellular carcinoma, autoimmune diseases associated with cancer therapy in post-transplant patients, eosinophilic esophagitis, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease, and acute graft-versus-host disease following liver transplantation.
DOI: https://doi.org/10.37349/edd.2026.1005122
Hepatocellular carcinoma (HCC) functions as a major cancer-related death factor around the world. Research indicates that long non-coding RNAs (lncRNAs) play essential roles during HCC onset and development because they belong to the novel RNA subclass that extends beyond 200 nucleotides without protein-coding capability. LncRNAs regulate the expression of downstream target genes and cancer-related signaling pathways, thereby promoting the proliferation, migration, invasion, autophagy, and apoptosis of tumor cells. The study of lncRNA function has been substantially facilitated by the emergence of lncRNA-specific microarrays and the increased accessibility of next-generation sequencing technologies. The function of lncRNAs can be predicted using computational and molecular methodologies. LncRNAs have the potential to function as repressors, scaffolds, regulators of super-enhancers, or molecular decoys. Proliferation, invasion, survival, DNA damage response (DDR), and chromatin dynamics can all be influenced by lncRNAs. Additionally, they can affect stemness/differentiation. The recurrence of tumors may be facilitated by the aberrant expression of these transcripts, which may result in therapy resistance. LncRNAs have the potential to function as innovative prognostic or theranostic biomarkers in HCC and other malignancies. In addition, RNA-based therapeutics may be implemented to target lncRNAs as a novel treatment approach for primary or recurrent HCC. In this review, we investigate the functions of lncRNAs in the pathophysiology of HCC and suggest their potential for novel therapeutic application in the treatment of HCC.
Hepatocellular carcinoma (HCC) functions as a major cancer-related death factor around the world. Research indicates that long non-coding RNAs (lncRNAs) play essential roles during HCC onset and development because they belong to the novel RNA subclass that extends beyond 200 nucleotides without protein-coding capability. LncRNAs regulate the expression of downstream target genes and cancer-related signaling pathways, thereby promoting the proliferation, migration, invasion, autophagy, and apoptosis of tumor cells. The study of lncRNA function has been substantially facilitated by the emergence of lncRNA-specific microarrays and the increased accessibility of next-generation sequencing technologies. The function of lncRNAs can be predicted using computational and molecular methodologies. LncRNAs have the potential to function as repressors, scaffolds, regulators of super-enhancers, or molecular decoys. Proliferation, invasion, survival, DNA damage response (DDR), and chromatin dynamics can all be influenced by lncRNAs. Additionally, they can affect stemness/differentiation. The recurrence of tumors may be facilitated by the aberrant expression of these transcripts, which may result in therapy resistance. LncRNAs have the potential to function as innovative prognostic or theranostic biomarkers in HCC and other malignancies. In addition, RNA-based therapeutics may be implemented to target lncRNAs as a novel treatment approach for primary or recurrent HCC. In this review, we investigate the functions of lncRNAs in the pathophysiology of HCC and suggest their potential for novel therapeutic application in the treatment of HCC.
DOI: https://doi.org/10.37349/edd.2026.1005120
This article belongs to the special issue Prevention, Screening and Diagnosis for Primary Liver Cancer
Acute mesenteric ischemia (AMI) is a rare but highly lethal vascular emergency resulting from the abrupt interruption of intestinal blood flow. In advanced stages, extensive bowel necrosis may require near total enterectomy, leading to short bowel syndrome and permanent dependence on parenteral nutrition. An 86-year-old woman with atrial fibrillation and multiple cardiometabolic comorbidities presented with acute abdominal pain, nausea, and vomiting. Initial laboratory findings revealed marked leukocytosis and severe systemic inflammation (CRP: 21.0 mg/L). Computed tomography (CT) angiography demonstrated impaired perfusion of the superior mesenteric artery. Emergency laparotomy confirmed extensive jejunoileal ischemic necrosis, necessitating near total enterectomy with stapled jejunoileal anastomosis. Second-look surgery revealed progressive ischemia of the ileocecal region and right colon, requiring extended right hemicolectomy. Postoperatively, the patient was managed with total parenteral nutrition and intensive supportive care. Despite temporary stabilization and discharge on home parenteral nutrition, she died six months later. AMI complicated by short bowel syndrome is associated with poor prognosis in elderly patients. Persistent systemic inflammation, progressive organ dysfunction, and intestinal failure remain major determinants of adverse long-term outcomes, highlighting the critical importance of early diagnosis, prompt surgical intervention, and multidisciplinary postoperative management.
Acute mesenteric ischemia (AMI) is a rare but highly lethal vascular emergency resulting from the abrupt interruption of intestinal blood flow. In advanced stages, extensive bowel necrosis may require near total enterectomy, leading to short bowel syndrome and permanent dependence on parenteral nutrition. An 86-year-old woman with atrial fibrillation and multiple cardiometabolic comorbidities presented with acute abdominal pain, nausea, and vomiting. Initial laboratory findings revealed marked leukocytosis and severe systemic inflammation (CRP: 21.0 mg/L). Computed tomography (CT) angiography demonstrated impaired perfusion of the superior mesenteric artery. Emergency laparotomy confirmed extensive jejunoileal ischemic necrosis, necessitating near total enterectomy with stapled jejunoileal anastomosis. Second-look surgery revealed progressive ischemia of the ileocecal region and right colon, requiring extended right hemicolectomy. Postoperatively, the patient was managed with total parenteral nutrition and intensive supportive care. Despite temporary stabilization and discharge on home parenteral nutrition, she died six months later. AMI complicated by short bowel syndrome is associated with poor prognosis in elderly patients. Persistent systemic inflammation, progressive organ dysfunction, and intestinal failure remain major determinants of adverse long-term outcomes, highlighting the critical importance of early diagnosis, prompt surgical intervention, and multidisciplinary postoperative management.
DOI: https://doi.org/10.37349/edd.2026.1005119
Exploring long non-coding RNAs (lncRNAs) in liver diseases, particularly liver fibrosis, presents significant opportunities for augmenting our understanding and treatment of these conditions. The rapid advancement of high-throughput sequencing technologies has revealed the complex networks of lncRNAs, highlighting their crucial functions in liver fibrosis. Identifying dysregulated lncRNAs offers promising diagnostic and prognostic biomarkers, as well as potential therapeutic targets. Extracellular vesicles contribute to the relevance of lncRNAs by protecting them from degradation and maintaining their activity in circulation, as exemplified by the role of lncRNA H19 in liver fibrosis. LncRNAs are vital in liver pathology, influencing fibrosis and cirrhosis by modulating responses to liver injury from ethanol. They affect inflammation, oxidative stress, and apoptosis through interactions with pathways like NF-κB and microRNA networks. LncRNAs also control hepatic stellate cells, the production of extracellular matrix, and the activation of stem cells, which opens up new ways to treat fibrosis. Ethanol modulates lncRNA expression, impacting liver fibrosis and cirrhosis development. LncRNAs also influence hepatocellular carcinoma progression by affecting cell proliferation, immune response, and tumor growth. Despite these insights, the regulatory networks and molecular mechanisms of lncRNAs in liver disorders are not entirely understood. In this review, we focus on unraveling these complexities and identifying effective lncRNAs that could revolutionize liver disease treatment, offer novel diagnostic and therapeutic avenues, and improve patient outcomes.
Exploring long non-coding RNAs (lncRNAs) in liver diseases, particularly liver fibrosis, presents significant opportunities for augmenting our understanding and treatment of these conditions. The rapid advancement of high-throughput sequencing technologies has revealed the complex networks of lncRNAs, highlighting their crucial functions in liver fibrosis. Identifying dysregulated lncRNAs offers promising diagnostic and prognostic biomarkers, as well as potential therapeutic targets. Extracellular vesicles contribute to the relevance of lncRNAs by protecting them from degradation and maintaining their activity in circulation, as exemplified by the role of lncRNA H19 in liver fibrosis. LncRNAs are vital in liver pathology, influencing fibrosis and cirrhosis by modulating responses to liver injury from ethanol. They affect inflammation, oxidative stress, and apoptosis through interactions with pathways like NF-κB and microRNA networks. LncRNAs also control hepatic stellate cells, the production of extracellular matrix, and the activation of stem cells, which opens up new ways to treat fibrosis. Ethanol modulates lncRNA expression, impacting liver fibrosis and cirrhosis development. LncRNAs also influence hepatocellular carcinoma progression by affecting cell proliferation, immune response, and tumor growth. Despite these insights, the regulatory networks and molecular mechanisms of lncRNAs in liver disorders are not entirely understood. In this review, we focus on unraveling these complexities and identifying effective lncRNAs that could revolutionize liver disease treatment, offer novel diagnostic and therapeutic avenues, and improve patient outcomes.
DOI: https://doi.org/10.37349/edd.2026.1005118
This article belongs to the special issue Cirrhosis and Its Complications
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated condition typically requiring invasive endoscopy for monitoring. The bidirectional oral-gut axis suggests that saliva may serve as a non-invasive diagnostic fluid for studying gut inflammations. Studies of salivary biomarkers have shown varying results. Inflammatory biomarkers such as IL-6 are the most robust salivary biomarker, consistently correlating with endoscopic activity. In contrast, salivary calprotectin lacks the reliability of its fecal counterpart, showing diagnostic value primarily in pediatric cases with oral manifestations. Microbial analysis indicates reduced salivary diversity, specifically an enrichment of Prevotella and Veillonella alongside a depletion of core commensals like Streptococcus. While oxidative stress markers such as advanced oxidation protein products (AOPPs) can distinguish disease severity, they lack long-term prognostic utility. Conversely, recent shifts toward exosome-based transcriptomic analysis have improved the stability of salivary microRNAs, offering high precision in differentiating IBD phenotypes. Despite these advancements, clinical integration is currently hindered by small cohort sizes, the confounding effects of local oral health, and a lack of standardized collection protocols. To establish saliva as a reliable tool in the IBD clinical toolkit, future research must prioritize multi-panel biomarker approaches and longitudinal studies to validate diagnostic accuracy across diverse patient populations.
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic immune-mediated condition typically requiring invasive endoscopy for monitoring. The bidirectional oral-gut axis suggests that saliva may serve as a non-invasive diagnostic fluid for studying gut inflammations. Studies of salivary biomarkers have shown varying results. Inflammatory biomarkers such as IL-6 are the most robust salivary biomarker, consistently correlating with endoscopic activity. In contrast, salivary calprotectin lacks the reliability of its fecal counterpart, showing diagnostic value primarily in pediatric cases with oral manifestations. Microbial analysis indicates reduced salivary diversity, specifically an enrichment of Prevotella and Veillonella alongside a depletion of core commensals like Streptococcus. While oxidative stress markers such as advanced oxidation protein products (AOPPs) can distinguish disease severity, they lack long-term prognostic utility. Conversely, recent shifts toward exosome-based transcriptomic analysis have improved the stability of salivary microRNAs, offering high precision in differentiating IBD phenotypes. Despite these advancements, clinical integration is currently hindered by small cohort sizes, the confounding effects of local oral health, and a lack of standardized collection protocols. To establish saliva as a reliable tool in the IBD clinical toolkit, future research must prioritize multi-panel biomarker approaches and longitudinal studies to validate diagnostic accuracy across diverse patient populations.
DOI: https://doi.org/10.37349/edd.2026.1005117
Microbial metabolites are now recognized as central mediators of host–microbe communication that shape intestinal immune homeostasis and influence the development of inflammatory gastrointestinal diseases. The objective of this review is to synthesize current mechanistic evidence on how microbiota-derived metabolites regulate epithelial and immune functions in the gut, with a focus on metabolite-driven inflammatory pathways. In the healthy intestine, short-chain fatty acids (SCFAs), indole derivatives, secondary bile acids, and polyamines support epithelial integrity, regulate mucosal immunity, and maintain metabolic balance. SCFAs, particularly butyrate, attenuate inflammation by serving as an energy source for colonocytes, inhibiting histone deacetylases, activating G protein-coupled receptors (GPCRs; GPR41, GPR43, GPR109A), and reinforcing epithelial barrier function. In parallel, microbial tryptophan metabolites such as indole-3-propionic acid and indole-3-aldehyde activate aryl hydrocarbon receptor signaling, promoting IL-22 production, antimicrobial peptide expression, and Th17–Treg balance. In inflammatory bowel disease, dysbiosis disrupts these protective pathways, leading to depletion of SCFA- and indole-producing taxa and accumulation of pro-inflammatory metabolites such as succinate. These metabolic shifts impair epithelial-immune crosstalk, amplify NF-κB-dependent inflammation, and compromise mucosal repair. Therapeutic strategies targeting microbial metabolites, including precision prebiotics, next-generation probiotics, engineered microbial consortia, and postbiotics, show translational promise. However, their clinical application remains constrained by interindividual variability, incomplete causal resolution, and challenges in targeted delivery. Integrative multi-omics approaches and mechanistically informed models are therefore essential to advance metabolite-based diagnostics and therapies for gut inflammation.
Microbial metabolites are now recognized as central mediators of host–microbe communication that shape intestinal immune homeostasis and influence the development of inflammatory gastrointestinal diseases. The objective of this review is to synthesize current mechanistic evidence on how microbiota-derived metabolites regulate epithelial and immune functions in the gut, with a focus on metabolite-driven inflammatory pathways. In the healthy intestine, short-chain fatty acids (SCFAs), indole derivatives, secondary bile acids, and polyamines support epithelial integrity, regulate mucosal immunity, and maintain metabolic balance. SCFAs, particularly butyrate, attenuate inflammation by serving as an energy source for colonocytes, inhibiting histone deacetylases, activating G protein-coupled receptors (GPCRs; GPR41, GPR43, GPR109A), and reinforcing epithelial barrier function. In parallel, microbial tryptophan metabolites such as indole-3-propionic acid and indole-3-aldehyde activate aryl hydrocarbon receptor signaling, promoting IL-22 production, antimicrobial peptide expression, and Th17–Treg balance. In inflammatory bowel disease, dysbiosis disrupts these protective pathways, leading to depletion of SCFA- and indole-producing taxa and accumulation of pro-inflammatory metabolites such as succinate. These metabolic shifts impair epithelial-immune crosstalk, amplify NF-κB-dependent inflammation, and compromise mucosal repair. Therapeutic strategies targeting microbial metabolites, including precision prebiotics, next-generation probiotics, engineered microbial consortia, and postbiotics, show translational promise. However, their clinical application remains constrained by interindividual variability, incomplete causal resolution, and challenges in targeted delivery. Integrative multi-omics approaches and mechanistically informed models are therefore essential to advance metabolite-based diagnostics and therapies for gut inflammation.
DOI: https://doi.org/10.37349/edd.2026.1005116
This article belongs to the special issue Inflammatory Diseases of the Gastrointestinal Tract
