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Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets

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A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 30 April 2027 | Viewed by 8945

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Dr. Konstantinos Arvanitakis

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Division of Gastroenterology and Hepatology, First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1, 54636 Thessaloniki, Greece
Interests: hepatology; inflammatory bowel disease; gastroenterology; MASLD; hepatocellular carcinoma

Special Issue Information

Dear Colleagues,

Liver diseases represent a growing global health burden, ranging from metabolic dysfunction-associated steatotic liver disease (MASLD) and alcoholic liver disease to fibrosis, cirrhosis, and hepatocellular carcinoma. Despite significant advances, our understanding of the molecular mechanisms that underlie these conditions remains incomplete. Recent discoveries in hepatocellular stress responses, immune interactions, lipid metabolism, and gene regulation are redefining our view of liver disease pathogenesis and opening new therapeutic avenues.

We are pleased to invite you to contribute to this Special Issue, which focuses on unraveling the molecular and cellular basis of liver diseases. By highlighting critical pathways and molecular interactions, we aim to build a platform for knowledge exchange between basic researchers and clinical scientists, fostering translational progress.

This Special Issue aims to bring together high-quality research papers and review articles addressing the molecular underpinnings of liver diseases. The scope aligns closely with the journal’s mission to support research that advances our understanding of disease mechanisms and therapeutic development. Contributions will offer mechanistic insights into liver pathology and suggest new strategies for diagnosis, prevention, and treatment.

Research areas may include (but are not limited to) the following:

Endoplasmic reticulum (ER) stress and the unfolded protein response;
Mitochondrial dysfunction and metabolic reprogramming;
Activation of hepatic stellate cells and fibrogenic signaling;
Crosstalk between hepatocytes and immune cells;
Non-coding RNAs in liver disease (miRNAs, lncRNAs, circRNAs);
Epigenetic and transcriptomic alterations in liver fibrosis and cancer;
Molecular drivers of MASLD and MASH progression;
Gut–liver axis and the influence of microbial metabolites;
Molecular pathways of Hepatocellular Carcinoma development and progression;
Single-cell omics and spatial transcriptomics in liver pathology;
Target discovery and drug development for liver diseases.

We look forward to receiving your contributions.

Dr. Konstantinos Arvanitakis
Guest Editor

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Keywords

liver disease
molecular mechanisms
hepatocellular stress
fibrosis
non-coding RNAs
metabolism
MASLD
liver fibrosis
hepatocellular carcinoma
therapeutics

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Published Papers (6 papers)

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Research

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16 pages, 1827 KB

Open AccessArticle

Explainable Artificial Intelligence and Gene-Network Analysis Prioritise a TREM2/LGALS3/GPNMB Scar-Associated Macrophage Programme in Human Liver Cirrhosis

by Shah Faisal, Muhammad Adeel Ejaz, Piniel Alphayo Kambey, Abdul Malik and Yin-Xiong Li

Int. J. Mol. Sci. 2026, 27(18), 8023; https://doi.org/10.3390/ijms27188023 - 9 Sep 2026

Viewed by 238

Abstract

Macrophages organise the fibrotic niche of liver cirrhosis. The scar-associated macrophage state is well described, but the genes that define it have rarely been ranked in an unbiased, model-based way, and the statistical limits of such re-analyses are seldom reported. Here we set out to re-derive the scar-associated macrophage programme without supervision, to rank its constituent genes by convergent computational evidence, and to state explicitly what a cohort of this size can and cannot support. We re-analysed 58,358 single-cell transcriptomes from five uninjured and five cirrhotic human livers (GEO GSE136103; Edinburgh DataShare DS_10283_3433). After quality control, Harmony batch integration and Leiden clustering, the mononuclear-phagocyte compartment (9869 cells) was re-clustered. We applied donor-level compositional testing stratified within the CD45+/CD45− sorted fractions, donor-level pseudobulk differential expression, three classifiers with SHapley Additive exPlanations (SHAP) under donor-grouped cross-validation, transcription-factor differential expression, diffusion pseudotime, ligand–receptor modelling and CellOracle in silico perturbation. The donor, never the cell, was the unit of analysis for every condition comparison. A discrete macrophage cluster (390 cells; 60.5% cirrhotic; contributed by all 10 donors) carried a coherent lipid/scar programme comprising LGALS3, GPNMB, TREM2, CD9, FABP5, APOE, APOC1 and CTSD, and was recovered in all 22 clustering configurations tested. The integrated prioritisation was robust: seven genes remained in the top 20 in 100% of 1000 Dirichlet re-weightings. MAFB, MITF and TFEC were significantly enriched transcription factors, and pseudotime placed the state downstream of a monocyte root. Three findings temper these results. No lineage showed a significant compositional change after multiple-testing correction, and every test was underpowered for its observed effect. No gene reached significance in donor-level pseudobulk differential expression. Classifier performance of 0.99 reflects the circularity of predicting a cluster defined from the same matrix; the non-circular contrast of cirrhotic versus uninjured cells gave 0.61–0.65. Overall, a documented, fully reproducible framework re-derives and ranks a TREM2/LGALS3/GPNMB scar-associated macrophage programme and nominates galectin-3, GPNMB and the SPP1 axis as prioritised, clinically unproven candidates. The prioritisation is a hypothesis requiring independent, spatial, protein-level and functional validation. Full article

(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)

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30 pages, 2176 KB

Open AccessArticle

Divergence of the CYB5R3–mARC1 Redox Axis Across the Human MASLD-to-Hepatocellular-Carcinoma Continuum: An Exploratory Analysis of Liver-Biopsy and Tumor Cohorts

by Soon Woo Nam

Int. J. Mol. Sci. 2026, 27(17), 7806; https://doi.org/10.3390/ijms27177806 - 31 Aug 2026

Viewed by 233

Abstract

CYB5R3 (NADH–cytochrome b5 reductase 3) and mARC1, the product of MTARC1, draw on the same cytochrome-b5 electron relay, so they are usually treated as two ends of one redox axis. Whether they behave as a unit across the continuum from metabolic dysfunction–associated steatotic liver disease (MASLD) to hepatocellular carcinoma (HCC) has not been established. In TCGA-LIHC, higher CYB5R3 expression was associated with shorter overall survival in a continuous multivariable Cox model adjusted for age, sex, and stage (n = 339, 114 deaths; HR 1.23 per SD, 95% CI 1.01–1.48, p = 0.035), although it added essentially nothing to a clinical model containing age, sex, and stage (change in Harrell C-index 0.005, 95% CI −0.015 to +0.037). The direction was reproduced in the only independent cohort examined, GSE14520 (n = 242, 96 deaths; unadjusted HR 1.42 per SD, 95% CI 1.14–1.76, p = 0.0015), in which higher MTARC1 was associated with longer survival (unadjusted HR 0.73 per SD, 95% CI 0.60–0.89, p = 0.0017); both single-gene estimates fall below conventional significance after adjustment for age, sex, and TNM stage (HR 1.24, 95% CI 0.99–1.56, p = 0.058 and HR 0.89, 95% CI 0.72–1.10, p = 0.29; n = 225, 86 deaths), although CYB5R3 remains nominally significant in an adjusted model containing both genes (HR 1.27, 95% CI 1.01–1.59, p = 0.039), so that cohort replicates direction rather than independent prognostic value. Across the primary tumors of the analysis set, no correlation between the two transcripts was detectable (Spearman r_s = −0.03, 95% CI −0.13 to +0.08, p = 0.62; n = 339), so the axis is not demonstrably a unit at the expression level. In three human liver-biopsy cohorts spanning the MASLD histological spectrum (393 biopsies with fibrosis staging), CYB5R3 gave estimates that differed in sign between cohorts and were uninformative when pooled (fibrosis stage, random-effects r_s = +0.01, 95% CI −0.24 to +0.26, q = 0.95, I² = 83%). MTARC1 behaved differently, falling with fibrosis stage in all three cohorts (pooled r_s = −0.22, 95% CI −0.32 to −0.13, q = 3 × 10⁻⁵, I² = 0%), as did PARP16 (−0.17, I² = 0%), while SCD rose in all three (+0.13, I² = 0%). This is consistent with the inconsistency being specific to CYB5R3 rather than a property of the cohorts, although the fibrogenic positive controls were themselves heterogeneous (I² = 53–62%), I² is estimated from only three cohorts, and the difference between the CYB5R3 and MTARC1 coefficients was not formally tested. These observations are associative and hypothesis-generating. They provide no support for the widely assumed corollary that hepatic CYB5R3 becomes deficient as steatotic liver disease advances, so a therapeutic strategy predicated on that corollary currently rests on mouse gain-of-function data alone, without corroboration from human tissue. What they do support is narrower: within a single physically coupled electron-transfer axis, the two members behave differently before malignancy—MTARC1 tracks fibrosis stage reproducibly while CYB5R3 shows no reproducible relationship—and carry opposite prognostic directions after malignancy, significant for MTARC1 only before covariate adjustment. Full article

(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)

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19 pages, 6591 KB

Open AccessArticle

Pirfenidone Suppresses Liver Fibrosis Through Inhibition of TGF-β-Associated Lipid Metabolic Remodeling in Hepatic Stellate Cells

by Yuelu Lan, Sijia Li, Shuangli Zhu, Can Pan, Kai Fu, Xueping Wang, Liwu Fu and Fang Wang

Int. J. Mol. Sci. 2026, 27(9), 4061; https://doi.org/10.3390/ijms27094061 - 30 Apr 2026

Cited by 1 | Viewed by 970

Abstract

Chronic liver injury is characterized by sustained activation of transforming growth factor-β (TGF-β) signaling within the fibrotic microenvironment, yet the contribution of TGF-β-associated metabolic remodeling to hepatic stellate cell (HSC) activation remains incompletely understood. Here, we investigated whether TGF-β signaling is associated with lipid metabolic remodeling in HSCs and whether pirfenidone (PFD) interferes with this process. We found that TGF-β1 was spatially associated with lipid accumulation in fibrotic liver tissue and that TGF-β1/2 promoted HSC proliferation. In vitro, TGF-β1/2 coordinately upregulated sterol regulatory element-binding protein 1 (SREBP1) and fatty acid synthase (FASN), accompanied by increased intracellular lipid accumulation and enhanced oleic acid (OA)-associated lipid responses. Low-dose OA further activated AKT/ERK/p70 S6K signaling in HSCs, whereas PFD attenuated these signaling events. In parallel, PFD suppressed TGF-β-associated lipid accumulation in vitro, reduced SREBP1/FASN expression in activated HSC-rich regions in vivo, and alleviated CCl₄-induced liver fibrosis. Together, these findings support a model in which TGF-β-associated lipogenic remodeling contributes to HSC activation and suggest that interference with this metabolic state may represent one component of the antifibrotic action of pirfenidone. Full article

(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)

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21 pages, 3220 KB

Open AccessArticle

Immune and Endothelial-Related Extracellular Vesicles Are Associated with Corticosteroid Response and Mortality in Alcohol-Associated Hepatitis

by Albert Guinart-Cuadra, Anna Brujats, Justyna Szafranska, Rubén Guerrero, Fernándo Dinamarca, Elisabet Cantó, Maria Poca, Eva Román, Elisabet Sánchez-Ardid, Javier Fajardo, Montserrat Camps, Maria Mulet, German Soriano, Àngels Escorsell, Juan M. Falcon-Perez, Esperanza Gonzalez, Andreu Ferrero-Gregori, Cristina Gely, Jorge Villalba, Ramón Bataller, Josepmaria Argemi, Rubén Osuna-Gómez, Silvia Vidal and Edilmar Alvarado-Tapias Show full author list Hide full author list

Int. J. Mol. Sci. 2026, 27(3), 1258; https://doi.org/10.3390/ijms27031258 - 27 Jan 2026

Cited by 1 | Viewed by 1251

Abstract

Alcohol-associated hepatitis (AH) is the most severe clinical manifestation of alcohol-associated liver disease. Corticosteroids are the only disease-specific therapy shown to improve short-term survival. Currently, no non-invasive markers are available to predict patient response to corticosteroids or long-term survival in AH. This study investigates whether surface antigens on plasma extracellular vesicles (EVs), key mediators of intercellular communication, can reflect the underlying immune dysregulation in AH and serve as prognostic markers. Patients with AH were prospectively enrolled between 2020 and 2024. Blood samples were collected before corticosteroid initiation during the first 24 h of hospitalization. EVs were characterized using nanoparticle tracking analysis, cryo-electron microscopy, and flow cytometry. Interleukin-6 (IL-6), soluble (s)CD62p, Circulating Vascular Cell Adhesion Molecule-1 (sVCAM), tumor necrosis factor receptor superfamily member 1 (TNRFS1a), and Intercellular Adhesion Molecule 1 (ICAM-1) were quantified by ELISA. Key outcome variables included response to corticosteroids and mortality. A total of 46 patients with AH and 28 healthy donors (HD) were included. EV concentration was significantly higher in AH patients than in HD (9.3 × 10¹¹ [IQR 4–24] versus 2.4 × 10¹¹ [IQR 2–4], p = 0.03). Specific EV antigens were associated with key clinical outcomes: CD20 and CD2 levels differed between patients with or without infections (bacterial, viral, and fungal) developed during hospitalization; CD40 and CD146 were elevated in patients who developed acute kidney injury. EVs enriched in monocyte (CD14) and T-reg (CD25) markers were associated with plasma IL-6 levels, while endothelial markers CD105 and CD146 correlated with sVCAM and sCD62p. EVs enriched in platelet (CD49e) and endothelial (CD31) markers were associated with corticosteroid response, whereas EVs enriched with endothelial (CD105 and CD146) and B lymphocyte (CD19) markers were associated with mortality. Overall, EVs enriched in endothelial and monocyte markers may represent a candidate non-invasive tool for predicting corticosteroid response and mortality in AH, aiding risk stratification and early identification of non-responders for timely transplant evaluation. Full article

(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)

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16 pages, 2693 KB

Open AccessArticle

Vitamin E Modulates Hepatic Extracellular Adenosine Signaling to Attenuate Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

by Mengting Shan, Magdeline E. Carrasco Apolinario, Tomoko Tokumaru, Kenshiro Shikano, Phurpa Phurpa, Ami Kato, Hitoshi Teranishi, Shinichiro Kume, Nobuyuki Shimizu, Tatsuki Kurokawa, Takatoshi Hikida, Toshikatsu Hanada, Yulong Li and Reiko Hanada

Int. J. Mol. Sci. 2026, 27(2), 614; https://doi.org/10.3390/ijms27020614 - 7 Jan 2026

Cited by 1 | Viewed by 2002

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves early disturbances such as excessive lipid accumulation, sterile inflammation, and hepatocellular stress. The results of recent studies have highlighted extracellular ATP and its metabolite adenosine (Ado) as damage-associated molecular patterns (DAMPs) that drive inflammation, endoplasmic reticulum (ER) stress, and steatosis, contributing to MASLD progression. Although vitamin E is clinically used for its antioxidant and anti-inflammatory properties, it remains unclear whether its therapeutic effects involve modulation of DAMP-associated signaling. To address this gap, we used transgenic zebrafish expressing a liver-specific G-protein-coupled receptor activation-based adenosine sensor (GRAB_Ado). We found that a high-cholesterol diet markedly increased hepatic extracellular Ado levels, combined with inflammatory and ER stress-associated gene expression. Vitamin E significantly reduced extracellular Ado levels and hepatic lipid accumulation. Based on RNA sequencing results, vitamin E restored the expression of genes encoding calcium-handling proteins, including atp2a1 and atp1b1b. These genes encode components of the sarco/ER Ca²⁺-ATPase (SERCA) machinery, which is essential for maintaining ER Ca²⁺ homeostasis and preventing stress-induced hepatic injury. CDN1163-mediated SERCA activation phenocopied the protective effect of vitamin E, supporting a Ca²⁺-dependent mechanism. Together, these findings highlight extracellular Ado signaling and impaired SERCA-mediated Ca²⁺ regulation as early drivers of MASLD and demonstrate that vitamin E ameliorates steatosis by targeting both pathways. Full article

(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)

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Review

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20 pages, 952 KB

Open AccessReview

Contradictory Effects on Hepatocytes in ASMD

by Maksim Sysoev, Dmitri Solovyov, Aleksandr Shestopalov and Sergey Kutsev

Int. J. Mol. Sci. 2026, 27(11), 5070; https://doi.org/10.3390/ijms27115070 - 3 Jun 2026

Cited by 1 | Viewed by 587

Abstract

Acid sphingomyelinase deficiency is a lysosomal storage disease that is characterized by the systemic accumulation of sphingomyelin in cells. This condition is frequently associated with hepatomegaly and hepatic dysfunction, with 91.4% of patients showing clinically relevant signs of liver involvement. Both clinical observations and experimental models show excessive sphingomyelin accumulation in hepatocytes. Studies using ASMD models have yielded conflicting results, showing hepatoprotective effects on one hand and detrimental effects on the other. Murine models demonstrated hepatoprotective effects of ASMD due to the modulation of endoplasmic reticulum stress. Patients with ASMD exhibit signs of impaired autophagy, which can lead to the accumulation of damaged cellular components and metabolic dysfunction. Furthermore, patients exhibit disrupted lipid metabolism, highlighting the dysfunction of hepatic lipid homeostasis. This review explores the involvement of ASMD in hepatocytes to better understand the disease mechanisms and possible therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Mechanisms Driving Liver Disease: From Cellular Stress to Therapeutic Targets)

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