Search Results (240)

Background and objectives: Occupational and environmental inhalation exposures, including high-aspect-ratio carbon nanotubes, can trigger pulmonary fibrosis (PF). The relationship between exposure-specific fibrogenic pathways (granulomatous inflammation versus diffuse epithelial injury) and lung microbiome dysbiosis remains incompletely understood. We therefore compared lung microbiome alterations in rat PF models induced by multi-walled carbon nanotubes (MWCNTs) and bleomycin. Materials and Methods: Female Wistar rats received a single intratracheal instillation of vehicle, MWCNTs (750 μg/rat), or bleomycin (1 mg/rat). At day 28, fibrosis and inflammation were evaluated by histopathology and bronchoalveolar lavage fluid (BALF) profiling. Lung microbial communities were characterized by 16S rRNA gene sequencing (V3–V4). Seventeen lung samples passed stringent quality control and were analyzed (control n = 5; bleomycin n = 7; MWCNT n = 5). Results: Both agents induced PF with increased profibrotic signaling, but with distinct pathological signatures: MWCNTs produced localized granulomatous lesions and a robust neutrophilic response (25% of BALF cells), whereas bleomycin caused diffuse interstitial remodeling. Bleomycin increased microbial richness (alpha diversity; p < 0.05) and significantly shifted community structure (beta diversity; p < 0.05), while MWCNT exposure showed comparatively limited changes in global diversity. The relative abundance of Pseudogracilibacillus (including P. marinus) was higher in the bleomycin group than in controls, whereas Facklamia tabacinasalis and Corynebacterium maris were more abundant in the MWCNT group. Across samples, Proteobacteria abundance was inversely correlated with BALF TGF-β, MCP-1, and neutrophil proportion. At the species level, Pseudogracilibacillus marinus was positively correlated with BALF TGF-β, while Facklamia tabacinasalis and Corynebacterium maris were positively correlated with MCP-1, CINC-3, and neutrophil proportion (Spearman; p < 0.05). Conclusions: Mechanistically distinct fibrogenic exposures generate exposure-linked lung microbiome signatures that track with host inflammatory and profibrotic responses. These signatures may support biomarker development for environmentally and occupationally relevant PF and motivate longitudinal and functional studies to clarify causality. Full article

Cytoglobin (Cygb) was discovered in 2001 as a cytoplasmic globin predominantly expressed in hepatic stellate cells (HSCs). While its initial physiological role remained elusive, subsequent studies using Cygb-deficient mouse models of liver injury have demonstrated that Cygb exerts protective effects against liver fibrosis and inflammation. It achieves this by regulating HSC activation, thereby preserving hepatic homeostasis. Furthermore, accumulating evidence suggests a significant role for Cygb in hepatocarcinogenesis. Analysis of human liver tissues and cell-based models has further confirmed the critical involvement of CYGB in liver pathology. Functionally, Cygb acts as an antioxidant protein that mitigates oxidative stress, a property that appears to modulate transforming growth factor-beta signaling and downstream fibrogenic responses. Based on these findings, therapeutic strategies employing recombinant CYGB for the treatment of human liver cirrhosis are currently being explored, and their potential clinical applications are eagerly anticipated. Full article

Background: Chronic liver fibrosis is a progressive pathological condition characterized by excessive extracellular matrix deposition and architectural remodeling, which may ultimately lead to cirrhosis and liver failure. Although mesenchymal stem cells (MSCs) exhibit antifibrotic and immunomodulatory properties, their therapeutic effects in established chronic liver fibrosis remain incompletely defined. This study aimed to evaluate the biochemical, hematological, and histopathological effects of MSC therapy in a chronic thioacetamide-induced liver fibrosis model. Methods: A controlled preclinical experimental study was conducted using rats with liver fibrosis induced by intraperitoneal thioacetamide administration for 24 weeks. Animals were allocated into three groups: control, untreated fibrosis, and fibrosis treated with MSCs derived from human umbilical cord tissue after fibrosis establishment. Serum biochemical markers, hematological parameters, and liver histopathology were assessed. Fibrosis severity was evaluated using hematoxylin–eosin and Masson’s trichrome staining and graded according to the METAVIR scoring system. Results: Thioacetamide exposure induced chronic liver injury characterized by marked elevations in serum transaminases, reduced albumin and total protein levels, hematological alterations, and early-to-intermediate fibrosis stages (METAVIR F1–F2). MSC-treated animals exhibited approximately 40–45% reductions in transaminase levels, partial recovery of hepatic synthetic function, and attenuation of hematological alterations. Histopathological analysis demonstrated a reduction in fibrotic burden and limitation of fibrogenic progression within METAVIR F1–F2 stages. Conclusions: MSC therapy partially mitigates biochemical, hematological, and histopathological alterations associated with chronic thioacetamide-induced liver fibrosis, supporting its potential as a modulatory strategy to attenuate fibrogenic progression and stabilize liver function rather than as a curative intervention. Full article

Background/Objectives: Pulmonary fibrosis is a chronic, progressive lung disease marked by scarring and inflammation, leading to impaired respiratory function. This study aimed to investigate the combined therapeutic effects of pirfenidone (PFD), metformin (MET), and bone marrow-derived mesenchymal stem cells (BM-MSCs) on bleomycin (BLM)-induced pulmonary fibrosis in rats. Methods: Forty-eight Western Albino rats were divided into six groups: normal control, BLM-positive control, and four treatment groups receiving PFD, MET, BM-MSCs, and their combination. Treatments were administered for four weeks starting on day 21 post-BLM instillation. Lung tissues were analyzed for oxidative stress markers, inflammatory cytokines, apoptotic markers, and fibrogenic gene expression. Histopathological changes were assessed using hematoxylin and eosin (H&E) and Masson’s trichrome staining. Results: The combination therapy significantly reduced oxidative stress and inflammatory markers while enhancing antioxidant capacity. It decreased pro-apoptotic Bcl-2-associated X protein (BAX) and increased anti-apoptotic B-cell lymphoma 2 (Bcl-2) levels. Additionally, anti-inflammatory interleukin-10 (IL-10) was elevated, while tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta 1 (TGF-β1) levels were markedly lowered. Gene expression analysis showed a significant downregulation of matrix metalloproteinase-9 (MMP-9) and collagen type 1 alpha 1 (Col1α1). Histologically, the combination treatment group exhibited minimal fibrosis and inflammation, closely resembling normal lung tissue. Conclusions: The combination of PFD, MET, and BM-MSCs offered superior therapeutic efficacy in treating BLM-induced pulmonary fibrosis compared to individual treatments. This multimodal approach effectively targets oxidative stress, inflammation, apoptosis, and fibrosis, suggesting strong potential for future clinical application. Full article

This study aimed to investigate the effect and underlying mechanism of Taxus cuspidata seed oil (TCSO) on carbon tetrachloride (CCl₄)-induced hepatic fibrosis in mice. A mouse model of hepatic fibrosis was established by CCl₄ induction, and the model mice were subsequently treated orally with high dose or low dose TCSO for eight weeks. The degree of liver fibrosis and the mechanism of action were assessed through organ indices, serum biochemical markers, oxidative stress levels, histopathological examination, and molecular biological analyses. The results demonstrated that TCSO significantly reduced serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP). Concurrently, it decreased the concentrations of liver fibrosis markers, including procollagen III (PC III), collagen IV (IV-C), hyaluronic acid (HA), and laminin (LN), and reduced hepatic collagen deposition. Furthermore, TCSO enhanced the activities of the antioxidants superoxide dismutase (SOD) and glutathione (GSH) while inhibiting the production of the lipid peroxidation product malondialdehyde (MDA), and it ameliorated histopathological alterations in liver tissue. Additionally, TCSO markedly downregulated the expression of key fibrogenic proteins, such as transforming growth factor-β1 (TGF-β1), matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinases-1 (TIMP-1), thereby effectively suppressing the progression of hepatic fibrosis. In conclusion, TCSO ameliorates hepatic fibrosis in mice by reducing hepatotoxic enzyme activity and collagen deposition, enhancing antioxidant capacity, and downregulating the expression of fibrosis-related proteins. Full article

Objective: Rare-earth elements are extensively employed across diverse industrial sectors, increasingly raising concerns about their potential health hazards in both occupational and environmental contexts. Samarium oxide (Sm₂O₃), a routinely processed rare-earth product, reproducibly precipitates pulmonary fibrosis in experimental models, yet the molecular circuitry that transduces its fibrogenic signal remains almost entirely unmapped. This study aims to elucidate the role of miR-214-3p in Sm₂O₃-induced pulmonary fibrosis and to investigate its regulatory mechanism at the molecular level. Methods: A murine model of pulmonary fibrosis was established via intratracheal instillation of Sm₂O₃, and histopathological changes were assessed using hematoxylin and eosin (H&E) and Masson’s trichrome staining. RNA sequencing was performed on lung tissues to identify differentially expressed mRNAs. Leveraging our previously generated miRNA landscape of Sm₂O₃-exposed lungs, we subjected the dataset to Gene Ontology and KEGG enrichment analyses, which convergently identified miR-214-3p as the top-ranking candidate regulator of the fibrogenic MAPK axis. The direct targeting of MAP2K3 by miR-214-3p was validated using a dual-luciferase reporter assay. Expression levels of fibrotic markers (α-SMA, Collagen I) and key components of the MAPK signaling pathway (MAP2K3, p-MAPK14, MST1) were quantified in both in vivo and in vitro models using qRT-PCR and Western blotting. Gain- and loss-of-function studies, complemented by rescue assays, were performed in human embryonic lung fibroblasts (HELFs) via transient transfection of miR-214-3p mimics, inhibitors, or MAP2K3-overexpression plasmids. Cell proliferation was evaluated using the EdU assay, and TGF-β1 secretion was measured by ELISA. Results: Sm₂O₃ exposure induced significant pulmonary fibrosis in mice, accompanied by marked downregulation of miR-214-3p and upregulation of MAP2K3 in lung tissues. Overexpression of miR-214-3p or silencing of MAP2K3 effectively suppressed Sm₂O₃-induced fibroblast activation, including reduced cell proliferation, decreased expression of α-SMA and Collagen I, and inhibition of p38 MAPK phosphorylation. Notably, ectopic overexpression of MAP2K3 reversed the protective effects conferred by miR-214-3p, confirming a functional rescue. Conclusions: miR-214-3p directly silences MAP2K3, thereby blunting p38 MAPK-driven fibrogenesis after Sm₂O₃ exposure. Our data unveil a miR-214-3p–MAP2K3–p38 MAPK axis that constitutes a readily druggable target for rare-earth-element-induced pulmonary fibrosis. Full article

Tubule-derived pro-fibrotic mediators are central for the development of kidney fibrosis. We previously showed that fibrotic stimuli activate and elevate GEF-H1 (ARHGEF2) in tubular cells, leading to RhoA-dependent fibrotic reprogramming. In search of new mechanisms of GEF-H1 regulation, here we used immunoprecipitation and proximity ligation assay to show interaction between GEF-H1 and Myotonic Dystrophy Kinase-related Cdc42-binding kinase (MRCK)α in tubular cells. MRCKα silencing elevated GEF-H1 activity, and induced GEF-H1-dependent RhoA activation, stress fibre formation and myosin light chain phosphorylation. MRCKα depletion also elevated phospho-cofilin levels in a RhoA-dependent manner. The fibrogenic cytokine TGFβ1 rapidly increased binding between GEF-H1 and MRCKα, while MRCKα silencing augmented TGFβ1-induced GEF-H1 activation, suggesting a negative feedback loop. An mRNA array detecting fibrogenic genes revealed increase in a subset of basal and TGFβ1-induced genes following MRCKα depletion. MRCKα silencing promoted nuclear translocation of the profibrotic transcriptional co-activator Myocardin-Related Transcription Factor (MRTF), and MRTF-A+B depletion prevented increase in ACTA2 (α-smooth muscle actin), a key marker of fibrotic reprogramming. Finally, total MRCKα mRNA was reduced in a murine kidney fibrosis model, and immunohistochemistry revealed a decrease in tubular MRCKα. Taken together, we identified MRCKα as a new suppressor of GEF-H1/RhoA/MRTF signaling. Reduced MRCKα expression in kidney fibrosis may promote tubular fibrotic gene expression. Full article

Post-cholecystectomy non-alcoholic fatty liver disease (NAFLD), now encompassed within metabolic dysfunction-associated steatotic liver disease (MASLD), is increasingly linked to persistent disruption of bile acid kinetics and gut–liver axis signaling after gallbladder removal. Continuous bile delivery to the intestine reshapes the bile acid pool, perturbs FXR–FGF19/TGR5 pathways, remodels gut microbiota, and compromises epithelial barrier integrity, collectively promoting portal endotoxemia, chronic hepatic inflammation, and fibrogenic remodeling. Hydrogel-based biomaterials offer a mechanistically aligned therapeutic platform for this setting because they enable localized, sustained, and stimuli-responsive interventions at intestinal or hepatic sites. Functional hydrogels can sequester excess bile acids, protect and deliver probiotics/prebiotics/postbiotics, reinforce mucosal barrier function, and provide controlled release of anti-inflammatory or antifibrotic agents with reduced systemic exposure. In this review, we map emerging hydrogel strategies relevant to post-cholecystectomy NAFLD across four pathogenic nodes, bile acid dysregulation, dysbiosis, inflammation, and fibrosis, and highlight design principles (polymer chemistry, charge/hydrophobicity balance, mucoadhesion, and pH/redox/enzyme responsiveness) that enable targeted modulation of the gut–liver axis. Finally, we identify key translational gaps, including the lack of post-cholecystectomy-specific experimental models and standardized outcome measures integrating bile acid profiling, microbiome readouts, and hepatic histology. Hydrogel technologies represent a promising route toward localized and multimodal therapy in metabolic liver disease, warranting focused preclinical validation and clinical development. Full article

Chronic liver injury is accompanied by coordinated disturbances in lipid trafficking and inflammatory–fibrogenic signaling. Transforming growth factor beta 1 (TGF-β1) signaling has been implicated in hepatic fibrogenesis and tumor-associated remodeling and may co-vary with disturbances in lipid trafficking. Lisosan G (LG), a fermented wheat-derived nutraceutical, has reported antioxidant and anti-inflammatory activity and may influence these interconnected pathways. This study evaluated whether dietary LG alters the lipid composition of plasma lipoprotein fractions and hepatic TGF-β1 levels across distinct liver contexts. Seventy-two female Wistar rats were randomized into nine groups (n = 8/group) defined by liver condition, consisting of healthy control (Control), non-neoplastic liver (PH), and neoplastic liver injury (HCC; PH followed by diethylnitrosamine, DEN), and diet (standard diet, SD + 2.5% LG, or SD + 5% LG). Plasma lipoproteins (VLDL, LDL, HDL₁, HDL₂) were isolated by stepwise KBr density-gradient ultracentrifugation, and cholesterol (TC), phospholipids (PL), and triacylglycerols (TG) were quantified in each fraction. Hepatic TGF-β1 was measured by ELISA and normalized to total protein. LG effects depended strongly on baseline liver status, with significant Condition × Diet interactions for most lipid endpoints and for hepatic TGF-β1. In healthy rats, LG produced fraction-selective remodeling rather than uniform lipid lowering, including increased VLDL-TG at both doses and non-linear changes in cholesterol distribution across LDL and HDL subfractions. After PH, LG broadened lipid remodeling, including reduced VLDL-PL, increased VLDL-TG (both doses), and an increase in LDL-TC at 5% LG, accompanied by marked changes in HDL₁/HDL₂ cholesterol partitioning. In HCC, LG induced pronounced, often dose-dependent increases in LDL-associated lipids (LDL-PL, LDL-TG, LDL-TC) and increased HDL₁-TC while decreasing HDL₂-TC. Hepatic TGF-β1 was elevated in PH and further increased in HCC versus controls; LG reduced hepatic TGF-β1 in a condition-dependent manner, with the strongest reduction at 5% LG in HCC. Dietary Lisosan G remodels circulating lipoprotein lipid composition in a liver-status-dependent manner and is associated with reduced hepatic TGF-β1 abundance in injured liver, most prominently in neoplastic injury. These findings are consistent with the notion that nutraceutical interventions may show stronger phenotypic effects under perturbed metabolic–fibrogenic states than under stable physiology, while highlighting the need for mechanistic work to distinguish altered lipoprotein secretion from changes in peripheral clearance and to assess pathway-level TGF-β signaling. Full article

We hypothesized that maternal overfeeding and restricted feeding during gestation would alter the collagen content, muscle fiber cross-sectional area (CSA), and meat tenderness in offspring. Pregnant ewes were fed 100% (CON), 60% (RES), or 140% (OVER) of their requirements from day 30 of gestation until parturition. Male offspring were necropsied at 282 ± 1.8 days of age. Gene expression and CSA were quantified in the longissimus (LM) and semitendinosus (STN) muscles. The Warner–Bratzler shear force (WBSF) was quantified in LM. Data were analyzed by one-way ANOVA, with diet as a fixed effect. Differences were considered significant at p ≤ 0.05 or a tendency at p ≤ 0.10. Semitendinosus CSA was smaller in OVER and RES than CON rams (p = 0.02). Longissimus CSA was larger in RES than OVER and CON rams (p = 0.002). OVER LM had reduced WBSF compared with CON rams (p = 0.03). Myogenic genes bone morphogenic protein 1 (BMP1) and paired box 7 were greater in RES LM than OVER (p ≤ 0.02). Maternal diet altered the fibrogenic genes fibronectin 1 (p = 0.07), lysyl oxidase (p = 0.07), and collagen 1A1 (COL1A1; p = 0.08) in the LM and COL1A1, COL3A1, and BMP1 (p ≤ 0.09) in the STN. Poor maternal diet during gestation alters muscle and meat characteristics that may impact meat quality. Full article

Forkhead box protein A3 (FOXA3), also known as hepatocyte nuclear factor 3g (HNF3g), is a member of the FOX family of transcription factors and regulates lipid and glucose metabolism and liver regeneration. Hepatic FOXA3 is reduced in obesity and patients with metabolic dysfunction-associated steatohepatitis (MASH). So far, it remains unknown whether hepatic FOXA3 is essential for regulating lipid metabolism or metabolic dysfunction-associated liver disease (MASLD). In this study, we first investigated whether genetic inactivation of hepatocyte Foxa3 affected the development of MASLD/MASH in C57BL/6 mice and then explored whether loss of hepatocyte Foxa3 regulated atherosclerosis development in Ldlr-deficient mice. Inactivation of Foxa3 in hepatocytes did not affect the development of Western diet-induced MASLD/MASH in C57BL/6 mice but attenuated MASH development in Western diet-fed Ldlr-deficient mice. Moreover, genetic loss of hepatocyte Foxa3 ameliorated hyperlipidemia and atherosclerosis in Ldlr-deficient mice. In Ldlr-deficient mice, loss of hepatocyte Foxa3 resulted in reduced expression of lipogenic, pro-inflammatory, or fibrogenic genes in the liver and reduced cholic acid levels in plasma and bile. Thus, hepatocyte FOXA3 loss confers protection against the development of MASH and atherosclerosis in hyperlipidemic Ldlr-deficient mice. Full article

Hepatic osteodystrophy (HOD) is a frequent complication of chronic liver disease, marked by impaired osteogenesis and elevated fracture risk, particularly under sustained alcohol exposure. Bone morphogenetic proteins (BMPs), which play a crucial role in maintaining bone homeostasis, are dysregulated in alcoholic liver disease. Specifically, decreased BMP2 and increased BMP13 have been linked to impaired osteogenesis and cartilage-like shifts in bone progenitors. A human in vitro system that recapitulates this hepatic BMP imbalance is needed to dissect mechanisms and identify targets. To address this, we established a long-term human three-dimensional liver–bone co-culture model that integrates hepatocytes (HepaRG), hepatic stellate cells (LX-2), and human umbilical vein endothelial cells (HUVECs) with bone scaffolds seeded with osteoblast precursors (SCP-1) and osteoclast precursors (THP-1). This study aimed to characterize the effects of chronic 50 mM alcohol exposure on hepatic fibrogenic activation and BMP ligand secretion, and to investigate the associated BMP-responsive signaling involved in bone cell lineage differentiation and functional activity. The results demonstrated alcohol-induced hepatic CYP2E1 activation and fibrogenic remodeling with EMT signatures, as well as a decrease in BMP2 and an increase in BMP13, without affecting BMP9. Liver-derived factors activated both canonical and non-canonical BMP signaling in bone progenitors, reduced osteoblast activity and mineralization, preserved osteoclast TRAP activity, and shifted the lineage toward chondrogenesis (SOX9↑, RUNX2↓). Notably, this BMP profile and skeletal phenotype reflect clinical observations in chronic liver disease, indicating that the model recapitulates key in vivo pathological features. This human liver micro-organoid co-culture reproduces alcohol-induced hepatic BMP dysregulation and downstream bone defects, offering an organoid-centric, microengineered platform for mechanistic studies and BMP-targeted therapeutic screening in HOD. Full article

Skeletal muscle orchestrates a remarkable journey from embryonic formation to age-related decline, yet its cellular intricacies in goats remain largely uncharted. We present the first single-cell RNA sequencing (scRNA-seq) atlas of the longissimus dorsi muscle from goats, profiling 120,944 cells across 14 developmental stages from embryonic day 30 (E30) to 11 years postnatal (Y11). We focused on skeletal muscle satellite cells (MuSCs) and fibro-adipogenic progenitors (FAPs), identifying a unique MuSCs_ACT1_high subpopulation in early embryogenesis and a senescence-associated MuSCs_CDKN1A_high subpopulation in later developmental stages. In FAPs, we characterized the early-stage FAPs_MDFI_high subpopulation with differentiation potential, which further exhibited the capacity to commit to both adipogenic and fibrogenic lineages. Transcription factor analysis revealed strikingly similar regulatory profiles between MuSCs and FAPs, suggesting that these two cell types are governed by shared signaling pathways during development. Cell–cell interaction analysis demonstrated that the DLK1-NOTCH3 ligand-receptor pair plays a critical role in enabling early embryonic FAPs to maintain the quiescent state of MuSCs. This dynamic single-cell transcriptomic atlas, spanning 14 developmental stages of skeletal muscle in ruminants for the first time, provides a valuable theoretical foundation for further elucidating the differentiation of skeletal muscle satellite cells and fibro-adipogenic progenitors in ruminants. Full article

Endometriosis (EDT) is a chronic, estrogen-dependent disease characterized by inflammation, fibrosis, pelvic pain, and infertility. Current therapies show limited long-term efficacy and adverse effects, underscoring the need for novel therapeutic approaches. Elevated copper (Cu) levels have been reported in both patients and animal models of EDT, making Cu chelation a promising strategy. This work aimed to evaluate the impact of ammonium tetrathiomolybdate (TM) on the expression of markers related to the interconnected processes of inflammation, innervation, and fibrogenesis in mice with induced EDT. Twenty-four female C57BL/6 mice were assigned to Sham, EDT, or EDT+TM groups. Treatment with TM began on postoperative day 15, with samples collected one month after EDT induction. Peritoneal fluid cytokines (TNF-α, IL-1β, IL-6, TGF-β1) were quantified by ELISA. Endometriotic-like lesions were examined for mRNA expression of cytokines, neurotrophins (Ngf, Bdnf, Ngfr), neural markers (Uchl1, Gap43), neuropeptides and nociceptive markers (Tac1/Tacr1, Calca/Calcrl/Ramp1, Trpv1), and fibrogenic markers (Vim, Acta2, Col1a1, Fmod) by RT-qPCR. Neurotrophin protein levels were measured by ELISA, and collagen content was assessed through Masson’s staining. TM significantly modulated inflammatory, neural, nociceptive, and fibrogenic markers, reducing most of them along with collagen content. These findings suggest that TM could impact key pathological mechanisms involved in EDT. Full article

Alcohol-associated liver disease (ALD) contributes substantially to the global burden of cirrhosis and liver-related mortality, driven by ethanol metabolism, oxidative stress, and dysregulated immune signaling. Despite rapidly growing evidence implicating interferon regulatory factors (IRFs) in ALD pathogenesis, an integrated framework linking ethanol-induced danger signals to cell-type-specific IRF programs is lacking. In this comprehensive review, we summarize current knowledge on IRF-centered signaling networks in ALD, spanning DAMP–PAMP sensing, post-translational IRF regulation, and downstream inflammatory, metabolic, and fibrogenic outcomes across various cell types in the liver, including hepatocytes and immune-related cells such as Kupffer cells, monocyte-derived macrophages, dendritic cells, T cells, hepatic stellate cells (HSC), and neutrophils. We also focus on how ethanol-driven DAMP and PAMP signals activate TLR4, TLR9, and cGAS–STING pathways to engage a coordinated network of IRFs—including IRF1, IRF3, IRF4, IRF5, IRF7, and IRF9—that collectively shape inflammatory, metabolic, and cell-fate programs across hepatic cell populations. We further highlight emerging therapeutic strategies such as STING/TBK1 inhibition, NETosis blockade, IL-22-based epithelial repair, and JAK-STAT modulation that converge on IRF pathways. In summary, this review outlines how IRFs contribute to ALD pathogenesis and discusses the potential implications for the development of targeted therapies. Full article