Background and Aims: Alcohol-perturbed gut immune homeostasis is associated with the development of alcoholic liver disease (ALD). However, the role of intestinal dendritic cells (DCs) in ALD progression is still unknown. This study aimed to investigate the cellular and molecular mechanisms through which intestinal DCs respond to alcohol exposure and contribute to the pathogenesis of ALD. Approach and Results: After 8 weeks of alcohol consumption, the number of basic leucine zipper transcription factor ATF-like 3 (Batf3)-dependent conventional type 1 DCs (cDC1s) was dramatically decreased in the intestine but not the liver. cDC1 deficient Batf3 knockout mice along with wild-type mice were subjected to chronic-binge ethanol feeding to determine the role of intestinal cDC1s reduction in ALD. cDC1s deficiency exacerbated alcohol-induced gut barrier disruption, bacterial endotoxin translocation into the circulation, and liver injury. Adoptive transfer of cDC1s to alcohol-fed mice ameliorated alcohol-mediated gut barrier dysfunction and liver injury. Further studies revealed that intestinal cDC1s serve as a positive regulator of Akkermansia muciniphila (A. muciniphila). Oral administration of A. muciniphila markedly reversed alcoholic steatohepatitis in mice. Mechanistic studies revealed that cDC1s depletion exacerbated alcohol-downregulated intestinal antimicrobial peptides which play a crucial role in maintaining A. muciniphila abundance, by disrupting the IL-12-interferon gamma signaling pathway. Lastly, we identified that intestinal cDC1s were required for the protective role of Lactobacillus reuteri in alcoholic steatohepatitis. Conclusions: This study demonstrated that cDC1s protect alcohol-induced liver injury by maintaining A. muciniphila abundance in mice. Targeting cDC1s may serve as a promising therapeutic approach for treating ALD.

Background: Dysregulation of bile acids (BAs) has been reported in alcohol-associated liver disease. However, the causal relationship between BA dyshomeostasis and alcohol-associated liver disease remains unclear. The study aimed to determine whether correcting BA perturbation protects against alcohol-associated liver disease and elucidate the underlying mechanism. Methods: BA sequestrant cholestyramine (CTM) was administered to C57BL/6J mice fed alcohol for 8 weeks to assess its protective effect and explore potential BA targets. The causal relationship between identified BA metabolite and cellular damage was examined in hepatocytes, with further manipulation of the detoxifying enzyme cytochrome p450 3A11. The toxicity of the BA metabolite was further validated in mice in an acute study. Results: We found that CTM effectively reversed hepatic BA accumulation, leading to a reversal of alcohol-induced hepatic inflammation, cell death, endoplasmic reticulum stress, and autophagy dysfunction. Specifically, nordeoxycholic acid (NorDCA), a hydrophobic BA metabolite, was identified as predominantly upregulated by alcohol and reduced by CTM. Hepatic cytochrome p450 3A11 expression was in parallel with NorDCA levels, being upregulated by alcohol and reduced by CTM. Moreover, CTM reversed alcohol-induced gut barrier disruption and endotoxin translocation. Mechanistically, NorDCA was implicated in causing endoplasmic reticulum stress, suppressing autophagy flux, and inducing cell injury, and such deleterious effects could be mitigated by cytochrome p450 3A11 overexpression. Acute NorDCA administration in mice significantly induced hepatic inflammation and injury along with disrupting gut barrier integrity, leading to subsequent endotoxemia. Conclusions: Our study demonstrated that CTM treatment effectively reversed alcohol-induced liver injury in mice. The beneficial effects of BA sequestrant involve lowering toxic NorDCA levels. NorDCA not only worsens hepatic endoplasmic reticulum stress and inhibits autophagy but also mediates gut barrier disruption and systemic translocation of pathogen-associated molecular patterns in mice.

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.

Our previous work has demonstrated that some acute promyelocytic leukemia (APL) patients had significantly elevated circulating CD34+ cell count (≥ 10 × 10⁶/L), and these patients with higher CD34+ cell level usually presented with high-risk disease (WBC > 10,000/μL). The aim of this study was to investigate whether circulating CD34+ cell count is a prognostic marker in intermediate-low risk APL patients. In this study, 76 intermediate-low risk APL patients and 56 age-adjusted healthy volunteers were evaluated. Enumeration of CD34+ cells was investigated before the treatment. A cut-off value of 10 × 10⁶/L CD34+ cells could just distinguish APL patients with adverse prognostic factors from others and may have the power to predict shorter progression-free survival (PFS) and poor prognosis. Higher count of CD34+ cells was usually associated with nonclassical chromosomal translocation, PML/RARα gene complex fusion, APL history, chemotherapy-related APL, disease progression, second tumor, extramedullary infiltration, FLT3-ITD positive mutation, atypical morphology, BM promyelocyte CD56/CD34 positive expression, myelofibrosis, PCR-positive PML/RARa gene fusion but FISH-negative, marrow necrosis and shorter PFS. Our results suggest that the level of CD34+ cells can be further the stratification of disease risk, a higher CD34+ cell count may be indicative of inferior survival and serve as an adverse biomarker for intermediate-low risk APL.

Metabolic-dysfunction-associated fatty liver disease (MAFLD) and alcohol-associated liver disease (ALD) represent two of the most prevalent chronic liver diseases globally, collectively affecting hundreds of millions of individuals

Fatty liver disease is no longer a niche hepatology problem but is increasingly recognized as a systemic metabolic-inflammatory disorder. Large-scale epidemiological analyses have estimated that metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the general population and is tightly associated with obesity, insulin resistance, and type 2 diabetes (Younossi et al., 2023;Cusi et al., 2025). In parallel, alcohol-associated liver disease (ALD), spanning from steatosis to cirrhosis, remains one of the leading causes of liver-related deaths worldwide. Its development, in addition to its unique triggers related to alcohol metabolism, is often linked to a dangerous combination of metabolic dysfunction (Gao et al., 2025;Pan et al., 2025). These observations challenge traditional binary disease classifications and underscore the need for integrated pathogenic frameworks.At the mechanistic level, metabolic overload and alcohol exposure function as primary upstream stressors that initiate hepatocellular injury. Excess nutrient availability promotes hepatic lipid accumulation and associated lipotoxicity, alters fatty acid flux, and induces insulin resistance, while ethanol metabolism generates toxic intermediates (e.g., acetaldehyde) and oxidative stress (Cheng et al., 2016;Lee et al., 2025). These primary hepatocellular stresses subsequently engage innate immune sensing and adaptive immune polarization, shaping whether injury resolves or progresses toward fibrogenesis. Importantly, innate and adaptive immune remodeling is increasingly recognized predominantly not as the initiating event but as a secondary amplification system that sustains inflammation and fibrogenesis once hepatocyte injury is established (Peiseler et al., 2022). This hierarchical organization helps explain why distinct etiologies converge on overlapping inflammatory and fibrotic phenotypes during disease progression.At the cellular execution layer, while distinct upstream injuries are not entirely identical, they functionally converge on a limited set of conserved stress-response pathways. Lipotoxicityinduced organelle dysfunction, mitochondrial impairment, oxidative injury, and dysregulated wound-healing responses are common molecular nodes in both metabolic liver diseases and alcoholic liver diseases (Garcia-Ruiz and Fernandez-Checa, 2018;Kim and Kim, 2020;Prasun et al., 2021;Contreras-Zentella et al., 2025). These processes shape hepatocyte fate decisions, inflammatory signaling, and extracellular matrix remodeling, thereby providing a mechanistic basis for the overlapping histological features observed in MASLD and ALD, particularly during the transition from steatosis to steatohepatitis and fibrosis.The rapid conceptual evolution of the field is reflected in recent changes to disease nomenclature. A multisociety Delphi consensus introduced steatotic liver disease as an umbrella term and repositioned NAFLD/NASH as MASLD/MASH, while explicitly defining overlap categories such as metabolic and alcohol related/associated liver disease (MetALD) (Rinella et al., 2023). This nomenclature update coincides with, but is conceptually distinct from, ongoing discussions comparing MASLD and MAFLD, in which MAFLD has been reported to better capture all-cause mortality as well as hepatic and extrahepatic outcomes that closely track fibrosis severity (Lonardo et al., 2025). Importantly, these parallel frameworks converge on a shared conclusion: metabolic dysfunction and alcohol exposure frequently coexist and interact. Consistent with this view, cohort studies further suggest that mixed metabolic-alcoholic phenotypes exhibit distinct trajectories of fibrosis progression and clinical outcomes, reinforcing the clinical relevance of overlap states (Sogabe et al., 2023;Marti-Aguado et al., 2024).Within this evolving scenario, immunometabolic coupling has emerged as a central organizing principle. Hepatic immune cells respond dynamically to metabolic and toxic stress, with macrophages, dendritic cells, and lymphocyte subsets adopting context-dependent phenotypes that can either exacerbate injury or promote resolution. Reviews within this Research Topic emphasize that cytokine signaling networks integrate metabolic cues with inflammatory responses. Liu et al. synthesized evidence indicating that members of the interleukin-6 cytokine family participate in regulating lipid metabolism, insulin sensitivity, inflammatory amplification, and fibrogenesis in MASLD, supporting the view that cytokine pathways function as active immunometabolic regulators rather than passive downstream markers.Beyond immune signaling, regulated inflammatory cell death pathways have gained increasing attention as critical links between hepatocyte injury and immune activation. Pyroptosis and related execution programs promote the release of danger-associated molecular patterns, thereby reinforcing inflammatory feedback loops (Farrell et al., 2018). In this context, Deng et al. provided evidence suggesting that short-term high-fat diet exposure synergizes with acute ethanol binge to exacerbate liver injury through oxidative stress, MAPK/NF-κB activation, and engagement of both canonical and non-canonical pyroptotic pathways. These findings provide mechanistic insight into the convergence of metabolic and alcohol-related stressors at the level of inflammatory execution programs, thereby offering a biologically grounded explanation for the heightened inflammatory injury observed in mixed-exposure contexts.Translationally, the absence of effective pharmacological therapies for advanced fatty liver disease has long represented a major unmet need. This landscape is now rapidly changing. In 2024, the U.S. Food and Drug Administration approved resmetirom for adults with noncirrhotic MASH and moderate-to-advanced fibrosis, marking the first disease-modifying therapy for this indication (Huang et al., 2025). More recently, incretin-based...