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Nuclear Prohibitin 1 Protects Against Alcohol-Associated Liver Injury and Sensitization to Colon Cancer Liver Metastasis [Spatial Transcriptomics]

ABSTRACT: Alcohol-associated liver disease (ALD) is associated with higher incidence of colorectal liver metastasis (CRLM); prohibitin 1 (PHB1) defends against CRLM yet its role in ALD and ALD-CRLM is unknown and was investigated here. In human, murine, and in vitro ALD models, cytosolic and nuclear PHB1 were depleted, whereas mitochondrial PHB1 was preserved. Nuclear PHB1 loss was driven by CRM1-mediated export, and blocking this interaction with a PHB1 nuclear export signal (NES) peptide retained nuclear PHB1, ameliorating both ALD and ALD-CRLM. PHB1 NES prevented depletion of nuclear methionine adenosyltransferase α1, oxidative stress, and induction of matrix metalloproteinase 7 (MMP-7) and multiple oncogenes. Single-nucleus RNA sequencing of NIAAA diet-fed mouse livers revealed that PHB1 NES treatment mitigated alcohol-induced metabolic and oncogenic stress, attenuated pro-inflammation and pro-fibrogenic responses, and contributed to overall hepatoprotection. These findings identify nuclear PHB1 depletion as a driver and a promising therapeutic target in ALD and ALD-CRLM.

ORGANISM(S): Mus musculus

PROVIDER: GSE338350 | GEO | 2026/09/14

REPOSITORIES: GEO

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Nuclear Prohibitin 1 Protects Against Alcohol-Associated Liver Injury and Sensitization to Colon Cancer Liver Metastasis [snRNA-seq]

Project description:Alcohol-associated liver disease (ALD) is associated with higher incidence of colorectal liver metastasis (CRLM); prohibitin 1 (PHB1) defends against CRLM yet its role in ALD and ALD-CRLM is unknown and was investigated here. In human, murine, and in vitro ALD models, cytosolic and nuclear PHB1 were depleted, whereas mitochondrial PHB1 was preserved. Nuclear PHB1 loss was driven by CRM1-mediated export, and blocking this interaction with a PHB1 nuclear export signal (NES) peptide retained nuclear PHB1, ameliorating both ALD and ALD-CRLM. PHB1 NES prevented depletion of nuclear methionine adenosyltransferase α1, oxidative stress, and induction of matrix metalloproteinase 7 (MMP-7) and multiple oncogenes. Single-nucleus RNA sequencing of NIAAA diet-fed mouse livers revealed that PHB1 NES treatment mitigated alcohol-induced metabolic and oncogenic stress, attenuated pro-inflammation and pro-fibrogenic responses, and contributed to overall hepatoprotection. These findings identify nuclear PHB1 depletion as a driver and a promising therapeutic target in ALD and ALD-CRLM.

2026-09-14 | GSE316359 | GEO

Prohibitin cross-linked aided interactome in yeast

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Deletion of adipocyte prohibitin 1 exacerbates high-fat diet-induced steatosis but not liver inflammation and fibrosis

Project description:Adipose tissue dysfunction is closely associated with the development and progression of nonalcoholic fatty liver disease (NAFLD). Recent studies have implied an important role of prohibitin-1 (PHB1) in adipose tissue function. In the current study, we aimed to explore the function of adipocyte PHB1 in the development and progression of NAFLD. The PHB1 protein levels in adipose tissues were markedly decreased in mice fed a high-fat diet (HFD) compared to those fed a chow diet. To explore the function of adipocyte PHB1 in the progression of NAFLD, mice with adipocyte-specific (adipo) deletion of Phb1 (Phb1adipo-/- mice) were generated. Notably, Phb1adipo-/- mice did not develop obesity but displayed severe liver steatosis under HFD feeding. Compared to HFD-fed wild-type (WT) mice, HFD-fed Phb1adipo-/- mice displayed dramatically lower fat mass with significantly decreased levels of total adipose tissue inflammation, including macrophage and neutrophil number as well as the expression of inflammatory mediators. To our surprise, although liver steatosis in Phb1adipo-/- mice was much more severe, liver inflammation and fibrosis were similar to WT mice after HFD feeding. RNA sequencing analyses revealed that the interferon pathway was markedly suppressed while the bone morphogenetic protein 2 pathway was significantly up-regulated in the liver of HFD-fed Phb1adipo-/- mice compared with HFD-fed WT mice. Conclusion: HFD-fed Phb1adipo-/- mice display a subtype of the lean NAFLD phenotype with severe hepatic steatosis despite low adipose mass. This subtype of the lean NAFLD phenotype has similar inflammation and fibrosis as obese NAFLD in HFD-fed WT mice; this is partially due to reduced total adipose tissue inflammation and the hepatic interferon pathway.

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Project description:To determine the effect of prohibitin overexpression on global gene expression in Caco2-BBE intestinal epithelial cells. 4 individual wells of Caco2-BBE cells, passage 41, were transfected with either empty vector (pcDNA4) or prohibitin/pcDNA4 for 72 hours. Total RNA isolated from 4 wells of cells/per treatment were pooled together for labeling and hybridization purposes.

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Hepatic NMNAT1 is required to defend against alcohol-associated fatty liver disease

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2025-05-25 | GSE297696 | GEO

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Project description:Background & Aims: Alcohol-related liver disease (ALD) lacks effective therapies, and understanding extracellular matrix (ECM) remodeling during disease progression may reveal novel therapeutic targets. Matrix-bound nanovesicles (MBVs), embedded within ECM, contain bioactive proteins and microRNAs and promote tissue repair in various injury models. However, MBVs remain unexplored in ALD. In the present study, we not only characterized how alcohol alters hepatic MBV composition, but also evaluated therapeutic effects of exogenous healthy MBVs in alcohol-induced liver injury. Approach: Using the NIAAA chronic-plus-binge ethanol model, we first isolated hepatic MBVs and performed LC-MS/MS proteomic analysis with pathway enrichment to define alcohol-induced cargo alterations. We then administered MBVs from healthy porcine urinary bladder matrix to ethanol-exposed mice and assessed therapeutic effects through histopathological evaluation and bulk RNA sequencing. Results and Conclusions: Ethanol exposure enriched hepatic MBVs for metabolic stress and detoxification proteins, indicating disease-associated cargo remodeling. Therapeutic administration of healthy MBVs reduced steatosis, lipid peroxidation, and fibrogenic gene expression while normalizing ethanol-induced transcriptional programs related to oxidative stress, inflammation, and metabolism. MBVs acted context-dependently. That is, they promoted mild ECM remodeling in healthy livers while attenuating pathological signaling in injured tissue, suggesting they stabilize hepatocyte homeostasis rather than directly suppressing immunity. These findings establish MBVs as both disease-responsive biomarkers and therapeutic modulators of the hepatic microenvironment in ALD.

2026-06-23 | GSE316773 | GEO

Nuclear Prohibitin 1 Protects Against Alcohol-Associated Liver Injury and Sensitization to Colon Cancer Liver Metastasis.

Project description:Nuclear Prohibitin 1 Protects Against Alcohol-Associated Liver Injury and Sensitization to Colon Cancer Liver Metastasis.

| PRJNA1494354 | ENA

The effect of prohibitin overexpression in Caco2-BBE intestinal epithelial cells

Project description:To determine the effect of prohibitin overexpression on global gene expression in Caco2-BBE intestinal epithelial cells.

2008-09-05 | GSE12605 | GEO

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2026-06-24 | GSE284311 | GEO

Mislocalization of FTD3-Associated Mutant CHMP2B to the Nucleus of Human Neurons Due to Loss of a Nuclear Export Signal

Project description:Frontotemporal dementia linked to chromosome 3 (FTD3) is caused by a splice site point mutation in CHMP2B, resulting in the production of mutant proteins CHMP2BIntron5 and CHMP2BΔ10. Here, we found that wildtype CHMP2B (CHMP2BWT) is mostly present in the cytoplasm, but CHMP2BIntron5 is mislocalized to the nucleus of human induced pluripotent stem cell (iPSC)-derived cortical neurons. To understand the underlying mechanism, we identified a previously unreported nuclear export signal (NES) in the C-terminus of CHMP2B. Functional assays, including CRM1 inhibition and site-directed mutagenesis of key hydrophobic residues, demonstrated that this NES motif is both necessary and sufficient for nuclear export of CHMP2BWT and ALS-associated CHMP2BQ206H, and its loss in CHMP2BIntron5 is responsible for the observed nuclear mislocalization. CHMP2BΔ10 remains in the cytoplasm due to the presence of an artificial NES in the C-terminus. These results reveal the presence of an NES in CHMP2B and highlight the need to dissect the gain-of-toxic nuclear functions of CHMP2BIntron5 in FTD3 pathogenesis.

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