Targeting the Chromatin Remodeler BAZ2B Mitigates Hepatic Senescence and MASH Fibrosis

Geriatrics Hepatobiliary System Cell Biology Gastroenterology Biochemistry Genetics Life Sciences Medicine
chromatin remodeling BAZ2B hepatic aging MASH fibrosis lipid metabolism PPARα epigenetic mechanism

1. Research Background and Significance

With global population aging on the rise, the incidence of metabolic dysfunction-associated steatohepatitis (MASH, also known as NASH) and related chronic liver diseases such as hepatic fibrosis is increasing year by year. These disorders have become a major focus and challenge in basic and clinical hepatology research. MASH is a progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), characterized primarily by disordered hepatic lipid metabolism, inflammation, hepatocyte senescence, and fibrosis, ultimately leading to cirrhosis and even liver cancer. Notably, aging of the liver is not only an important risk factor for the onset and progression of MASH, but cellular senescence and epigenetic dysregulation are increasingly recognized for their roles in hepatic aging and MASH-associated fibrosis.

Previous studies have shown that hepatocyte senescence promotes liver fibrosis, functional injury, and impaired tissue regeneration through mechanisms such as secretion of inflammatory factors and disruptions in energy metabolism. However, the specific molecular mechanisms underlying the formation of aging-related cells and their link with MASH fibrosis remain unclear, which restricts the development of therapeutic drugs.

Epigenetic regulation, especially the plasticity of chromatin structure, acts as a central player in gene expression, cell fate, and disease progression. Elucidating the intrinsic connection between hepatic aging and MASH from an epigenetic perspective is a major scientific question of this study, with particular emphasis on identifying key chromatin regulatory factors with druggable potential, thereby providing innovative concepts and molecular targets to reverse hepatic aging and fibrosis and prevent or treat MASH.

2. Paper Source and Author Information

This original research was published in the June 2025 issue of Nature Aging (Volume 5, Pages 1063–1078), DOI: 10.1038/s43587-025-00862-w. The title of the paper is: “Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis”.

The research team is primarily from Shanghai Public Health Clinical Center, Fudan University; Zhongshan Hospital, Fudan University; and CAS Center for Excellence in Brain Science and Intelligence Technology. The corresponding authors are Chuantao Tu and Shi-Qing Cai.

3. Detailed Study Design and Technical Approaches

1. Overall Design Concept

The authors focused on the expression changes and functions of the hepatic chromatin remodeler BAZ2B (Bromodomain adjacent to zinc finger domain protein 2B), systematically investigating its role and mechanisms in liver aging and MASH pathology. The overall workflow of the research is as follows:

  1. Patient-Level and Database Analyses: Analyzed the relationship and distribution characteristics of BAZ2B with MASH and fibrosis using liver tissue samples from patients and public datasets.
  2. Animal Models and Genetic Manipulation: Established liver aging and MASH mouse models, employing strategies such as gene knockout (baz2b−/−) and hepatocyte-specific knockdown to assess the pathological function of BAZ2B.
  3. Investigation of Molecular Mechanisms: Utilized transcriptomic, epigenetic (ChIP-seq, ATAC-seq), chromatin binding, and functional experiments to elucidate the epigenetic mechanisms by which BAZ2B regulates downstream metabolic pathways.
  4. Functional Intervention Verification: Verified the therapeutic potential of specifically targeting hepatic BAZ2B in both young and aged MASH animal models.

2. Study Subjects and Sample Description

  • Human Samples: Included liver tissues from 5 healthy controls, 6 MASLD patients, and 7 MASH patients.
  • Animal Models: Mainly used C57BL/6J background baz2b−/−, baz2b+/−, and WT male mice; natural aging group (18-19 months old), young group (2-3 months old). MASH models were induced by choline-deficient high-fat diet (CDAHFD) or high-calorie, high-fructose models for durations of 2, 8, or 16 weeks.
  • Single-nucleus RNA Sequencing Data: Public dataset GSE189600 was reanalyzed for fine classification of different liver cell clusters and single-cell expression of BAZ2B.

3. Main Experiments and Technical Methods

3.1. Clinical Data and Molecular Detection

  • Detected human liver BAZ2B expression and its correlation with pathological infiltration areas using RNAscope in situ hybridization and immunohistochemistry (IHC/IF).
  • Used databases GSE61260 and GSE189600 for bioinformatics data mining, single-nucleus transcriptome cell classification, and expression comparison.

3.2. Animal Experiments and Phenotypic Analyses

  • Created BAZ2B gene knockout and hepatocyte-specific shRNA knockdown models.
  • Evaluated markers of liver aging (senescence-associated β-gal, p16, p21 immunostaining), lipid accumulation (Oil Red O staining), fibrosis (Sirius Red staining, αSMA immunolabeling), inflammation, and liver function (ALT/AST).
  • Metabolomics: Indirect calorimetry (VO2, VCO2, RER), glucose tolerance testing, assessment of mouse liver mitochondrial function.
  • Molecular biology assays: Immunoblotting (IB), quantitative PCR, and protein level analysis.

3.3. Mechanistic Studies

  • Transcriptomic Sequencing (RNA-seq): Analyzed global changes in hepatic gene expression regulated by BAZ2B and enriched pathways.
  • Chromatin Immunoprecipitation Sequencing (ChIP-seq): Examined genome-wide BAZ2B binding sites and, combined with omics analysis, identified its regulatory target genes.
  • ATAC-seq: Assessed chromatin accessibility, along with active marker changes (H3K27ac, H3K4me3), to uncover epigenetic regulatory mechanisms.
  • Functional Analysis: Used AAV8-TBG vectors to deliver hepatocyte-specific shRNA, knocking down BAZ2B and PPARα to investigate their functional hierarchy.

4. Data Analysis Methods

  • Biostatistics using GraphPad Prism, Shapiro-Wilk normality testing, Brown-Forsythe test, and multi-group variance analysis (ANOVA).
  • Bioinformatic pipelines included algorithms and databases such as Seurat for single-cell analysis, DeSeq2, DiffBind, MACS2, HOMER, and DAVID.

4. Main Experimental Results and Evidence Chain

1. Expression and Distribution of BAZ2B in Liver Aging and MASH Fibrosis

  • BAZ2B mRNA is almost undetectable in healthy human liver tissue but is highly expressed in MASLD and MASH patient livers, mainly distributed in hepatocytes of diseased regions rather than non-lesion areas.
  • Large sample data (GSE61260) and single-nucleus RNA data (GSE189600) show that BAZ2B expression is significantly elevated in specific hepatocyte subpopulations (hmash-heps) of MASH patients, with concurrent enrichment of aging- and immunity-related gene sets.
  • Double-label pathology experiments (BAZ2B mRNA co-stained with HNF4α and senescence markers) further confirmed a strong correlation between areas of high BAZ2B expression and hepatocyte senescence.

2. Animal Models Confirm BAZ2B Promotes Liver Aging and Pathological Progression

  • In naturally aged mice (18–19 months), liver BAZ2B protein and mRNA levels are significantly higher than in young mice.
  • BAZ2B knockout (baz2b−/−) markedly improves the overall metabolic profile of aged mice (oxygen consumption, RER, glucose tolerance), enhances mitochondrial function, reduces lipid accumulation, and ameliorates hepatocyte senescence, inflammation, and fibrosis markers.
  • In MASH models induced by CDAHFD, mice lacking BAZ2B display lower levels of hepatocyte senescence, inflammation, and fibrosis, with reduced ALT/AST transaminases, indicating a protective effect. These results are validated using an independent high-calorie, high-fat (HFHCD) diet model.

3. Mechanistic Exploration: Mediation Through the PPARα Signaling Pathway

  • RNA-seq analysis demonstrates that the PPAR pathway (especially PPARα) in the livers of aged and MASH mice is significantly downregulated, accompanied by disordered lipid metabolism. BAZ2B knockout upregulates PPARα and downstream lipid oxidation and metabolic genes (e.g., ACSL1, ACOX1, CPT1α).
  • Hepatocyte-specific knockdown of PPARα (via AAV8-TBG-shRNA-PPARα) completely negates the anti-aging and anti-fibrotic phenotypes conferred by BAZ2B deletion, underscoring its central mediating role.

4. Epigenetic Layer: BAZ2B Regulates Chromatin Accessibility and Metabolic Gene Expression

  • ChIP-seq shows that the BAZ2B protein binds to promoters of about 1,456 genes, enriched in metabolism and PPARα pathway-related genes.
  • ATAC-seq, along with H3K27ac and H3K4me3 ChIP-seq, proves that BAZ2B deletion increases chromatin accessibility and active histone modifications at the promoters of target genes, activating metabolic pathway genes.
  • This tightly links BAZ2B upregulation, epigenetic remodeling, downregulation of PPARα expression, and liver aging/fibrosis phenotypes in a coherent, top-down mechanism.

5. Targeting Hepatocyte BAZ2B Significantly Alleviates Aging and MASH

  • Specific AAV8-TBG-shBAZ2B knockdown of BAZ2B in hepatocytes of aged mice dramatically suppresses hepatocyte senescence, lipid accumulation, and fibrosis, and improves metabolic and inflammatory phenotypes.
  • In both young and aged MASH mouse models, hepatocyte-specific knockdown of BAZ2B similarly reduces the severity of liver lesions, as measured by decreased pathological scores and reduced inflammation and fibrosis markers.
  • These results illustrate that BAZ2B is not only a pathological marker but also a druggable molecular target.

5. Conclusions, Significance, and Research Highlights

This work conducts innovative exploration of the pathogenesis of hepatic aging and metabolic liver diseases, both at the fundamental and applied levels. Its principal conclusions include:

  1. Clarification of the Molecular Bridge Linking Liver Aging and MASH Fibrosis: For the first time, systematically reveals that the chromatin remodeler BAZ2B, through epigenetic regulation, negatively controls the PPARα signaling pathway and downstream lipid metabolic genes, forming a core molecular axis in hepatocyte aging and MASH fibrosis.
  2. Filling the Gaps in Mechanistic Links Between Liver Aging and Fibrosis Progression: Elucidates the dynamic regulation and pathological role of BAZ2B, resulting in a coherent mechanism loop involving epigenetics, metabolism, inflammation, and tissue injury.
  3. Providing New Therapeutic Concepts and Targets for Aging-Related Chronic Liver Diseases: Demonstrates through genetic and hepatocyte-specific interventions that BAZ2B can be targeted for inhibition to achieve ‘rejuvenation’ of the liver and anti-fibrotic effects. This provides theoretical and experimental foundations for developing new precision drugs that reverse epigenetic aging and hepatic fibrosis.
  4. Methodological Innovation and Technological Integration: Employs multi-omics (transcriptome, epigenome, single-cell), novel AAV-mediated hepatocyte shRNA delivery, and precise phenotyping technologies, enhancing the depth and breadth of mechanistic elucidation and target validation.
  5. Translational and Clinical Potential: Inhibiting BAZ2B activates the intrinsic anti-fibrotic and metabolic reprogramming capacity of hepatocytes, with no observed serious side effects such as carcinogenicity. Given the reversibility of epigenetic modifications, BAZ2B is expected to become an ideal drug target for promoting healthy hepatic aging and treating MASH and its associated fibrosis.

6. Outlook and Conclusion

The theoretical breakthrough and technical innovation from this study provide a robust platform for deeper understanding of hepatic aging and the essence of metabolic chronic diseases, and for exploring anti-aging and anti-fibrotic strategies based on epigenetic remodeling. In the future, drug screening for BAZ2B, development of small molecule inhibitors, and multi-system mechanistic research promise to drive the transition from basic research to clinical application, bringing new hope for ‘reversal and regeneration’ of liver health in aging populations.