Abstract
With increased age, the liver becomes more vulnerable to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Deciphering the complex interplay between aging, the emergence of senescent cells in the liver and MASH fibrosis is critical for developing treatments. Here we report an epigenetic mechanism that links liver aging to MASH fibrosis. We find that upregulation of the chromatin remodeler BAZ2B in a subpopulation of hepatocytes (HEPs) is linked to MASH pathology in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b in mice attenuates HEP senescence and MASH fibrosis by preserving peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aged and MASH mouse livers. Mechanistically, Baz2b downregulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Thus, our study unravels the BAZ2B–PPARα–lipid metabolism axis as a link from liver aging to MASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for HEP senescence and fibrosis.
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Data availability
The raw sequence data generated in this study are available from the NCBI Gene Expression Omnibus under accession no. GSE280663. Other data supporting the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank Y. Li for providing the AVV8-TBG plasmid, Y. Xiao for providing additional information on the small nuclear RNA data, and the Optical Imaging Facility, Gene Editing Facility and Animal Facility at the Institute of Neuroscience, Chinese Academy of Sciences for technical support. This work was funded by the National Key R&D Program of China (grant nos. 2023YFC3603400 and 2023YFC3603300), the National Natural Science Foundation of China (grant nos. 31925022, 82330047, 81970531, 32400979) and the Natural Science Foundation of Shanghai Municipality (grant no. 22ZR1448500).
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Conceptualization: C.T. and S.-Q.C. Methodology: C.Q., S.L., D.-Y.L., Z.-Y.L., W.-G.O., X.-L.K., F.C. and S.S. Supervision: S.-Q.C. and C.T. Writing—original draft: C.T. Writing—review and editing: S.-Q.C., C.T. and C.Q. Funding acquisition: S.-Q.C., C.T. and C.Q.
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Extended data
Extended Data Fig. 1 Baz2b affects body metabolism and aging phenotypes of the liver.
a-c, Total activity (a), average daily water intake (b), and average daily food intake (c) of mice housed in metabolic cages. d, Representative fluorescence images and quantitative analysis of RNAscope in livers of young or aged WT mice. Baz2b mRNAs were highlighted in red, and nuclei were stained with DAPI (4′, 6-diamidino-2-phenylindole, blue). Scale bar, 50 μm. e, qPCR analysis of Baz2b expression in livers from 2- to 24-month-old WT mice. Baz2b mRNA levels were normalized to the level of Baz2b mRNA in livers of 2-month-old WT mice. n = 3 mice per age group. Experiments were repeated three times. f, Oxygen consumption rates (OCR) of mitochondria isolated from 6-month-aged WT, Baz2b+/− and Baz2b−/− mouse livers. Experiments were repeated three times. g-j, Representative images of gross livers from young (3- month-old) and aged (19-month-old) WT, Baz2b+/− and Baz2b−/− mice (g) and quantitative analysis of body weight (h), liver weight (i) and the ratio (%) of liver to body weight (j). k, l, Representative images (k) and quantifications (l) of CD11b and F4/80 staining in liver sections from indicated mice. Scale bars, 50 μm. m, n, Representative images (m) and quantification (n) of αSMA staining in liver sections from indicated mice. Scale bar, 50 μm. The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse. Data are means ± SEM.; *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant. For a, f, two-way ANOVA with Dunnett’s test; for (b-e) and (h-j, l, n), one-way ANOVA with Dunnett’s test.
Extended Data Fig. 2 Baz2b does not affect liver phenotypes of young mice.
a-c, Representative images of H&E, ORO, and Sirius red staining and αSMA immunofluorescence (a) in liver sections from 3-month-old (young) WT, Baz2b+/− and Baz2b−/− mice and their quantitative analysis (b, c). Scale bars, 50 μm. (d, e) Representative immunofluorescence staining of p16, p21, CD11b, and F4/80 in liver sections from indicated mice (d) and their quantitative analysis (e). Scale bars, 50 μm. The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse. Data are means ± s.e.m. *P < 0.05, **P < 0.01, ***P < ns, not significant. One-way ANOVA with Dunnett’s post-test was used for (b, c, e).
Extended Data Fig. 3 BAZ2B is distributed in lesion areas of MASH livers in patients.
a-c, Representative images of Sirius red staining and co-immunofluorescence staining of BAZ2B mRNAs, αSMA, and DAPI (a) and RNAscope score analysis between lesion and nonlesion areas in the same liver samples from patients with MASL (n = 3) (b) or MASH (n = 5) (c) patients. For each patient, 3 lesion and 3 nonlesion areas in the same liver section were analyzed. Scale bars, 20 μm. d, Representative images of co-staining of BAZ2B mRNAs (red) and CD11b (green) or F4/80 (green) in liver sections from MASH patients. Scale bars, 100 μm. e, Violin plots of BAZ2B expression levels in non-parenchymal cell clusters between healthy subjects and NASH patients. EC: endothelial cell; VSMC: vascular smooth muscle cell. f, immunofluorescence staining of p16 and p21 (left) in liver samples from healthy (n = 3), MASL (nonalcoholic fatty liver, n = 3), and MASH (n = 4) patients and their quantitative analysis (right). Scale bars, 20 μm. g, Representative images of co-staining of BAZ2B mRNAs (red) and p16 (green) in liver sections from MASH patients. Scale bar, 100 μm. Data are means ± s.e.m.; **P < 0.01, ***P < 0.001. Unpaired two-sided t-test was used for b and c, and one-way ANOVA with Dunnett’s test was used for f.
Extended Data Fig. 4 Up-regulated Baz2b contributes to CDAHFD-indued MASH pathologies in mice.
a, Representative images of livers from WT, Baz2b+/− and Baz2b−/− mice fed with chow diet and CDAHFD. b, Quantitative analysis of the ratio (%) of liver to body weight. c, Representative images showing RNAscope analysis of Baz2b expression in liver sections from WT mice after feeding with chow diet (control) or CDAHFD for 8 weeks (left) and quantification of Baz2b mRNA expression (right). Scale bars, 20 μm. d, Western blot analysis of Baz2b in livers from mice fed with chow diet or CDAHFD for 8 weeks. Protein levels were normalized to that in livers of WT CDAHFD mice. Experiments were repeated three times. e, f, Representative images of co-staining of HNF4α (red), nuclei (DAPI-stained blue), and p21 (green) (e) or p16 (green) (f) in liver sections from WT mice fed with CDAHFD for 8 weeks. g, Representative images of co-staining of CD11b or αSMA (red), with p21 or p16 (green) in liver sections from WT mice fed with CDAHFD for 8 weeks. h-j, Representative images (h) and quantifications of p21 (i) and p16 staining (j) of liver sections from WT, Baz2b+/− and Baz2b−/− mice fed with chow diet or CDAHFD for 8 weeks. k-o, Representative CD11b (k left), F4/80 (k right), and αSMA (n) immunostaining in liver sections from WT, Baz2b+/− and Baz2b−/− mice fed with chow diet or CDAHFD for 8 weeks and their quantifications (l,m,o). Scale bars, 20 μm. The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse. Data are means ± s.e.m.; *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant. One-way ANOVA with Dunnett’s post-test was used for b, i, l, m, o, and unpaired t-test was used for c and d to determine the P value.
Extended Data Fig. 5 Baz2b regulates HFHCD-indued MASH pathologies in mice.
a, Representative images showing RNAscope analysis of Baz2b expression in liver sections from WT mice after feeding with chow diet (control) or HFHCD for 16 weeks (left) and quantification of Baz2b mRNA expression (right). Scale bar, 20 μm. b, Western blot analysis of Baz2b in livers from indicated mice. Experiments were repeated three times. Protein levels were normalized to that in livers of WT HFHCD mice. c-f, Representative images of CD11b (c), F4/80(d), and αSMA(e) immunostaining in liver sections from WT, Baz2b+/− and Baz2b−/− mice fed with chow diet or HFHCD for 16 weeks and their quantifications (f). Scale bars, 20 μm. g, Heatmap showing qPCR analysis of changes in the expression of genes related to the Ppara signaling pathway, inflammation, and fibrosis from the mice fed with HFHCD for 16 weeks. Red font highlights DEG with P < 0.05. Experiments were repeated three times. h, Western blot analysis of Pparα, Cpt1α, and Acsl1 proteins from indicated mice. Protein levels were normalized to the level of individual protein in livers of WT control mice. Experiments were repeated three times. The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse. Data are means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant; unpaired two-sided Student’s t test was used for a and b; one-way ANOVA with Dunnett’s test was used for f-h.
Extended Data Fig. 6 Baz2b regulates the expression of genes related to lipid metabolism.
a, Heatmap showing DEGs in livers from young and aged WT, Baz2b+/− and Baz2b−/− mice. b, Top gene-ontology (GO) terms of DEGs in livers between young and aged WT mice. c, GO terms of DEGs in livers between aged WT and aged Baz2b−/− mice. d, Heatmap showing DEGs in livers from WT, Baz2b and Baz2b−/− mice fed with chow diet (control) or CDAHFD for 8 weeks. e, GO terms of DEGs in livers between WT mice fed with chow diet or CDAHFD for 8 weeks. f, GO terms of DEGs in livers between WT and Baz2b−/− mice fed with CDAHFD for 8 weeks. g, h, qPCR analysis of expression levels of genes related to the Ppara signal pathway and immune response in livers from indicated aged (g) or MASH WT mice (h). Red font highlights DEG with P < 0.05. n = 3 mice for each group and experiments were repeated 3 times. i-j, Western blot images (i) and quantitative analysis (j) of the Pparα, Acsl1, and Cpt1α proteins in livers from young and aged WT, Baz2b+/− and Baz2b−/− mice fed with chow diet. Protein levels were normalized to the level of individual protein in livers of WT young control mice. The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse, data are means ± s.e.m.*P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant; One-way ANOVA test with Dunnett’s test was used.
Extended Data Fig. 7 Hepatocyte-specific knock-down of Pparα restores MASH pathologies in Baz2b−/− mice.
a, b, Representative images of CD11b, F4/80, and αSMA (a) immunostaining in liver sections and their quantifications (b). Scale bars, 50 μm. c, Western blot analysis of the level of proteins related to the Ppara signaling pathway. n = 3 independent experiments. Protein levels were normalized to the level of individual protein in livers of WT control mice. d-f Quantitative analysis of body weight (d), liver weight (e), and the ratio (%) of liver to body weight (f) in mice with hepatocyte-specific knock-down of Ppara. The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse. All data are means ± s.e.m. *P < 0.05, **P < 0.01 and ***P < 0.001; ns, not significant. One-way ANOVA with Dunnett’s post-test was used for b-f.
Extended Data Fig. 8 BAZ2B influences chromatin accessibility.
a, Heatmap of normalized read densities around a 3 kb window upstream and downstream of the TSS for BAZ2B-occupied genes. ChIP-seq analysis of BAZ2B binding DNA regions in AML12 hepatocyte cells expressing Flag-tagged BAZ2B was performed using anti-Flag antibodies. AML12 cells expressing empty plasmids were used as a control. b, Pie chart showing the distribution of BAZ2B-binding sites in genomic loci. TSS, the transcription start site. c, Profile heatmap around TSS of reference sequence (RefSeq) genes. Read counts were extracted for all ChIP-seq and ATAC-seq experiments within a region spanning ± 3 kb around TSS in livers of WT and Baz2b−/− CDAHFD-induced MASH mice. The heatmap showed the normalized results combined from three biological replicates. d, RNA-seq track of Pparα, Acsl1, Acadm, and Gls2 loci in livers of WT and Baz2b−/− CDAHFD-induced MASH mice.
Extended Data Fig. 9 Hepatocyte-specific knock-down of Baz2b attenuates MASH pathology.
a, qPCR analysis of Baz2b expression in livers from young mice (2-3 months) fed with chow diet (control) or CDAHFD for 8 weeks. Baz2b mRNA levels were normalized to the level of Baz2b mRNA in livers of WT control mice. Experiment were repeated three times. b, Ratio (%) of liver to body weight of indicated mice. c, Heatmap showing qPCR analysis of changes in the expression of genes related to the Ppara signaling pathway, inflammation, and fibrosis. Red font highlights DEG with P < 0.05. d, e, Representative images (d) and quantifications (e) of CD11b and F4/80 staining in liver sections from indicated mice. Scale bar, 50 μm. f, g, Serum levels of AST (f) and ALT (g). The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse. Data are means ± s.e.m. *P < 0.05, **P < 0.01 and ***P < 0.001. One-way ANOVA with Dunnett’s post-test was used for a-c and e-g.
Extended Data Fig. 10 Hepatocyte-specific knock-down of Baz2b attenuates MASH pathologies in aged mice.
a-e, Representative images of H&E and ORO staining (a) in liver sections from aged (18-month-old) mice fed with CDAHFD for 4 or 8 weeks and quantitative analysis of liver to body ratio (b), lipid droplets (c), inflammation score (d), ORO+ areas (e), and. Naïve group refers to mice that not injected; shNC group refers to mice that injected with non-targeting control shRNAs; shBaz2b group refers to mice that injected with non-targeting shBaz2b. Scale bars, 50 μm. f, g, Representative staining of SA-β-gal and immunofluorescence staining of p16 and p21 in liver sections from indicated mice (f) and their quantitative analysis (g). h, i, Representative staining of Sirius red and αSMA immunofluorescence (h) in liver sections from aged mice fed with CDAHFD for 8 weeks and their quantitative analysis (i). Scale bars, 50 μm. j, k, Representative staining of CD11b and F4/80 immunofluorescence (j) in liver sections from aged mice fed with CDAHFD for 8 weeks and their quantitative analysis (k). Scale bars, 50 μm. l, Heatmap showing qPCR analysis of changes in the expression of genes related to the Ppara signaling pathway, inflammation, and fibrosis, from the aged mice fed with CDAHFD for 8 weeks. Experiments were repeated three times. Red font highlights DEG with P < 0.05. The numbers of tested mice were indicated in parentheses. Each data point represents a value from one mouse. Data are means ± s.e.m. *P < 0.05, **P < 0.01, ***P < 0.001; ns, not significant; one-way ANOVA with Dunnett’s test was used for determining P values in b-e, g, i, l, k.
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qPCR primer sequence.
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WT young versus WT elder DEGs.
Supplementary Table 3
WT elder versus KO elder DEGs.
Supplementary Table 4
CDAHFD WT versus control WT DEGs.
Supplementary Table 5
CDAHFD KO versus WT DEGs.
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Tu, C., Qian, C., Li, S. et al. Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis. Nat Aging 5, 1063–1078 (2025). https://doi.org/10.1038/s43587-025-00862-w
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DOI: https://doi.org/10.1038/s43587-025-00862-w
