Abstract
Liver fibrosis is an urgent clinical problem without effective therapies. Here we conducted a high-content screening on a natural Euphorbiaceae diterpenoid library to identify a potent anti-liver fibrosis lead, 12-deoxyphorbol 13-palmitate (DP). Leveraging a photo-affinity labeling approach, apolipoprotein L2 (APOL2), an endoplasmic reticulum (ER)-rich protein, was identified as the direct target of DP. Mechanistically, APOL2 is induced in activated hepatic stellate cells upon transforming growth factor-β1 (TGF-β1) stimulation, which then binds to sarcoplasmic/ER calcium ATPase 2 (SERCA2) to trigger ER stress and elevate its downstream protein kinase R-like ER kinase (PERK)–hairy and enhancer of split 1 (HES1) axis, ultimately promoting liver fibrosis. As a result, targeting APOL2 by DP or ablation of APOL2 significantly impairs APOL2–SERCA2–PERK–HES1 signaling and mitigates fibrosis progression. Our findings not only define APOL2 as a novel therapeutic target for liver fibrosis but also highlight DP as a promising lead for treatment of this symptom.
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Data availability
RNA sequencing data can be retrieved using accession number GSE250087. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with dataset identifiers PXD047924 and PXD047815. All other data supporting the findings of this study are available from the corresponding authors upon reasonable request. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Open Program of Shenzhen Bay Laboratory (SZBL2021080601007 to S.Y.); the National Natural Science Foundation of China (82273804 to S.Y. and 32070767 to J.G.); the Guangdong Basic and Applied Basic Research Foundation, China (2021B1515140062 to S.Y.); the Science and Technology Program of Guangzhou, China (2024B03J1322 to S.Y.); and the Science and Technology Planning Project of Guangdong Province, China (2023A1111120025 to S.Y.). Cartoons in the graphical abstract were created with BioRender.
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S.Y., J.G., X.D.L. and Y.J. conceived and designed this study. L.G., Q.J. and J.H. developed the methods. L.G., Q.J., X.W. and X.Z. acquired the data (western blot, qRT–PCR and immunohistochemistry analysis, RNA-seq analysis and pulldown experiment analysis). D.H. and G.T. performed the chemical work (extraction and separation of compounds, structural modification and probe synthesis). L.G., Q.J., X.W., X.Z., L.W., W.X. and R.F. analyzed and interpreted the data (statistical analysis, biostatistics and computational analysis). S.Y., J.G. and L.G. wrote the paper. S.Y., J.G., X.D.L. and G.T. provided administrative, technical or material support (for example, reporting or organizing data). S.Y., J.G., X.D.L. and Y.J. were responsible for research supervision. All authors approved the paper.
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Extended data
Extended Data Fig. 1 Discovery of DP as a potent inhibitor of HSCs activation.
a, 11 different skeletal types in Euphorbiaceae diterpenoid library and the sample size of each skeleton. b, Representative fluorescent photographs of immunofluorescence staining for fibronectin (FN) in TGF-β1-stimulated LX-2 cells treated with DMSO (CTR), compounds (10 μM) or PFD (500 μM) for 48 h (left). Quantification for fluorescence intensity of fibronectin in indicated groups (right). Scale bar, 100 μm. UND, untreated. Data presented are means ± s.d. c, Representative western blot for fibrotic markers in 10 ng/mL PDGF, 10 μM Angiotensin II (Ang II), 10 ng/mL CTGF or 1 μg/mL lipopolysaccharide (LPS) stimulated LX-2 cells treated with DP (10 μM) for 48 h. d, Representative western blot for FN, collagen I, and α-SMA in TGF-β1-stimulated NRK-49F and MRC-5 cells treated with indicated concentrations of DP or PFD for 48 h. e, IC50 curves of DP in different cell lines treated for 48 h. CI, confidence interval. For b−e, n = 3 independent experiments.
Extended Data Fig. 2 Toxicity evaluation on DP in mouse models.
a, b, Representative images of mouse kidney, lung, heart and spleen tissues stained with H&E in indicated groups. Scale bar, 250 μm. n = 5 independent mice. c, Representative images of mouse articulatio genus stained with H&E in indicated groups. Scale bar, 250 μm. n = 3 independent mice.
Extended Data Fig. 3 DP alleviates DDC-induced mouse liver fibrosis.
a, Representative images of mouse liver tissues stained with H&E, Sirus Red, Masson and α-SMA in indicated groups. Scale bar, 250 μm. n = 5 independent mice. b, Levels of ALP, TBIL, UREA and CREA in serum from mice in indicated groups. n = 7 independent mice. Data presented are means ± s.e.m. Statistical significance was determined by two-tailed unpaired Student’s t-test (ALP and TBIL) or one-way ANOVA followed by Dunnett’s multiple comparisons test (UREA and CREA). n.s., no significance. c, Representative western blot for fibrotic markers in indicated groups. n = 3 independent experiments.
Extended Data Fig. 4 DP directly targets APOL2.
a, Representative western blot for fibrotic markers in TGF-β1-stimulated LX-2 cells treated with indicated concentrations of DP-PT (left) or DP-BOD (right) for 48 h. b, SDS-PAGE gels of fluorescence scanning imaging and coomassie brilliant blue (CBB) staining in vitro. c, Western blot analysis on endogenous APOL2 protein after DP-PT pull-down in LX-2 cell lysis. d, Western blot analysis on exogenous APOL2 protein after DP-PT pull-down in 293 T cells. 293 T cells were transfected with V5-tagged APOL2 for 6 h. After 24 h, the cells were incubated with indicated concentrations of DP-PT in the presence or absence of DP for 3 h. After photocross-linking, the probe-bound protein was precipitated by streptavidin beads and was immunoblotted with an antibody against V5. e, Western blot analysis on endogenous APOL1 protein after DP-PT pull-down in LX-2 cells. f, The influence of DP on APOL2 protein levels in LX-2 cells. g, Quantification for APOL2 protein levels in the cellular thermal shift assay. Data presented are means ± s.d. Statistical significance was determined by two-tailed unpaired Student’s t-test compared with untreated (UND) group. For a−g, n = 3 independent experiments.
Extended Data Fig. 5 Identification of modification sites by LC-MS/MS.
a, b, Recombinant APOL2 was incubated with DP-PT and was then successively subjected to photocross-linking. The labeled protein was digested with trypsin and analyzed by LC-MS/MS. The data was processed in Proteome Discoverer 2.2.0. c. Binding modes in the top ten scoring rankings between DP and APOL2 according to docking simulation using Schrodinger software. The different conformations of DP were labeled as blue, the amino acid residues involved in covalent interactions were labeled as green, the representative amino acid residues involved in interactions were labeled as yellow. d, Pull-down experiments of DP-PT on different APOL2 mutants in 293 T cells. V199/G200A: Val199 and Gly200 mutate into Ala; N212/V216A: Asn212 and Val216 mutate into Ala; L209A: Leu209 mutates into Ala; I227A: Ile227 mutates into Ala; I246A: Ile246 mutates into Ala. EV, empty vehicle. n = 3 independent experiments.
Extended Data Fig. 6 APOL2 overexpressed in activated HSCs is required for the progression of liver fibrosis and the antifibrotic effects of DP is APOL2 dependent.
a, APOL2 transcript expression analysis of GEO database. b, mRNA levels of Apol2 in mouse liver tissues. c, Representative western blot for APOL2 in CTGF-, Ang II-, LPS- or PDGF-stimulated LX-2 cells. d, Representative fluorescent photographs for co-staining of APOL2 with albumin, CD31, or F4/80 in mouse liver tissues. Scale bar, 50 μm. e,f, LX-2 cells were transfected with siAPOL2-1/2/3 (e) or APOL2 plasmid (f) for 6 h and subsequently treated with or without TGF-β1 or different concentrations of DP for 48 h. The indicated protein expressions were detected. g, Levels of mouse serum UREA and CREA in indicated groups. h, Representative images of mouse kidney, lung, heart, and spleen tissues stained with H&E in indicated groups. Scale bar, 250 μm. i−l, LX-2 cells were transfected with siAPOL2-1, APOL2 or APOL22A plasmid for 6 h and subsequently treated with or without TGF-β1 or different concentrations of DP for 48 h. The indicated protein expressions were detected. For c, d, e, f and i−l, n = 3 independent experiments. For b, g and h, n = 5 independent mice. For a, b and g, data presented are means ± s.e.m. Statistical significance was determined by two-tailed unpaired Student’s t-test (a,b) or one-way ANOVA followed by Dunnett’s multiple comparisons test (g).
Extended Data Fig. 7 DP alleviates liver fibrosis via the PERK-HES1 axis.
a, LX-2 cells were treated with indicated concentrations of DP (left) or transfected with 80 nM siAPOL2-1/2 or siControl (right) for 6 h and subsequently treated with or without TGF-β1 for 3 h. The protein expressions of total Smad2/3, phosphorylated Smad2/3 were determined by immunoblotting. b. The coomassie brilliant blue staining of interacting proteins of APOL2. c, Colocalization analysis of APOL2 and SERCA2. Plots of pixel intensity along the white line from left to the right of each plot, colors as in merged images. d, Immunofluorescence assay of APOL2 (red) and α-SMA (green) in indicated groups. Scale bar, 15 μm. e, Representative western blot for indicated proteins in LX-2 cells treated with DP (5 μM) at different time points. f, Representative western blot for indicated proteins in LX-2 cells transfected with siAPOL2-1/2 or siControl for 6 h and subsequently treated with TGF-β1 for 48 h. Protein ratios (normalized to GAPDH) were used to quantify fold change relative to control and are shown in a plot graph below each blot. For a, b and d−f, n = 3 independent experiments.
Extended Data Fig. 8 The anti-ER stress efficacy of DP is APOL2 dependent.
a, LX-2 cells were transfected with siAPOL2-1 or siControl for 6 h and subsequently treated with TGF-β1 with or without different concentrations of DP for 48 h. The indicated protein expressions were detected. b, LX-2 cells were transfected with APOL2 or vector for 6 h and subsequently treated with or without DP (1 μM) for 48 h. The indicated protein expressions were detected. c, LX-2 cells were transfected with APOL22A or vector for 6 h and subsequently treated with or without DP (1 μM) for 48 h. The indicated protein expressions were detected. d, LX-2 cells were transfected with APOL2WT or APOL22A for 6 h and subsequently treated with or without DP (1 μM) for 48 h. The indicated protein expressions were detected. Protein ratios (normalized to GAPDH) were used to quantify fold change relative to control and are shown in a plot graph below each blot. For a−d, n = 3 independent experiments.
Extended Data Fig. 9 The anti-fibrotic efficacy of DP or APOL2 loss was exerted via PERK-HES1 signaling.
a, Representative western blot for indicated proteins in TGF-β1-stimulated LX-2 cells treated with indicated concentrations of GSK2656157 (GSK) for 48 h. b, LX-2 cells were transfected with sieIF2α or siATF4 for 6 h and subsequently treated with or without indicated concentration of DP for 48 h. The indicated protein expressions were detected. c, LX-2 cells were transfected with siAPOL2-1 for 6 h and subsequently treated with or without sieIF2α or siATF4 for 6 h. After further cultivation for 48 h, the indicated protein expressions were detected. d, Representative western blot for indicated proteins in TGF-β1-stimulated LX-2 treated with indicated concentrations of DP with or without 10 μM GSK for 48 h. Protein ratios (normalized to GAPDH) were used to quantify fold change relative to control and are shown in a plot graph below each blot. For a−d, n = 3 independent experiments.
Extended Data Fig. 10 DP treatment or Apol2 depletion inhibit the PERK-HES1 signaling in vivo.
a,b, Representative western blot for HES1, ATF4, PERK, p-PERK, eIF2α, p-eIF2α and APOL2 in (a) CCl4- or (b) DDC-induced mouse fibrotic liver tissues in indicated groups. c, Representative western blot for HES1, ATF4, PERK, p-PERK, eIF2α, p-eIF2α and APOL2 of mouse liver tissues in indicated groups. Protein ratios (normalized to GAPDH) were used to quantify fold change relative to control and are shown in a plot graph below each blot. For a−c, n = 3 independent experiments.
Supplementary information
Supplementary Table 1
Antibodies for immunoblotting
Supplementary Table 2
Primers for qPCR
Supplementary Table 3
List of quantified proteins with abundance ratio from LX-2 cells
Supplementary Table 4
Quantification for α-SMA and APOL2 immunostaining in human liver tissues
Supplementary Table 5
List of proteins that interact with APOL2 in LX-2 cells
Supplementary Table 6
RNA-seq data in LX-2 cells treated with DP
Supplementary Table 7
Statistical source data for immunoblot quantitation
Supplementary Data 1
Raw figures for IHC or H&E photos
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Gan, L., Jiang, Q., Huang, D. et al. A natural small molecule alleviates liver fibrosis by targeting apolipoprotein L2. Nat Chem Biol (2024). https://doi.org/10.1038/s41589-024-01704-3
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DOI: https://doi.org/10.1038/s41589-024-01704-3
