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Chrysophanol ameliorates ferroptosis in acute kidney injury by promoting SIRT3-mediated NRF2 deacetylation.

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Τίτλος: Chrysophanol ameliorates ferroptosis in acute kidney injury by promoting SIRT3-mediated NRF2 deacetylation.
Συγγραφείς: Cui M; The First Clinical College, Hubei University of Chinese Medicine, Wuhan, China.; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China., Tian H; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China., Zhu J; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China., Zhu J; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China. zhujing@hbhtcm.com.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China. zhujing@hbhtcm.com.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China. zhujing@hbhtcm.com.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China. zhujing@hbhtcm.com., Wang Q; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China. 149806520@qq.com.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China. 149806520@qq.com.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China. 149806520@qq.com.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China. 149806520@qq.com., Zou Y; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China. zouyinshui@hbhtcm.com.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China. zouyinshui@hbhtcm.com.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China. zouyinshui@hbhtcm.com.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China. zouyinshui@hbhtcm.com.
Πηγή: Naunyn-Schmiedeberg's archives of pharmacology [Naunyn Schmiedebergs Arch Pharmacol] 2026 Jul; Vol. 399 (10), pp. 15941-15953. Date of Electronic Publication: 2026 May 05.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0326264 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1912 (Electronic) Linking ISSN: 00281298 NLM ISO Abbreviation: Naunyn Schmiedebergs Arch Pharmacol Subsets: MEDLINE
Imprint Name(s): Original Publication: Berlin, New York, Springer Verlag.
Ιατρικοί όροι (MeSH): NF-E2-Related Factor 2*/metabolism , Acute Kidney Injury*/drug therapy , Acute Kidney Injury*/metabolism , Acute Kidney Injury*/pathology , Acute Kidney Injury*/chemically induced , Ferroptosis*/drug effects , Sirtuin 3*/metabolism , Sirtuin 3*/genetics, Acetylation/drug effects ; Anti-Inflammatory Agents/pharmacology ; Animals ; Male ; Mice, Knockout ; Mice, Inbred C57BL ; Mice ; Lipopolysaccharides ; Anthraquinones
Περίληψη: Ferroptosis is a critical driver of renal tubular cell death in acute kidney injury (AKI). The present study aimed to investigate the protective effects of chrysophanol (CHR) against AKI-associated ferroptosis and delineate the mechanistic pathway involving Sirtuin 3 (SIRT3)-mediated deacetylation of NRF2. AKI was induced by lipopolysaccharide (LPS) in wild-type (WT) and SIRT3 knockout (SIRT3-/-) mice. To evaluate its prophylactic potential, WT mice were pretreated with CHR (20 and 40 mg/kg, i.g.) for three consecutive days prior to a single LPS injection (15 mg/kg, i.p.), while dexamethasone (2.5 mg/kg, i.p.) served as a positive control. Renal function, histopathology, and mitochondrial ultrastructure were evaluated. To assess the inflammatory response, levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured. Additionally, ferroptosis markers, including glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and Fe2+, were determined using biochemical assay kits. NRF2 acetylation and nuclear translocation were further analyzed via Western blot. Pretreatment with CHR substantially attenuated renal dysfunction in AKI mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels. It also mitigated histopathological injury in kidney tissues. This protective effect was characterized by a significant reduction in TNF-α, IL-6, and IL-1β levels and the suppression of ferroptosis via restoring GSH while reducing MDA and Fe2+ deposition. Mechanistically, CHR enhanced SIRT3 expression, culminating in NRF2 deacetylation and its consequent translocation into the nucleus, ultimately promoting the activation of GPX4. Molecular docking experiments suggested a potential interaction between CHR and the active site pocket of SIRT3. Notably, the protective effects of CHR against both AKI and ferroptosis were largely abrogated in SIRT3-/- mice. CHR protects against LPS-induced AKI by inhibiting ferroptosis. This prophylactic process is linked to SIRT3-mediated deacetylation of NRF2, highlighting the potential of CHR as a preventive strategy for sepsis-induced renal injury.
(© 2026. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Competing Interests: Declarations. Ethics approval: All experimental protocols involving animals were performed in strict adherence to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, USA). The study was reviewed and approved by the Ethics Committee of Hubei University of Chinese Medicine (Approval No. HUCMS61616355). The experimental protocol was made to reduce potential animal discomfort and ensure the minimum number of animals necessary for valid results was used. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
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Grant Information: Nos. 2022CFD023 Innovation and Development Joint Fund Project of Hubei Provincial Natural Science Foundation; Nos. 2025AFD478 Innovation and Development Joint Fund Project of Hubei Provincial Natural Science Foundation; Nos. ZY2025M031 Traditional Chinese Medicine Research Project of Hubei Provincial Administration of Traditional Chinese Medicine; Nos. ZY2025L243 Traditional Chinese Medicine Research Project of Hubei Provincial Administration of Traditional Chinese Medicine
Contributed Indexing: Keywords: Acute kidney injury; Deacetylation; Ferroptosis; SIRT3
Substance Nomenclature: 0 (NF-E2-Related Factor 2)
EC 3.5.1.- (Sirtuin 3)
0 (Nfe2l2 protein, mouse)
0 (Sirt3 protein, mouse)
N1ST8V8RR2 (chrysophanic acid)
0 (Lipopolysaccharides)
0 (Anti-Inflammatory Agents)
0 (Anthraquinones)
Entry Date(s): Date Created: 20260505 Date Completed: 20260724 Latest Revision: 20260724
Update Code: 20260724
DOI: 10.1007/s00210-026-05350-5
PMID: 42084621
Βάση Δεδομένων: MEDLINE
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  Data: Chrysophanol ameliorates ferroptosis in acute kidney injury by promoting SIRT3-mediated NRF2 deacetylation.
– Name: Author
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  Data: <searchLink fieldCode="AU" term="%22Cui+M%22">Cui M</searchLink>; The First Clinical College, Hubei University of Chinese Medicine, Wuhan, China.; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China.<br /><searchLink fieldCode="AU" term="%22Tian+H%22">Tian H</searchLink>; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China.<br /><searchLink fieldCode="AU" term="%22Zhu+J%22">Zhu J</searchLink>; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China.<br /><searchLink fieldCode="AU" term="%22Zhu+J%22">Zhu J</searchLink>; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China. zhujing@hbhtcm.com.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China. zhujing@hbhtcm.com.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China. zhujing@hbhtcm.com.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China. zhujing@hbhtcm.com.<br /><searchLink fieldCode="AU" term="%22Wang+Q%22">Wang Q</searchLink>; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China. 149806520@qq.com.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China. 149806520@qq.com.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China. 149806520@qq.com.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China. 149806520@qq.com.<br /><searchLink fieldCode="AU" term="%22Zou+Y%22">Zou Y</searchLink>; Hubei Provincial Hospital of Traditional Chinese Medicine, 4 Garden 14 Hill Road, Wuchang District, Wuhan, 430000, Hubei, China. zouyinshui@hbhtcm.com.; Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, China. zouyinshui@hbhtcm.com.; Hubei Research Institute of Traditional Chinese Medicine, Wuhan, China. zouyinshui@hbhtcm.com.; Hubei Key Laboratory of Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Wuhan, China. zouyinshui@hbhtcm.com.
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  Data: <searchLink fieldCode="MM" term="%22NF-E2-Related+Factor+2%22">NF-E2-Related Factor 2*</searchLink>/<searchLink fieldCode="MM" term="%22NF-E2-Related+Factor+2+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Acute+Kidney+Injury%22">Acute Kidney Injury*</searchLink>/<searchLink fieldCode="MM" term="%22Acute+Kidney+Injury+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Acute+Kidney+Injury%22">Acute Kidney Injury*</searchLink>/<searchLink fieldCode="MM" term="%22Acute+Kidney+Injury+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Acute+Kidney+Injury%22">Acute Kidney Injury*</searchLink>/<searchLink fieldCode="MM" term="%22Acute+Kidney+Injury+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Acute+Kidney+Injury%22">Acute Kidney Injury*</searchLink>/<searchLink fieldCode="MM" term="%22Acute+Kidney+Injury+chemically+induced%22">chemically induced</searchLink> <br /><searchLink fieldCode="MM" term="%22Ferroptosis%22">Ferroptosis*</searchLink>/<searchLink fieldCode="MM" term="%22Ferroptosis+drug+effects%22">drug effects</searchLink> <br /><searchLink fieldCode="MM" term="%22Sirtuin+3%22">Sirtuin 3*</searchLink>/<searchLink fieldCode="MM" term="%22Sirtuin+3+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Sirtuin+3%22">Sirtuin 3*</searchLink>/<searchLink fieldCode="MM" term="%22Sirtuin+3+genetics%22">genetics</searchLink><br /><searchLink fieldCode="MH" term="%22Acetylation%22">Acetylation</searchLink>/<searchLink fieldCode="MH" term="%22Acetylation+drug+effects%22">drug effects</searchLink> ; <searchLink fieldCode="MH" term="%22Anti-Inflammatory+Agents%22">Anti-Inflammatory Agents</searchLink>/<searchLink fieldCode="MH" term="%22Anti-Inflammatory+Agents+pharmacology%22">pharmacology</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Male%22">Male</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Knockout%22">Mice, Knockout</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%2C+Inbred+C57BL%22">Mice, Inbred C57BL</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Lipopolysaccharides%22">Lipopolysaccharides</searchLink> ; <searchLink fieldCode="MH" term="%22Anthraquinones%22">Anthraquinones</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Ferroptosis is a critical driver of renal tubular cell death in acute kidney injury (AKI). The present study aimed to investigate the protective effects of chrysophanol (CHR) against AKI-associated ferroptosis and delineate the mechanistic pathway involving Sirtuin 3 (SIRT3)-mediated deacetylation of NRF2. AKI was induced by lipopolysaccharide (LPS) in wild-type (WT) and SIRT3 knockout (SIRT3<superscript>-/-</superscript>) mice. To evaluate its prophylactic potential, WT mice were pretreated with CHR (20 and 40 mg/kg, i.g.) for three consecutive days prior to a single LPS injection (15 mg/kg, i.p.), while dexamethasone (2.5 mg/kg, i.p.) served as a positive control. Renal function, histopathology, and mitochondrial ultrastructure were evaluated. To assess the inflammatory response, levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured. Additionally, ferroptosis markers, including glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), and Fe<superscript>2+</superscript>, were determined using biochemical assay kits. NRF2 acetylation and nuclear translocation were further analyzed via Western blot. Pretreatment with CHR substantially attenuated renal dysfunction in AKI mice, as evidenced by reduced blood urea nitrogen (BUN) and serum creatinine (SCr) levels. It also mitigated histopathological injury in kidney tissues. This protective effect was characterized by a significant reduction in TNF-α, IL-6, and IL-1β levels and the suppression of ferroptosis via restoring GSH while reducing MDA and Fe<superscript>2+</superscript> deposition. Mechanistically, CHR enhanced SIRT3 expression, culminating in NRF2 deacetylation and its consequent translocation into the nucleus, ultimately promoting the activation of GPX4. Molecular docking experiments suggested a potential interaction between CHR and the active site pocket of SIRT3. Notably, the protective effects of CHR against both AKI and ferroptosis were largely abrogated in SIRT3<superscript>-/-</superscript> mice. CHR protects against LPS-induced AKI by inhibiting ferroptosis. This prophylactic process is linked to SIRT3-mediated deacetylation of NRF2, highlighting the potential of CHR as a preventive strategy for sepsis-induced renal injury.<br /> (© 2026. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declarations. Ethics approval: All experimental protocols involving animals were performed in strict adherence to the Guide for the Care and Use of Laboratory Animals (National Institutes of Health, USA). The study was reviewed and approved by the Ethics Committee of Hubei University of Chinese Medicine (Approval No. HUCMS61616355). The experimental protocol was made to reduce potential animal discomfort and ensure the minimum number of animals necessary for valid results was used. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
– Name: Ref
  Label: References
  Group: RefInfo
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– Name: GrantInfo
  Label: Grant Information
  Group: Grant
  Data: Nos. 2022CFD023 Innovation and Development Joint Fund Project of Hubei Provincial Natural Science Foundation; Nos. 2025AFD478 Innovation and Development Joint Fund Project of Hubei Provincial Natural Science Foundation; Nos. ZY2025M031 Traditional Chinese Medicine Research Project of Hubei Provincial Administration of Traditional Chinese Medicine; Nos. ZY2025L243 Traditional Chinese Medicine Research Project of Hubei Provincial Administration of Traditional Chinese Medicine
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  Group:
  Data: <i>Keywords: </i>Acute kidney injury; Deacetylation; Ferroptosis; SIRT3
– Name: NumberCAS
  Label: Substance Nomenclature
  Group: ID
  Data: 0 (NF-E2-Related Factor 2)<br />EC 3.5.1.- (Sirtuin 3)<br />0 (Nfe2l2 protein, mouse)<br />0 (Sirt3 protein, mouse)<br />N1ST8V8RR2 (chrysophanic acid)<br />0 (Lipopolysaccharides)<br />0 (Anti-Inflammatory Agents)<br />0 (Anthraquinones)
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  Data: <i>Date Created: </i>20260505 <i>Date Completed: </i>20260724 <i>Latest Revision: </i>20260724
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  Data: 20260724
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  Data: 10.1007/s00210-026-05350-5
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  Data: 42084621
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        Value: 10.1007/s00210-026-05350-5
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        Text: English
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      Pagination:
        StartPage: 15941
    Subjects:
      – SubjectFull: Acetylation drug effects
        Type: general
      – SubjectFull: Anti-Inflammatory Agents pharmacology
        Type: general
      – SubjectFull: Animals
        Type: general
      – SubjectFull: Male
        Type: general
      – SubjectFull: Mice, Knockout
        Type: general
      – SubjectFull: Mice, Inbred C57BL
        Type: general
      – SubjectFull: Mice
        Type: general
      – SubjectFull: Lipopolysaccharides
        Type: general
      – SubjectFull: Anthraquinones
        Type: general
      – SubjectFull: NF-E2-Related Factor 2 metabolism
        Type: general
      – SubjectFull: Acute Kidney Injury drug therapy
        Type: general
      – SubjectFull: Acute Kidney Injury metabolism
        Type: general
      – SubjectFull: Acute Kidney Injury pathology
        Type: general
      – SubjectFull: Acute Kidney Injury chemically induced
        Type: general
      – SubjectFull: Ferroptosis drug effects
        Type: general
      – SubjectFull: Sirtuin 3 metabolism
        Type: general
      – SubjectFull: Sirtuin 3 genetics
        Type: general
    Titles:
      – TitleFull: Chrysophanol ameliorates ferroptosis in acute kidney injury by promoting SIRT3-mediated NRF2 deacetylation.
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            – D: 01
              M: 07
              Text: 2026 Jul
              Type: published
              Y: 2026
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              Value: 399
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            – TitleFull: Naunyn-Schmiedeberg's archives of pharmacology
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