Item request has been placed! ×
Item request cannot be made. ×
loading  Processing Request

Alnustone Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Facilitating Mitochondrial Fatty Acid β-Oxidation via Targeting Calmodulin.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE
    • Publication Information:
      Original Publication: Weinheim : WILEY-VCH, [2014]-
    • Subject Terms:
      Calmodulin*/metabolism ; Calmodulin*/drug effects ; Fatty Acids*/metabolism ; Fatty Liver*/metabolism ; Fatty Liver*/drug therapy ; Mitochondria*/metabolism ; Mitochondria*/drug effects ; Non-alcoholic Fatty Liver Disease*/metabolism ; Non-alcoholic Fatty Liver Disease*/drug therapy; Animals ; Mice ; Male ; Humans ; Oxidation-Reduction/drug effects ; Female ; Mice, Inbred C57BL ; Disease Models, Animal ; Mitochondria, Liver/metabolism ; Mitochondria, Liver/drug effects ; Liver/metabolism ; Liver/drug effects
    • Abstract:
      Metabolic dysfunction-associated steatotic liver disease (MASLD), including its more severe manifestation metabolic dysfunction-associated steatohepatitis (MASH), poses global public health threats with limited therapeutics. Here, the role of alnustone is explored, a natural compound derived from the traditional Chinese herb Alpinia katsumadai Hayata, in the treatment of MASLD and MASH. It is shown that alnustone administration potently reduces serum triacylglycerol levels, reverses liver steatosis, and alleviates insulin resistance in both male and female MASLD mice. It also effectively ameliorates established fibrosis in MASH mice without any side effects. Mechanistically, hepatic lipidome profiling and energy metabolic assays reveal that alnustone facilitates mitochondrial fatty acid β-oxidation. Employing limited proteolysis-mass spectrometry (LiP-SMap) and further validation, calmodulin is identified as a direct molecular target of alnustone. Alnustone interacts with the Ca 2+ -binding site of calmodulin, leading to increased cytosolic and mitochondrial Ca 2+ levels and enhanced mitochondrial function, whereas liver-specific calmodulin knockdown abrogates alnustone's therapeutic effects. Moreover, calmodulin is downregulated in human livers of patients with MASLD and MASH, and is genetically associated with reduced MASLD risk. These findings establish alnustone as a promising natural compound and highlight calmodulin as a target for treating MASLD.
      (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)
    • References:
      Planta Med. 1996 Jun;62(3):236-40. (PMID: 8693036)
      J Intern Med. 2024 Jul;296(1):24-38. (PMID: 38738988)
      Cell Metab. 2021 Mar 2;33(3):565-580.e7. (PMID: 33657393)
      Nat Rev Gastroenterol Hepatol. 2018 Jun;15(6):349-364. (PMID: 29740166)
      Adv Exp Med Biol. 2020;1276:37-52. (PMID: 32705593)
      Curr Mol Pharmacol. 2024 Jan 26;17:e18761429252459. (PMID: 38284732)
      Cell. 2002 Mar 22;108(6):739-42. (PMID: 11955428)
      Hepatology. 2016 Nov;64(5):1577-1586. (PMID: 27543837)
      Eur J Pharmacol. 2024 May 15;971:176548. (PMID: 38570080)
      Nat Rev Drug Discov. 2025 Mar;24(3):171-189. (PMID: 39609545)
      Nat Med. 2003 Sep;9(9):1187-94. (PMID: 12937413)
      J Hepatol. 2024 Feb;80(2):194-208. (PMID: 38438948)
      Nat Rev Dis Primers. 2015 Dec 17;1:15080. (PMID: 27188459)
      Nat Med. 2018 Jul;24(7):908-922. (PMID: 29967350)
      J Hepatol. 2024 Sep;81(3):492-542. (PMID: 38851997)
      Chin Med J (Engl). 2025 Apr 05;138(7):829-837. (PMID: 39183555)
      Br J Pharmacol. 2024 Aug;181(15):2583-2599. (PMID: 38604611)
      J Hepatol. 2006 Jan;44(1):197-208. (PMID: 16274837)
      Nat Commun. 2023 Dec 18;14(1):8391. (PMID: 38110408)
      Zhongguo Zhong Yao Za Zhi. 2010 Jul;35(13):1710-4. (PMID: 20862963)
      Cell. 2007 Dec 14;131(6):1047-58. (PMID: 18083096)
      JHEP Rep. 2023 Mar 27;5(7):100744. (PMID: 37235137)
      Cell. 2021 May 13;184(10):2537-2564. (PMID: 33989548)
      Genome Biol. 2018 Jun 20;19(1):79. (PMID: 29925420)
      Gut. 2022 Apr;71(4):807-821. (PMID: 33903148)
      Histol Histopathol. 2022 Sep;37(9):813-824. (PMID: 35475465)
      Cell Discov. 2025 Apr 15;11(1):37. (PMID: 40234379)
      Biochem J. 1972 Jun;128(1):161-3. (PMID: 4343661)
      Nat Rev Gastroenterol Hepatol. 2018 Jan;15(1):11-20. (PMID: 28930295)
      Nat Rev Endocrinol. 2018 May;14(5):259-269. (PMID: 29472712)
      Cell. 2018 Jan 11;172(1-2):358-372.e23. (PMID: 29307493)
      Nature. 2011 Jun 19;476(7360):336-40. (PMID: 21685888)
      N Engl J Med. 2024 Feb 8;390(6):497-509. (PMID: 38324483)
      J Hepatol. 2011 Dec;55(6):1383-90. (PMID: 21703200)
      Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21984-9. (PMID: 19995983)
      Planta Med. 1993 Oct;59(5):451-4. (PMID: 8255938)
      Lancet. 2019 Nov 30;394(10213):2012-2024. (PMID: 31727409)
      Nat Commun. 2023 Feb 23;14(1):1020. (PMID: 36823211)
      JHEP Rep. 2023 Mar 28;5(7):100746. (PMID: 37274776)
      Phytother Res. 2022 Jan;36(1):525-542. (PMID: 34847624)
      Nat Rev Immunol. 2022 Jul;22(7):429-443. (PMID: 34741169)
      Biosens Bioelectron. 2006 Aug 15;22(2):268-74. (PMID: 16487701)
      J Clin Invest. 2002 May;109(10):1345-50. (PMID: 12021250)
      Drug Discov Today. 2022 Jun;27(6):1560-1574. (PMID: 35202802)
      Am J Physiol Endocrinol Metab. 2009 Aug;297(2):E289-96. (PMID: 19401457)
      Complement Ther Med. 2020 Jan;48:102283. (PMID: 31987259)
      J Hepatol. 2023 Sep;79(3):842-852. (PMID: 37169151)
      Nature. 2011 Jun 19;476(7360):341-5. (PMID: 21685886)
      Adv Sci (Weinh). 2025 Aug;12(31):e11984. (PMID: 40470949)
      Metabolism. 2024 Mar;152:155766. (PMID: 38145825)
      Nat Metab. 2021 Jul;3(7):909-922. (PMID: 34158670)
      Cell Metab. 2024 Oct 1;36(10):2341-2354.e6. (PMID: 39317186)
      World J Gastroenterol. 2014 May 14;20(18):5320-30. (PMID: 24833862)
      Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11285-E11292. (PMID: 29237750)
      Nat Prod Commun. 2012 Jun;7(6):795-8. (PMID: 22816310)
      Nature. 1999 May 13;399(6732):159-62. (PMID: 10335846)
      J Biochem. 2017 Oct 1;162(4):259-270. (PMID: 28369416)
      Cell Metab. 2024 Oct 1;36(10):2329-2340.e4. (PMID: 39153480)
      Bioorg Med Chem. 2021 Feb 1;31:115971. (PMID: 33422907)
      Nutrients. 2021 Jul 30;13(8):. (PMID: 34444811)
    • Grant Information:
      32588201 National Natural Science Foundation of China; 82421004 National Natural Science Foundation of China; 82371644 National Natural Science Foundation of China; 82100839 National Natural Science Foundation of China; 2021-I2M-5-001 CAMS Innovation Fund for Medical Sciences; 2024CXPT087 Shandong Provincial Key Research and Development Program; 2024BEG02019 Ningxia Hui Autonomous Region Key Research and Developmental Program; ZR2020QH083 Shandong Provincial Natural Science Foundation; 2023KJ021 Fundamental Research Funds of Shandong University; 2023QNTD004 Fundamental Research Funds of Shandong University; ts20190988 Taishan Scholar Foundation of Shandong Province; tsqn202312387 Taishan Scholar Foundation of Shandong Province
    • Contributed Indexing:
      Keywords: alnustone; calmodulin; fatty acid β‐oxidation; metabolic dysfunction‐associated steatohepatitis; metabolic dysfunction‐associated steatotic liver disease
    • Accession Number:
      0 (Calmodulin)
      0 (Fatty Acids)
    • Publication Date:
      Date Created: 20250605 Date Completed: 20250823 Latest Revision: 20250827
    • Publication Date:
      20250902
    • Accession Number:
      PMC12376512
    • Accession Number:
      10.1002/advs.202411984
    • Accession Number:
      40470949