Schisandrin B (Sch B), a bioactive lignan derived from Schisandrae chinensis Fructus, exhibits well-documented tissue-protective properties, yet its systemic metabolic effects mediated by liver-derived factors remain elusive. This study investigated the capacity of Sch B to modulate systemic redox status and hepatokine secretion in a mouse model. Following oral administration of Sch B, treated animals demonstrated a significantly elevated plasma glutathione (GSH/GSSG) ratio, reflecting a robust enhancement of systemic antioxidant capacity essential for extrahepatic tissue protection. Concurrently, Sch B induced a highly favorable reprogramming of circulating hepatokines by downregulating angiopoietin-like proteins 3 and 4 (ANGPTL3 and ANGPTL4) while upregulating the insulin-sensitizing hormone adropin. Because ANGPTL3/4 act as lipase inhibitors, this coordinated shift theoretically promotes an atheroprotective lipid profile alongside enhanced energy expenditure and glucose homeostasis. Collectively, these findings demonstrate that Sch B exerts beneficial systemic metabolic effects through coupled redox enhancement and hepatokine regulation, underscoring its potential as a therapeutic agent for metabolic disorders.
References
[1]
Ko, K.M. and Leung, H.Y. (2024) How Schisandrae Fructus Benefits the Body: Mechanisms in Traditional Chinese Medicine and Modern Medicine. ChineseMedicine, 15, 75-81. https://doi.org/10.4236/cm.2024.153006
[2]
Zhang, Y. and Fang, X. (2023) The Pan-Liver Network Theory: From Traditional Chinese Medicine to Western Medicine. ChineseJournalofPhysiology, 66, 401-436. https://doi.org/10.4103/cjop.cjop-d-22-00131
[3]
Leung, H.Y., Sze, S.C. and Ko, K.M. (2024) Pharmacological Investigation on the Qi-Invigorating Action of Schisandrin B: Effects on Mitochondrial ATP Generation in Multiple Tissues and Innate/Adaptive Immunity in Mice. ChineseMedicine, 15, 15-26. https://doi.org/10.4236/cm.2024.152002
[4]
Guo, S., Yu, F., Wang, C., Zhao, W., Li, X., Liu, J., et al. (2026) Schisandrin B Confers Multi-Organ Protection via Regulation of Mitochondrial Homeostasis: Mechanistic Integration, Organ-Specific Differences, and Translational Challenges—A Review. FrontiersinPharmacology, 17, Article ID: 1781376. https://doi.org/10.3389/fphar.2026.1781376
[5]
Leung, H.Y., Chiu, P.Y., Poon, M.K.T. and Ko, K.M. (2005) A Yang-Invigorating Chinese Herbal Formula Enhances Mitochondrial Functional Ability and Antioxidant Capacity in Various Tissues of Male and Female Rats. RejuvenationResearch, 8, 238-247. https://doi.org/10.1089/rej.2005.8.238
[6]
Tipple, T.E. and Rogers, L.K. (2012) Methods for the Determination of Plasma or Tissue Glutathione Levels. In: MethodsinMolecularBiology, Humana Press, 315-324. https://doi.org/10.1007/978-1-61779-867-2_20
[7]
Vairetti, M., Di Pasqua, L.G., Cagna, M., Richelmi, P., Ferrigno, A. and Berardo, C. (2021) Changes in Glutathione Content in Liver Diseases: An Update. Antioxidants, 10, Article 364. https://doi.org/10.3390/antiox10030364
[8]
Ballatori, N., Krance, S.M., Notenboom, S., Shi, S., Tieu, K. and Hammond, C.L. (2009) Glutathione Dysregulation and the Etiology and Progression of Human Diseases. Biological Chemistry, 390, 191-214. https://doi.org/10.1515/bc.2009.033
[9]
Lushchak, V.I. (2012) Glutathione Homeostasis and Functions: Potential Targets for Medical Interventions. JournalofAminoAcids, 2012, Article ID: 736837. https://doi.org/10.1155/2012/736837
[10]
Vázquez-Meza, H., Vilchis-Landeros, M.M., Vázquez-Carrada, M., Uribe-Ramírez, D. and Matuz-Mares, D. (2023) Cellular Compartmentalization, Glutathione Transport and Its Relevance in Some Pathologies. Antioxidants, 12, Article 834. https://doi.org/10.3390/antiox12040834
[11]
Tenchov, R., Sasso, J.M., Wang, X. and Zhou, Q.A. (2024) Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement. ACSChemicalNeuroscience, 15, 1-30. https://doi.org/10.1021/acschemneuro.3c00531
[12]
Félix, J., Díaz-Del Cerro, E., Garrido, A. and De La Fuente, M. (2024) Characterization of a Natural Model of Adult Mice with Different Rate of Aging. MechanismsofAgeingandDevelopment, 222, Article 111991. https://doi.org/10.1016/j.mad.2024.111991
[13]
Ko, K.M., Chen, N., Leung, H.Y., Leong, E.P.K., Poon, M.K.T. and Chiu, P.Y. (2008) Long‐Term Schisandrin B Treatment Mitigates Age‐Related Impairments in Mitochondrial Antioxidant Status and Functional Ability in Various Tissues, and Improves the Survival of Aging C57BL/6J Mice. BioFactors, 34, 331-342. https://doi.org/10.1002/biof.5520340408
[14]
Landfors, F., Henneman, P., Chorell, E., Nilsson, S.K. and Kersten, S. (2024) Drug-target Mendelian Randomization Analysis Supports Lowering Plasma ANGPTL3, ANGPTL4, and APOC3 Levels as Strategies for Reducing Cardiovascular Disease Risk. European Heart Journal Open, 4, oeae035. https://doi.org/10.1093/ehjopen/oeae035
[15]
Iglesias, P. (2025) The Endocrine Role of Hepatokines: Implications for Human Health and Disease. Frontiers in Endocrinology, 16, Article ID: 1663353. https://doi.org/10.3389/fendo.2025.1663353
[16]
Jensen-Cody, S.O. and Potthoff, M.J. (2021) Hepatokines and Metabolism: Deciphering Communication from the Liver. Molecular Metabolism, 44, Article 101138. https://doi.org/10.1016/j.molmet.2020.101138
[17]
Cho, D.I., Ahn, J.H., Kang, B.G., Hwang, I., Cho, H.H., Jun, J.H., et al. (2025) ANGPTL4 Prevents Atherosclerosis by Preserving KLF2 to Suppress EndMT and Mitigates Endothelial Dysfunction. Arteriosclerosis, Thrombosis, and Vascular Biology, 45, 1742-1761. https://doi.org/10.1161/atvbaha.125.322700
[18]
Weng, S., Ding, C., Lin, J. and Chai, D. (2026) ANGPTL3 and Residual Atherosclerotic Risk: From Lipid Metabolism to Therapeutic Targeting. Frontiers in Endocrinology, 16, Article ID: 1706091. https://doi.org/10.3389/fendo.2025.1706091
[19]
Altamimi, T.R., Gao, S., Karwi, Q.G., Fukushima, A., Rawat, S., Wagg, C.S., et al. (2019) Adropin Regulates Cardiac Energy Metabolism and Improves Cardiac Function and Efficiency. Metabolism, 98, 37-48. https://doi.org/10.1016/j.metabol.2019.06.005
[20]
Chen, R., Wang, Q., Wang, Y., Wang, Y., Liu, J., Liao, Z., et al. (2023) Feeding-Induced Hepatokines and Crosstalk with Multi-Organ: A Novel Therapeutic Target for Type 2 Diabetes. FrontiersinEndocrinology, 14, Article ID: 1094458. https://doi.org/10.3389/fendo.2023.1094458
[21]
Ali, I.I., D’Souza, C., Singh, J. and Adeghate, E. (2022) Adropin’s Role in Energy Homeostasis and Metabolic Disorders. International Journal of Molecular Sciences, 23, Article 8318. https://doi.org/10.3390/ijms23158318
[22]
Jasaszwili, M., Billert, M., Strowski, M.Z., Nowak, K.W. and Skrzypski, M. (2020) Adropin as a Fat-Burning Hormone with Multiple Functions—Review of a Decade of Research. Molecules, 25, Article 549. https://doi.org/10.3390/molecules25030549
