Skip to content
2000
image of Aucubin Inhibits Liver Cancer via HMGB1-mediated Inactivation of the PI3K/AKT/mTOR Signaling Pathway
file format pdf download PDF

Abstract

Introduction

Liver cancer remains one of the most aggressive and lethal malignancies worldwide,and current therapeutic efforts show limited survival benefits. Based on our previous findings that aucubin attenuates liver ischemia-reperfusion injury by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway, this study aimed to elucidate the biological functions and molecular mechanisms of aucubin in liver cancer.

Methods

In this study, the role of aucubin in liver cancer was examined using liver cancer cell models and tumor-bearing mouse models. We evaluated whether the anti-tumor effect of aucubin is dependent on HMGB1 and its key signaling pathways. Intellectual property implications related to this small molecule are also explored.

Results

Results revealed that aucubin effectively reduced the Epithelial-Mesenchymal Transition (EMT) behavior of liver cancer in nude mice and inhibited the migration and invasion ability of liver cancer cells. The effect of aucubin on migration and proliferation was reversed by HMGB1 overexpression in HepG2 and HCCLM3 cells. Aucubin inhibited the levels of HMGB1, RAGE, p-PI3K, p-AKT, and p-mTOR proteins in mouse tumor tissues and this change was reversed by HMGB1 overexpression.

Discussion

We identified that aucubin exerts anti-liver cancer effects. By investigating the regulatory effects of HMGB1 overexpression and AKT agonist SC79 intervention on the HMGB1/
RAGE axis and PI3K/AKT/mTOR pathway, our findings confirmed the core role of the HMGB1/RAGE axis in aucubin’s anti-tumor activity, as well as aucubin’s regulation of liver cancer cell proliferation, migration, and invasion the PI3K/AKT/mTOR pathway-ultimately mediating its anti-tumor effects.

Conclusion

This study indicated that aucubin inhibits the proliferation, invasion, and metastasis of liver cancer by upregulating the HMGB1/RAGE axis and targeting the PI3K/AKT/mTOR signaling pathway. The results of this study highlighted the potential of aucubin as a therapeutic agent for suppressing liver cancer.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/pra/10.2174/0115748928420661250922102242
2025-10-08
2025-11-13

  • From This Site

    /content/journals/pra/10.2174/0115748928420661250922102242
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/pra/10.2174/0115748928420661250922102242/BMS-PRA-2025-74.html?itemId=/content/journals/pra/10.2174/0115748928420661250922102242&mimeType=html&fmt=ahah

References

  1. Bray F. Laversanne M. Sung H. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024 74 3 229 263 10.3322/caac.21834 38572751
    [Google Scholar]
  2. Chen L. Wei X. Gu D. Xu Y. Zhou H. Human liver cancer organoids: Biological applications, current challenges, and prospects in hepatoma therapy. Cancer Lett. 2023 555 216048 10.1016/j.canlet.2022.216048 36603689
    [Google Scholar]
  3. Tan E.Y. Danpanichkul P. Yong J.N. Liver cancer in 2021: Global Burden of Disease study. J. Hepatol. 2025 82 5 851 860 10.1016/j.jhep.2024.10.031 39481652
    [Google Scholar]
  4. Tayir M. Wang Y.W. Chu T. The function of necroptosis in liver cancer. Biochim. Biophys. Acta Mol. Basis Dis. 2025 1871 6 167828 10.1016/j.bbadis.2025.167828 40216370
    [Google Scholar]
  5. Wang Y. Deng B. Hepatocellular carcinoma: Molecular mechanism, targeted therapy, and biomarkers. Cancer Metastasis Rev. 2023 42 3 629 652 10.1007/s10555‑023‑10084‑4 36729264
    [Google Scholar]
  6. Chen J.G. Zhang Y.H. Lu J.H. Kensler T.W. Liver cancer etiology: Old issues and new perspectives. Curr. Oncol. Rep. 2024 26 11 1452 1468 10.1007/s11912‑024‑01605‑7 39388026
    [Google Scholar]
  7. Hwang S.Y. Danpanichkul P. Agopian V. Hepatocellular carcinoma: Updates on epidemiology, surveillance, diagnosis and treatment. Clin. Mol. Hepatol. 2025 31 S228 S254 [Suppl. 10.3350/cmh.2024.0824 39722614
    [Google Scholar]
  8. Villanueva A. Hepatocellular Carcinoma. N. Engl. J. Med. 2019 380 15 1450 1462 10.1056/NEJMra1713263 30970190
    [Google Scholar]
  9. Zhong B.Y. Fan W. Guan J.J. Combination locoregional and systemic therapies in hepatocellular carcinoma. Lancet Gastroenterol. Hepatol. 2025 10 4 369 386 10.1016/S2468‑1253(24)00247‑4 39993404
    [Google Scholar]
  10. Sangro B. Argemi J. Ronot M. EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma. J. Hepatol. 2025 82 2 315 374 10.1016/j.jhep.2024.08.028 39690085
    [Google Scholar]
  11. Goodwin G.H. Sanders C. Johns E.W. A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur. J. Biochem. 1973 38 1 14 19 10.1111/j.1432‑1033.1973.tb03026.x 4774120
    [Google Scholar]
  12. Tang D. Kang R. Zeh H.J. Lotze M.T. The multifunctional protein HMGB1: 50 years of discovery. Nat. Rev. Immunol. 2023 23 12 824 841 10.1038/s41577‑023‑00894‑6 37322174
    [Google Scholar]
  13. Wang S. Zhang Y. HMGB1 in inflammation and cancer. J. Hematol. Oncol. 2020 13 1 116 10.1186/s13045‑020‑00950‑x 32831115
    [Google Scholar]
  14. Shen P. Zhang L. Jiang X. Yu B. Zhang J. Targeting HMGB1 and its interaction with receptors: Challenges and future directions. J. Med. Chem. 2024 67 24 21671 21694 10.1021/acs.jmedchem.4c01912 39648929
    [Google Scholar]
  15. Watanabe H. Son M. The immune tolerance role of the HMGB1-RAGE axis. Cells 2021 10 3 564 10.3390/cells10030564 33807604
    [Google Scholar]
  16. Liu T. Son M. Diamond B. HMGB1 in systemic Lupus Erythematosus. Front. Immunol. 2020 11 1057 10.3389/fimmu.2020.01057 32536928
    [Google Scholar]
  17. Kim H. Kim B.J. Koh S. High mobility group box 1 in the central nervous system: Regeneration hidden beneath inflammation. Neural Regen. Res. 2025 20 1 107 115 10.4103/NRR.NRR‑D‑23‑01964 38767480
    [Google Scholar]
  18. Fan J. He K. Zhang Y. Li R. Yi X. Li S. HMGB1: New biomarker and therapeutic target of autoimmune and autoinflammatory skin diseases. Front. Immunol. 2025 16 1569632 10.3389/fimmu.2025.1569632 40308590
    [Google Scholar]
  19. Chen R. Zou J. Zhong X. Li J. Kang R. Tang D. HMGB1 in the interplay between autophagy and apoptosis in cancer. Cancer Lett. 2024 581 216494 10.1016/j.canlet.2023.216494 38007142
    [Google Scholar]
  20. Feng Z. Meng F. Huo F. Inhibition of ferroptosis rescues M2 macrophages and alleviates arthritis by suppressing the HMGB1/TLR4/STAT3 axis in M1 macrophages. Redox Biol. 2024 75 103255 10.1016/j.redox.2024.103255 39029270
    [Google Scholar]
  21. Liu H. Liao X. Zhang Z. HMGB1: Key mediator in digestive system diseases. Inflamm. Res. 2025 74 1 34 10.1007/s00011‑025‑02002‑x 39903246
    [Google Scholar]
  22. Lv G. Yang M. Gai K. Multiple functions of HMGB1 in cancer. Front. Oncol. 2024 14 1384109 10.3389/fonc.2024.1384109 38725632
    [Google Scholar]
  23. Sha X. Wang C. Liu Y. Multifunctional glycyrrhizic acid-loaded nanoplatform combining ferroptosis induction and HMGB1 blockade for enhanced tumor immunotherapy. J. Nanobiotechnology 2025 23 1 224 10.1186/s12951‑025‑03307‑z 40108690
    [Google Scholar]
  24. Özbay Kurt F.G. Cicortas B.A. Balzasch B.M. S100A9 and HMGB1 orchestrate MDSC-mediated immunosuppression in melanoma through TLR4 signaling. J. Immunother. Cancer 2024 12 9 009552 10.1136/jitc‑2024‑009552 39266214
    [Google Scholar]
  25. Xu Z. Ma W. Wang J. Nuclear HMGB1 is critical for CD8 T cell IFN-γ production and anti-tumor immunity. Cell Rep. 2024 43 8 114591 10.1016/j.celrep.2024.114591 39116204
    [Google Scholar]
  26. Fan A. Gao M. Tang X. HMGB1/RAGE axis in tumor development: Unraveling its significance. Front. Oncol. 2024 14 1336191 10.3389/fonc.2024.1336191 38529373
    [Google Scholar]
  27. Guo L. Han L. Zhang J. HMGB1 mediates epithelial-mesenchymal transition and fibrosis in silicosis via RAGE/β-catenin signaling. Chem. Biol. Interact. 2025 408 111385 10.1016/j.cbi.2025.111385 39800143
    [Google Scholar]
  28. Fan L. Zhang X. Song X. HMGB1/RAGE signaling mediates the activation of microglia and participates in depressive-like behaviors and cognitive deficits in rats after ischemia-reperfusion. Behav. Brain Res. 2025 492 115662 10.1016/j.bbr.2025.115662 40419119
    [Google Scholar]
  29. Pujals M. Mayans C. Bellio C. RAGE/SNAIL1 signaling drives epithelial-mesenchymal plasticity in metastatic triple-negative breast cancer. Oncogene 2023 42 35 2610 2628 10.1038/s41388‑023‑02778‑4 37468678
    [Google Scholar]
  30. Han J.Y. Rhee W.J. Shin J.S. Cytoplasmic HMGB1 promotes the activation of JAK2-STAT3 signaling and PD-L1 expression in breast cancer. Mol. Med. 2025 31 1 197 10.1186/s10020‑025‑01235‑0 40389855
    [Google Scholar]
  31. Yusein-Myashkova S. Vladimirova D. Gospodinov A. Ugrinova I. Todorova J. Metformin inhibits cell motility and proliferation of triple-negative breast cancer cells by blocking HMGB1/RAGE signaling. Cells 2025 14 8 590 10.3390/cells14080590 40277915
    [Google Scholar]
  32. Pu Z. Duda D.G. Zhu Y. VCP interaction with HMGB1 promotes hepatocellular carcinoma progression by activating the PI3K/AKT/mTOR pathway. J. Transl. Med. 2022 20 1 212 10.1186/s12967‑022‑03416‑5 35562734
    [Google Scholar]
  33. Trim A.R. Hill R. The preparation and properties of aucubin, asperuloside and some related glycosides. Biochem. J. 1952 50 3 310 319 10.1042/bj0500310 14915951
    [Google Scholar]
  34. Chen G. Lyu J. Yang L. Anti-lymphoma application of morusin. 2024 CN Patent 118976022
  35. Luo Z. Yang L. Zhu T. Aucubin ameliorates atherosclerosis by modulating tryptophan metabolism and inhibiting endothelial-mesenchymal transitions via gut microbiota regulation. Phytomedicine 2024 135 156122 10.1016/j.phymed.2024.156122 39396405
    [Google Scholar]
  36. Wang Y.P. Xu X.D. Xu X. Zhu L. Wang C. Ren K. Aucubin protects against myocardial ischemia-reperfusion injury via activation of the AKT/STAT3 pathway. Int. J. Cardiol. 2024 412 132311 10.1016/j.ijcard.2024.132311 38950786
    [Google Scholar]
  37. Zheng X.Z. Yu H.Y. Chen Y.R. Fang J.S. Aucubin mitigates the elevation of microglial aerobic glycolysis and inflammation in diabetic neuropathic pain via aldose reductase. World J. Diabetes 2025 16 5 103915 10.4239/wjd.v16.i5.103915 40487600
    [Google Scholar]
  38. Huang T.L. Yang S.H. Chen Y.R. Liao J.Y. Tang Y. Yang K.C. The therapeutic effect of aucubin-supplemented hyaluronic acid on interleukin-1beta-stimulated human articular chondrocytes. Phytomedicine 2019 53 1 8 10.1016/j.phymed.2018.09.233 30668389
    [Google Scholar]
  39. Zhang S. Feng Z. Gao W. Aucubin attenuates liver ischemia-reperfusion injury by inhibiting the HMGB1/TLR-4/NF-κB signaling pathway, oxidative stress, and apoptosis. Front. Pharmacol. 2020 11 544124 10.3389/fphar.2020.544124 33013386
    [Google Scholar]
  40. Gao Z.X. Zhang Z.S. Qin J. Aucubin enhances the antitumor activity of cisplatin through the inhibition of PD-L1 expression in hepatocellular carcinoma. Phytomedicine 2023 112 154715 10.1016/j.phymed.2023.154715 36821999
    [Google Scholar]
  41. Chen P. Dong Z. Zhu W. Noncanonical regulation of HOIL-1 on cancer stemness and sorafenib resistance identifies pixantrone as a novel therapeutic agent for HCC. Hepatology 2024 80 2 330 345 10.1097/HEP.0000000000000623 37820061
    [Google Scholar]
  42. Cao L.Q. Xie Y. Fleishman J.S. Liu X. Chen Z.S. Hepatocellular carcinoma and lipid metabolism: Novel targets and therapeutic strategies. Cancer Lett. 2024 597 217061 10.1016/j.canlet.2024.217061 38876384
    [Google Scholar]
  43. Yang C. Zhang H. Zhang L. Evolving therapeutic landscape of advanced hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol. 2023 20 4 203 222 10.1038/s41575‑022‑00704‑9 36369487
    [Google Scholar]
  44. Piñero F. Dirchwolf M. Pessôa M.G. Biomarkers in hepatocellular carcinoma: Diagnosis, prognosis and treatment response assessment. Cells 2020 9 6 1370 10.3390/cells9061370 32492896
    [Google Scholar]
  45. Kim H.S. Yoon J.H. Choi J.Y. GULP1 as a novel diagnostic and predictive biomarker in hepatocellular carcinoma. Clin. Mol. Hepatol. 2025 31 3 914 934 10.3350/cmh.2024.1038 39914372
    [Google Scholar]
  46. McGlynn K.A. Petrick J.L. Groopman J.D. Liver cancer: Progress and priorities. Cancer Epidemiol. Biomarkers Prev. 2024 33 10 1261 1272 10.1158/1055‑9965.EPI‑24‑0686 39354815
    [Google Scholar]
  47. Yang Y. Yu S. Lv C. Tian Y. NETosis in tumour microenvironment of liver: From primary to metastatic hepatic carcinoma. Ageing Res. Rev. 2024 97 102297 10.1016/j.arr.2024.102297 38599524
    [Google Scholar]
  48. Yang Y. Huang L. Zhang N. SUMOylation of annexin A6 retards cell migration and tumor growth by suppressing RHOU/AKT1–involved EMT in hepatocellular carcinoma. Cell Commun. Signal. 2024 22 1 206 10.1186/s12964‑024‑01573‑2 38566133
    [Google Scholar]
  49. Thapa R. Gupta S. Gupta G. Epithelial–mesenchymal transition to mitigate age-related progression in lung cancer. Ageing Res. Rev. 2024 102 102576 10.1016/j.arr.2024.102576 39515620
    [Google Scholar]
  50. Guo W. Duan Z. Wu J. Zhou B.P. Epithelial-mesenchymal transition promotes metabolic reprogramming to suppress ferroptosis. Semin. Cancer Biol. 2025 112 20 35 10.1016/j.semcancer.2025.02.013 40058616
    [Google Scholar]
  51. Li Y. Jiang Y. Yan H. Global isonicotinylome analysis identified SMAD3 isonicotinylation promotes liver cancer cell epithelial–mesenchymal transition and invasion. iScience 2024 27 9 110775 10.1016/j.isci.2024.110775 39286495
    [Google Scholar]
  52. Gerdes J. Li L. Schlueter C. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am. J. Pathol. 1991 138 4 867 873 2012175
    [Google Scholar]
  53. Guo X. Patel R.V. Lederer J.A. Meredith D.M. Bi W.L. Ki-67 in meningioma: Distribution and implications. J. Neurosurg. 2025 ••• 1 11 10.3171/2025.4.JNS25438 40712166
    [Google Scholar]
  54. Wu H. Han X. Wang Z. Prediction of the Ki-67 marker index in hepatocellular carcinoma based on CT radiomics features. Phys. Med. Biol. 2020 65 23 235048 10.1088/1361‑6560/abac9c 32756021
    [Google Scholar]
  55. Cai C. Wang L. Tao L. imaging‐based prediction of Ki‐67 expression in hepatocellular carcinoma: A retrospective study. Cancer Med. 2025 14 4 70562 10.1002/cam4.70562 39964132
    [Google Scholar]
  56. Huang H. Chang Y.H. Xu J. Aucubin as a natural potential anti-acute hepatitis candidate: Inhibitory potency and hepatoprotective mechanism. Phytomedicine 2022 102 154170 10.1016/j.phymed.2022.154170 35609387
    [Google Scholar]
  57. Liu P. Song S. Yang P. Rao X. Wang Y. Bai X. Aucubin improves chronic unpredictable mild stress-induced depressive behavior in mice via the GR/NF-κB/NLRP3 axis. Int. Immunopharmacol. 2023 123 110677 10.1016/j.intimp.2023.110677 37523973
    [Google Scholar]
  58. Bao X. Li J. Ren C. Aucubin ameliorates liver fibrosis and hepatic stellate cells activation in diabetic mice via inhibiting ER stress-mediated IRE1α/TXNIP/NLRP3 inflammasome through NOX4/ROS pathway. Chem. Biol. Interact. 2022 365 110074 10.1016/j.cbi.2022.110074 35961541
    [Google Scholar]
  59. Shi X. Jiang W. Yang X. Aucubin inhibits hepatic stellate cell activation through stimulating Nrf2/Smad7 axis. Eur. J. Pharmacol. 2023 957 176002 10.1016/j.ejphar.2023.176002 37607604
    [Google Scholar]
  60. Paggi J.M. Pandit A. Dror R.O. The art and science of molecular docking. Annu. Rev. Biochem. 2024 93 1 389 410 10.1146/annurev‑biochem‑030222‑120000 38594926
    [Google Scholar]
  61. Zhou Y. Liu X. Zhang W. HMGB1 released from dead tumor cells after insufficient radiofrequency ablation promotes progression of HCC residual tumor via ERK1/2 pathway. Int. J. Hyperthermia 2023 40 1 2174709 10.1080/02656736.2023.2174709 36755436
    [Google Scholar]
  62. El-Sahar A.E. Bekhit N. Eissa N.M. Abdelsalam R.M. Essam R.M. Targeting HMGB1/PI3K/Akt and NF-κB/Nrf-2 signaling pathways by vildagliptin mitigates testosterone-induced benign prostate hyperplasia in rats. Life Sci. 2023 322 121645 10.1016/j.lfs.2023.121645 37001804
    [Google Scholar]
  63. Wei Y. Ma Z. Li Z. Gentiopicroside ameliorates synovial inflammation and fibrosis in KOA rats by modulating the HMGB1-mediated PI3K/AKT signaling axis. Int. Immunopharmacol. 2025 147 113973 10.1016/j.intimp.2024.113973 39764995
    [Google Scholar]
/content/journals/pra/10.2174/0115748928420661250922102242
Loading
Aucubin Inhibits Liver Cancer via HMGB1-mediated Inactivation of the PI3K/AKT/mTOR Signaling Pathway
Bentham Science Publishers ; https://doi.org/10.2174/0115748928420661250922102242
/content/journals/pra/10.2174/0115748928420661250922102242
/content/journals/pra/10.2174/0115748928420661250922102242
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: PI3K/AKT/mTOR ; liver cancer ; RAGE ; Aucubin ; HMGB1 ; mechanisms

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test