AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO025390422
Submit to EJMO
Cite this article
1
Download
18
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

Erinacine A regulates autophagy-mediated apoptosis of hepatocellular carcinoma cells through the PI3K/Akt/mTOR/ULK1 signaling pathway

Lihui Zhang1† ,  Changqing Liu2† ,  Xiaocui Liu1 ,  Dandan Sheng1 ,  Man Li1 ,  Xia Wang3 ,  Mingkun Xie4 ,  Qingjie Feng1 ,  Yuxi Xie1*
Show Less
1 Department of Critical Care Medicine, Tianjin Beichen Traditional Chinese Medical Hospital, Tianjin, China
2 Department of General Surgery, Tianjin Beichen Traditional Chinese Medical Hospital, Tianjin, China
3 Department of Nursing, Tianjin Beichen Traditional Chinese Medical Hospital, Tianjin, China
4 Department of Emergency Medicine, Tianjin Beichen Traditional Chinese Medical Hospital, Tianjin, China
†These authors contributed equally to this work.
EJMO, 025390422 https://doi.org/10.36922/EJMO025390422
Received: 28 September 2025 | Revised: 8 January 2026 | Accepted: 12 January 2026 | Published online: 13 March 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Download PDF
XML
Cite
Abstract

Introduction: Erinacine A is a cancer autophagy inhibitor with proven efficacy in many cancers. However, its therapeutic role in liver cancer remains unknown.

Objective: This study investigates the effect of Erinacine A on autophagy-mediated apoptosis in HepG2 hepatocellular carcinoma cells.

Methods: HepG2 cells were divided into seven treatment groups: (i) NC: untreated cells, (ii) AC: cells treated with Erinacine A, (iii) HEG: cells with hig h protein kinase B (Akt) expression treated with Erinacine A, (iv) HEHAG: cells with high Akt expression treated with Erinacine A with and SC79, (v) LAR: cells treated with Erinacine A and GDC-0068, (vi) GD: cells with stably low Akt expression treated with Erinacine A, and (vii) GFR: cells with stably low Akt expression treated with Erinacine A, Akt, and SC79. Scratch tests, cell invasion tests, and Cell Counting Kit-8 were used to detect cell migration, invasion, and proliferation. Western blot and polymerase chain reaction were performed to assess the phosphoinositide 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR)/Unc-51-like autophagy activating kinase 1 (ULK1) signaling pathway, as well as protein expression and mRNA levels of apoptosis markers caspase-3 and caspase-9, and the expression of autophagy related proteins Beclin 1, microtubule-associated protein 1 light chain 3 (LC3)-I, and LC3 II.

Results: Cell migration, invasion, and proliferation in AC, HEG, and HEHAG groups were lower compared to the NC group (p < 0.05). In the AC group, LC3-I, LC3-II, and Beclin 1 showed reduced protein expression (p < 0.05), with Beclin 1 in the GFR group exhibiting a further significant reduction (p < 0.01). Protein levels and mRNA expression of caspase-3 and caspase-9 were elevated in the AC group (p <0.01). Phosphorylated PI3K/Akt/mTOR protein and mRNA levels were significantly increased in the AC, HEG, and HEHAG groups (p < 0.05), whereas ULK1 was decreased (p < 0.05). The GFR group showed a reversal of these trends (p < 0.05).

Conclusion: Erinacine A suppresses the proliferation, migration, and invasion of HepG2 cells, likely through the modulation of the PI3K/AKT/mTOR/ULK1 signaling pathway, which in turn inhibits autophagy-mediated apoptosis in these cells.

Graphical abstract
Keywords
Erinacine A
Hepatocellular carcinoma cells
PI3K/AKT/mTOR/ULK1 signaling pathway
Autophagy
Apoptosis
Funding
This study was funded by the Tianjin Municipal Health Commission (Approval No. 2023066).
Conflict of interest
The authors declare that they have no conflict of interest.
References
  1. Gaidai O, Yan P, Xing Y. Future world cancer death rate prediction. Sci Rep. 2023;13(1):303. doi: 10.1038/s41598-023-27547-x

 

  1. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022;135(5):584-590. doi: 10.1097/CM9.0000000000002108

 

  1. Anwanwan D, Singh SK, Singh S, Saikam V, Singh R. Challenges in liver cancer and possible treatment approaches. Biochim Biophys Acta Rev Cancer. 2020;1873(1):188314. doi: 10.1016/j.bbcan.2019.188314

 

  1. Benichou E, Seffou B, Topcu S, et al. The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism. Nat Commun. 2024;15(1):1879. doi: 10.1038/s41467-024-46234-7

 

  1. Xia C, Dong X, Li H, et al. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl). 2022;135(5):584-590. doi: 10.1097/CM9.0000000000002108

 

  1. Li IC, Lee LY, Chen YJ, et al. Erinacine A-enriched Hericium erinaceus mycelia promotes longevity in Drosophila melanogaster and aged mice. PLoS One. 2019;14(5):e0217226. doi: 10.1371/journal.pone.0217226

 

  1. Kuo HC, Kuo YR, Lee KF, et al. A Comparative Proteomic Analysis of Erinacine A’s Inhibition of Gastric Cancer Cell Viability and Invasiveness. Cell Physiol Biochem. 2017;43(1):195-208. doi: 10.1159/000480338

 

  1. Prasher P, Sharma M, Sharma AK, et al. Key oncologic pathways inhibited by Erinacine A: A perspective for its development as an anticancer molecule. Biomed Pharmacother. 2023;160:114332. doi: 10.1016/j.biopha.2023.114332

 

  1. Huang YM, Fu YS, Chen WL, Lu HC. In Vitro Assessment of 4-Acetyl-Antroquinonol B and Erinacine A in Suppressing Breast Cancer-Induced Osteoclastogenesis. Int J Med Mushrooms. 2024;26(8):41-57. doi: 10.1615/IntJMedMushrooms.2024054321

 

  1. Pinter M, Peck-Radosavljevic M. Review article: systemic treatment of hepatocellular carcinoma. Aliment Pharmacol Ther. 2018;48(6):598-609. doi: 10.1111/apt.14913

 

  1. Fulda S. Targeting autophagy for the treatment of cancer. Biol Chem. 2018;399(7):673-677. doi: 10.1515/hsz-2018-0108

 

  1. Bishop E, Bradshaw TD. Autophagy modulation: a prudent approach in cancer treatment. Cancer Chemother Pharmacol. 2018;82(6):913-922. doi: 10.1007/s00280-018-3676-6

 

  1. Debnath J, Gammoh N, Ryan KM. Autophagy and autophagy-related pathways in cancer. Nat Rev Mol Cell Biol. 2023;24(8):560-575. doi: 10.1038/s41580-023-00585-z

 

  1. Li X, Huang Q, Wang M, et al. Compound K Inhibits Autophagy-Mediated Apoptosis Through Activation of the PI3K-Akt Signaling Pathway Thus Protecting Against Ischemia/Reperfusion Injury. Cell Physiol Biochem. 2018;47(6):2589-2601. doi: 10.1159/000491655

 

  1. Pinter M, Peck-Radosavljevic M. Review article: systemic treatment of hepatocellular carcinoma. Aliment Pharmacol Ther. 2018;48(6):598-609. doi: 10.1111/apt.14913

 

  1. Zhang Q, Cao S, Qiu F, Kang N. Incomplete autophagy: Trouble is a friend. Med Res Rev. 2022;42(4):1545-1587. doi: 10.1002/med.21884

 

  1. Li YL, Wang TT, Sun YJ, et al. P53-mediated PI3K/AKT/mTOR pathway played a role in PtoxDpt-induced EMT inhibition in liver cancer cell lines. Oxid Med Cell Longev. 2019;2019:2531493. doi: 10.1155/2019/2531493

 

  1. Zhuo QY, Chen MX, Wang LL. Betulinic acid induces apoptosis and autophagy in human colon cancer cell SW620 by regulating PI3K/Akt/mTOR signaling pathway. Chin J Exp Tradit Med Form. 2022;28(14):99-106. doi: 10.13422/j.cnki.syfjx.20220921

 

  1. Cao QX, Lu WG, Zhou TT, et al. Analgesic-antitumor peptide inhibits angiogenesis by suppressing AKT activation in hepatocellular carcinoma. J Exp Clin Cancer Res. 2018;37(1):325. doi: 10.1186/s13046-018-0988-4

 

  1. Zhang Y, Wang LH, Xu N, et al. Erianin suppresses hepatocellular carcinoma cells through down-regulation of PI3K/AKT, p38 and ERK MAPK signaling pathways. Biomed Pharmacother. 2021;143:112215. doi: 10.1016/j.biopha.2021.112215

 

  1. Li J, Wang Y, Zhang L, et al. LncRNA SNHG1 promotes hepatocellular carcinoma cell invasion and migration via regulating PI3K/AKT signaling pathway. J Cell Biochem. 2022;123(8):1345-1356. doi: 10.1002/jcb.30289

 

  1. Zhang H, Liu Y, Wang F, et al. CCK-8 assay for evaluating the proliferation of hepatocellular carcinoma cells treated with traditional Chinese medicine extracts. J Cell Biochem. 2021;122(5):5890-5898. doi: 10.1002/jcb.30045

 

  1. Zhou LJ, Wang YJ, Hu HL, et al. Erinacine Facilitates the Opening of the Mitochondrial Permeability Transition Pore Through the Inhibition of the PI3K/Akt/GSK-3β Signaling Pathway in Human Hepatocellular Carcinoma. Cell Physiol Biochem. 2018;50(3):851-867. doi: 10.1159/000494472

 

  1. Lee KC, Lee KF, Tung SY, et al. Induction Apoptosis of Erinacine A in Human Colorectal Cancer Cells Involving the Expression of TNFR, Fas, and Fas Ligand via the JNK/p300/p50 Signaling Pathway With Histone Acetylation. Front Pharmacol. 2019;10:1174. doi: 10.3389/fphar.2019.01174

 

  1. Hanada M, Feng J, Hemmings BA. Structure, regulation and function of PKB/AKT--a major therapeutic target. Biochim Biophys Acta. 2004;1697(1-2):3-16. doi: 10.1016/j.bbapap.2003.11.009

 

  1. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129(7):1261-1274. doi: 10.1016/j.cell.2007.06.009

 

  1. Bahrami A, Khazaei M, Shahidsales S, et al. The Therapeutic Potential of PI3K/Akt/mTOR Inhibitors in Breast Cancer: Rational and Progress. J Cell Biochem. 2018;119(1):213-222. doi: 10.1002/jcb.26278

 

  1. Cao C, Ren Y, Barnett AS, et al. Increased Ca2+ signaling through CaV1.2 promotes bone formation and prevents estrogen deficiency-induced bone loss. JCI Insight. 2017;2(22):e95842. doi: 10.1172/jci.insight.95842

 

  1. Wang ZQ, Cui XP, Hao GP, et al. Aberrant expression of PI3K/AKT signaling is involved in apoptosis resistance of hepatocellular carcinoma. Open Life Sci. 2021;16(1):1037-1044. doi: 10.1515/biol-2021-0105

 

  1. Tao S, Xie SJ, Diao LT, et al. RNA-binding protein CCDC137 activates AKT signaling and promotes hepatocellular carcinoma through a novel non-canonical role of DGCR8 in mRNA localization. J Exp Clin Cancer Res. 2023;42(1):194. doi: 10.1186/s13046-023-02749-3

 

  1. Shi B, Ma M, Zheng Y, Pan Y, Lin X. mTOR and Beclin1: Two key autophagy-related molecules and their roles in myocardial ischemia/reperfusion injury. J Cell Physiol. 2019;234(8):12562-12568. doi: 10.1002/jcp.28125

 

  1. Huang Q, Zhan L, Cao H, et al. Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways. Autophagy. 2016;12(6):999-1014. doi: 10.1080/15548627.2016.1166318

 

  1. Sun Y, Yao X, Zhang QJ, et al. Beclin-1-Dependent Autophagy Protects the Heart During Sepsis. Circulation. 2018;138(20):2247-2262. doi: 10.1161/CIRCULATIONAHA.117.032821

 

  1. He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct Target Ther. 2021;6(1):425. doi: 10.1038/s41392-021-00828-5

 

  1. 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. doi: 10.1016/j.canlet.2023.216494
Share
Back to top
Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept