Betulinic acid: Pharmacological effects, mechanisms of action, and therapeutic potential
DOI:
https://doi.org/10.14748/j1prds45Keywords:
anti-tumor, anti-viral, anti-inflammatory, anti-microbial activity, betulinic acidAbstract
Introduction: Betulinic acid is a natural pentacyclic triterpenoid found in various plants, including birch, eucalyptus, plane trees, and valerian species. It possesses diverse pharmacological activities such as anti-inflammatory, antiviral, antimicrobial, and antitumor effects. However, its clinical application is limited due to low concentration in natural sources, poor water solubility, and low bioavailability.
Aim: This study aims to evaluate the pharmacological potential of betulinic acid, focusing on its biological activities and underlying mechanisms of action.
Materials and Methods: A literature review was conducted using peer-reviewed articles from databases such as PubMed, ScienceDirect, and Google Scholar. Keywords included “betulinic acid,” “anti-inflammatory,” “antiviral,” “antitumor,” and “antimicrobial activity”. Relevant in vitro and in vivo studies were analyzed and synthesized.
Results and Conclusion: Betulinic acid demonstrates significant pharmacological activity. Its anti-inflammatory effects are mediated through the modulation of cytokines and inhibition of nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Antiviral activity has been observed against dengue virus, hepatitis B and C, and HIV-1 by inhibiting viral replication and protein expression. In cancer models, betulinic acid induces apoptosis, inhibits proliferation, and suppresses metastasis through pathways such as phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) and cyclooxygenase-2 (COX-2), as well as the regulation of non-coding RNAs. Additionally, it exhibits antimicrobial effects by disrupting bacterial membranes and preventing biofilm formation, particularly in Staphylococcus aureus. Despite these promising findings, limitations in solubility and bioavailability hinder its clinical use. Further research is needed to improve its delivery and large-scale production, supporting its development as a multifunctional therapeutic agent.
References
[1] Lou H, Li H, Zhang S, et al. A Review on Preparation of Betulinic Acid and Its Biological Activities. Molecules. 2021;26(18):5583. doi: 10.3390/molecules26185583. DOI: https://doi.org/10.3390/molecules26185583
[2] Banerjee S, Banerjee S, Bishayee A, et al. Cellular and molecular mechanisms underlying the potential of betulinic acid in cancer prevention and treatment. Phytomedicine. 2024;132:155858. doi: 10.1016/j.phymed.2024.155858. DOI: https://doi.org/10.1016/j.phymed.2024.155858
[3] Cunha AB, Batista R, Castro MÁ, et al. Chemical Strategies towards the Synthesis of Betulinic Acid and Its More Potent Antiprotozoal Analogues. Molecules. 2021;26(4):1081. doi: 10.3390/molecules26041081. DOI: https://doi.org/10.3390/molecules26041081
[4] Loshali A, Rahman Z, Saifi S, et al. An overview of betulin: botanical source, derivatives and biological potential: Mini Review. J Exp Bio Ag Sci. 2025;13(1):11–28. doi: 10.18006/2025.13(1).11.28. DOI: https://doi.org/10.18006/2025.13(1).11.28
[5] Huang C, Ou Z, Kong L, et al. Betulinic acid attenuates T-2 toxin-induced lung injury by activating Nrf2 signaling pathway and inhibiting MAPK/NF-κB signaling pathway. Toxicon. 2024;241:107652. doi: 10.1016/j.toxicon.2024.107652. DOI: https://doi.org/10.1016/j.toxicon.2024.107652
[6] Azevedo L, Ferraz R, Vieira M, et al. Betulinic acid and obesity-related disorders. Front Pharmacol. 2025;16:1674713. doi: 10.3389/fphar.2025.1674713. DOI: https://doi.org/10.3389/fphar.2025.1674713
[7] Wang K, Shang J, Tao C, et al. Advancements in Betulinic Acid-Loaded Nanoformulations for Enhanced Anti-Tumor Therapy. Int J Nanomedicine. 2024;19:14075–103. doi: 10.2147/IJN.S493489. DOI: https://doi.org/10.2147/IJN.S493489
[8] Szlasa W, Slusarczyk S, Nawrot-Hadzik I, et al. Betulin and Its Derivatives Reduce Inflammation and COX-2 Activity in Macrophages. Inflammation. 2022;46. doi: 10.1007/s10753-022-01756-4. DOI: https://doi.org/10.21203/rs.3.rs-1998720/v1
[9] Dai L, Li D, Cheng J, et al. Water soluble multiarm-polyethylene glycol–betulinic acid prodrugs: design, synthesis, and in vivo effectiveness. Polym Chem. 2014. doi: 10.1039/C4PY00648H.
[10] Chavda VP, Feehan J, Apostolopoulos V. Inflammation: The Cause of All Diseases. Cells. 2024;13(22):1906. doi: 10.3390/cells13221906. DOI: https://doi.org/10.3390/cells13221906
[11] Oliveira-Costa JF, Meira CS, Neves MVG das, et al. Anti-Inflammatory Activities of Betulinic Acid: A Review. Front Pharmacol. 2022;13. doi: 10.3389/fphar.2022.883857. DOI: https://doi.org/10.3389/fphar.2022.883857
[12] Zhou Z, Choi JW, Shin JY, et al. Betulinic Acid Ameliorates the Severity of Acute Pancreatitis via Inhibition of the NF-κB Signaling Pathway in Mice. Int J Mol Sci. 2021;22(13):6871. doi: 10.3390/ijms22136871. DOI: https://doi.org/10.3390/ijms22136871
[13] Chauhan N, Gaur KK, Asuru TR, et al. Dengue virus: pathogenesis and potential for small molecule inhibitors. Biosci Rep. 2024;44(8):BSR20240134. doi: 10.1042/BSR20240134. DOI: https://doi.org/10.1042/BSR20240134
[14] Loe MWC, Hao E, Chen M, et al. Betulinic acid exhibits antiviral effects against dengue virus infection. Antiviral Research. 2020;184:104954. doi: 10.1016/j.antiviral.2020.104954. DOI: https://doi.org/10.1016/j.antiviral.2020.104954
[15] Liu Y, Yang L, Wang H, et al. Recent Advances in Antiviral Activities of Triterpenoids. Pharmaceuticals (Basel). 2022;15(10):1169. doi: 10.3390/ph15101169. DOI: https://doi.org/10.3390/ph15101169
[16] Tripathi N, Mousa OY. Hepatitis B. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 [cited 2026 Jun 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK555945/
[17] ResearchGate [Internet]. [cited 2026 Jun 16]. (PDF) Hepatitis - StatPearls - NCBI Bookshelf. Available from: https://www.researchgate.net/publication/347581660_Hepatitis_-_StatPearls_-_NCBI_Bookshelf
[18] Yao D, Li H, Gou Y, et al. Betulinic acid-mediated inhibitory effect on hepatitis B virus by suppression of manganese superoxide dismutase expression. FEBS J. 2009;276(9):2599–614. doi: 10.1111/j.1742-4658.2009.06988.x. DOI: https://doi.org/10.1111/j.1742-4658.2009.06988.x
[19] Naseer F. Hepatitis B Treatment in Light of Natural Sources. ARGH. 2019;13(1). doi: 10.19080/ARGH.2019.13.555852. DOI: https://doi.org/10.19080/ARGH.2019.13.555852
[20] Wu YH. Naturally derived anti-hepatitis B virus agents and their mechanism of action. World J Gastroenterol. 2016;22(1):188–204. doi: 10.3748/wjg.v22.i1.188. DOI: https://doi.org/10.3748/wjg.v22.i1.188
[21] Martinello M, Solomon SS, Terrault NA, et al. Hepatitis C. Lancet. 2023;402(10407):1085–96. doi: 10.1016/S0140-6736(23)01320-X. DOI: https://doi.org/10.1016/S0140-6736(23)01320-X
[22] Lin CK, Tseng CK, Chen KH, et al. Betulinic acid exerts anti-hepatitis C virus activity via the suppression of NF-κB- and MAPK-ERK1/2-mediated COX-2 expression. Br J Pharmacol. 2015;172(18):4481–92. doi: 10.1111/bph.13233. DOI: https://doi.org/10.1111/bph.13233
[23] Magomere E, Olwal CO, Tetteh BE, et al. The Confluence of HIV-1 and HIV-2: Implications for Disease Progression and Insights for Therapy. Int J Microbiol. 2025;2025:3145677. doi: 10.1155/ijm/3145677. DOI: https://doi.org/10.1155/ijm/3145677
[24] Williams A, Menon S, Crowe M, et al. Geographic and Population Distributions of Human Immunodeficiency Virus (HIV)–1 and HIV-2 Circulating Subtypes: A Systematic Literature Review and Meta-analysis (2010–2021). J Infect Dis. 2023;228(11):1583–91. doi: 10.1093/infdis/jiad327. DOI: https://doi.org/10.1093/infdis/jiad327
[25] Huang QX, Chen HF, Luo XR, et al. Structure and Anti-HIV Activity of Betulinic Acid Analogues. Curr Med Sci. 2018;38(3):387–97. doi: 10.1007/s11596-018-1891-4. DOI: https://doi.org/10.1007/s11596-018-1891-4
[26] Dang Z, Lai W, Qian K, et al. Betulinic Acid Derivatives as Human Immunodeficiency Virus Type 2 (HIV-2) Inhibitors. J Med Chem. 2009;52(23):7887–91. doi: 10.1021/jm9004253. DOI: https://doi.org/10.1021/jm9004253
[27] Agrawal N, Lanjhiyana SK, Jaiswal M, et al. Colorectal cancer spectrum: From subtypes and epidemiology to oncotherapies. Gastroenterol Endosc. 2025;3(2):55–64. doi: 10.1016/j.gande.2025.01.002. DOI: https://doi.org/10.1016/j.gande.2025.01.002
[28] Jiang W, Li X, Dong S, et al. Betulinic acid in the treatment of tumour diseases: Application and research progress. Biomedicine & Pharmacotherapy. 2021;142:111990. doi: 10.1016/j.biopha.2021.111990. DOI: https://doi.org/10.1016/j.biopha.2021.111990
[29] Wang S, Wang K, Zhang C, et al. Overaccumulation of p53-mediated autophagy protects against betulinic acid-induced apoptotic cell death in colorectal cancer cells. Cell Death Dis. 2017;8(10):e3087. doi: 10.1038/cddis.2017.485. DOI: https://doi.org/10.1038/cddis.2017.485
[30] Menon G, Alkabban FM, Ferguson T. Breast Cancer. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 [cited 2026 Jun 16]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK482286/
[31] Zheng Y, Liu P, Wang N, et al. Betulinic Acid Suppresses Breast Cancer Metastasis by Targeting GRP78-Mediated Glycolysis and ER Stress Apoptotic Pathway. Oxid Med Cell Longev. 2019;2019:8781690. doi: 10.1155/2019/8781690. DOI: https://doi.org/10.1155/2019/8781690
[32] Mahmoud MA, Abdo H, Mekky M, et al. Betulinic acid is associated with miR-21 modulation, apoptosis and redox changes in breast cancer cells: an in vitro and in silico study. Sci Rep. 2026;16:15225. doi: 10.1038/s41598-026-51156-z. DOI: https://doi.org/10.1038/s41598-026-51156-z
[33] Amin N, Anwar J, Sulaiman A, et al. Hepatocellular Carcinoma: A Comprehensive Review. Diseases. 2025;13(7):207. doi: 10.3390/diseases13070207. DOI: https://doi.org/10.3390/diseases13070207
[34] Chen F, Zhong Z, Tan HY, et al. Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p. Clin Transl Med. 2020;10(6):e190. doi: 10.1002/ctm2.190. DOI: https://doi.org/10.1002/ctm2.190
[35] Naganuma H, Ishida H, Matsumoto N, et al. Multiple Primary Malignancy-Related Gallbladder Cancer: An Important Recommendation for the Early Detection of Gallbladder Cancer. Diagnostics. 2026;16(4):605. doi: 10.3390/diagnostics16040605. DOI: https://doi.org/10.3390/diagnostics16040605
[36] Wang H, Dong F, Wang Y, et al. Betulinic acid induces apoptosis of gallbladder cancer cells via repressing SCD1. ABBS. 2020;52(2):200–6. doi: 10.1093/abbs/gmz148. DOI: https://doi.org/10.1093/abbs/gmz148
[37] Sekhoacha M, Riet K, Motloung P, et al. Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches. Molecules. 2022;27(17):5730. doi: 10.3390/molecules27175730. DOI: https://doi.org/10.3390/molecules27175730
[38] Liu S, Li X, Cheng Z, et al. Betulinic acid induces lysosome-dependent death in prostate cancer by targeting DDX5. Phytomedicine. 2026;155:158143. doi: 10.1016/j.phymed.2026.158143. DOI: https://doi.org/10.1016/j.phymed.2026.158143
[39] Linehan WM, Schmidt LS, Crooks DR, et al. The Metabolic Basis of Kidney Cancer. Cancer Discov. 2019;9(8):1006–21. doi:10.1158/2159-8290.CD-18-1354 DOI: https://doi.org/10.1158/2159-8290.CD-18-1354
[40] Ataş MN, Ertuğrul B, İplik ES, et al. Effects of betulinic acid on AKT/mTOR pathway in renal cell carcinoma. Turk J Urol. 2022;48(1):58–63. doi: 10.5152/tud.2022.21276. DOI: https://doi.org/10.5152/tud.2022.21276
[41] Lazar AM, Costea DO, Popp CG, et al. Skin Malignant Melanoma and Matrix Metalloproteinases: Promising Links to Efficient Therapies. Int J Mol Sci. 2024;25(14):7804. doi: 10.3390/ijms25147804. DOI: https://doi.org/10.3390/ijms25147804
[42] Zhang Y, Yuan M, Xu Q, et al. Betulinic Acid and Betulin Suppress Melanoma Growth by Modulating Apoptosis and Autophagy via PI3K/AKT/mTOR and MAPK Pathways. Int J Mol Sci. 2026;27(2):576. doi: 10.3390/ijms27020576. DOI: https://doi.org/10.3390/ijms27020576
[43] Bashabsheh RHF, AL-Fawares O, Natsheh I, et al. Staphylococcus aureus epidemiology, pathophysiology, clinical manifestations and application of nano-therapeutics as a promising approach to combat methicillin resistant Staphylococcus aureus. Pathog Glob Health. 118(3):209–31. doi: 10.1080/20477724.2023.2285187. DOI: https://doi.org/10.1080/20477724.2023.2285187
[44] Guo D, Tao Y, Sun L, et al. Betulinic Acid Eradicates Implant‐Associated Infections by Disrupting the S. aureus Biofilm Matrix and Potentiating Host Immune Clearance. Microb Biotechnol. 2025;19(1):e70293. doi: 10.1111/1751-7915.70293. DOI: https://doi.org/10.1111/1751-7915.70293
[45] Lao XY, Sun YL, Zhao ZJ, et al. Pharmacological effects of betulinic acid and its protective mechanisms on the cardiovascular system. Fitoterapia. 2025;183:106561. doi: 10.1016/j.fitote.2025.106561. DOI: https://doi.org/10.1016/j.fitote.2025.106561
[46] Selepe CT, Dhlamini KS, Tshweu L, et al. Advances and challenges in betulinic acid therapeutics and delivery systems for breast cancer prevention and treatment. RSC Adv. 2025;15(42):34874–901. doi: 10.1039/D5RA03190G. DOI: https://doi.org/10.1039/D5RA03190G
[47] Dai L, Li D, Cheng J, et al. Water soluble multiarm-polyethylene glycol–betulinic acid prodrugs: design, synthesis, and in vivo effectiveness. Polym Chem. 2014;5(19):5775–83. doi: 10.1039/C4PY00648H. DOI: https://doi.org/10.1039/C4PY00648H
[48] Wróblewska-Łuczka P, Cabaj J, Bąk W, et al. Additive Interactions between Betulinic Acid and Two Taxanes in In Vitro Tests against Four Human Malignant Melanoma Cell Lines. Int J Mol Sci. 2022;23(17):9641. doi: 10.3390/ijms23179641. DOI: https://doi.org/10.3390/ijms23179641
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Data Availability Statement
- The authors confirm that the data supporting the findings of this study are available within the article.
