Multi-Scale Mechanisms of Phaleria macrocarpa in Liver Fibrosis: From Hepatic Stellate Cell Reprogramming to Systems Pharmacology Insights
DOI:
https://doi.org/10.56951/4bxae078Kata Kunci:
Phaleria macrocarpa, fibrosis hati, hepatic stellate cells, farmakologi system, produk alamiAbstrak
Fibrosis hati merupakan proses patologis sentral yang menjembatani cedera hati kronis menuju sirosis dan karsinoma hepatoseluler, namun terapi efektif lintas etiologi masih terbatas. Phaleria macrocarpa (mahkota dewa), tanaman obat tradisional Indonesia, muncul sebagai kandidat potensial karena keragaman fitokimia dan efek polifarmakologinya. Tinjauan ini bertujuan mengintegrasikan bukti terkini pada tingkat molekuler, seluler, dan sistem untuk menjelaskan potensi antifibrotik P. macrocarpa, dengan fokus khusus pada biologi sel stelata hepatic (hepatic stellate cells/HSC). Studi ini menyintesis temuan dari profil fitokimia, model fibrosis in vivo, observasi klinis awal, dan pendekatan farmakologi sistemik terkini, termasuk data fraksi terstandardisasi seperti Proliverenol. Bukti yang tersedia menunjukkan bahwa P. macrocarpa mampu menekan pendorong utama fibrosis, termasuk stres oksidatif, sinyal inflamasi (misalnya NF-κB/TNF-α), dan mediator profibrogenik seperti TGF-β1, sehingga mengurangi derajat fibrosis pada model eksperimental. Pada tingkat senyawa, komponen seperti gallic acid dan mangiferin memberikan bukti awal terhadap modulasi langsung aktivasi HSC dan jalur fibrogenesis. Namun demikian, kesenjangan mekanistik utama masih terdapat pada terbatasnya bukti mengenai kemampuan P. macrocarpa dalam mereprogram HSC menuju keadaan quiescent, apoptosis, atau senescence. Analisis farmakologi jaringan terbaru menyoroti target regulator utama seperti RELA, PTGS2, SIRT1, dan GSK3B yang menunjukkan mekanisme multitarget pada jalur inflamasi, metabolik, dan kelangsungan hidup sel. Tinjauan ini mengusulkan kerangka multiskala yang menempatkan P. macrocarpa sebagai kandidat antifibrotik berbasis farmakologi sistem serta menekankan perlunya penelitian lanjutan yang berfokus pada fenotipe spesifik HSC, integrasi pendekatan single-cell omics, dan validasi translasi klinis. Untuk mengembangkan tanaman ini dari sekadar agen hepatoprotektif menjadi terapi yang berfokus pada fibrosis, diperlukan penyelidikan mekanistik langsung terhadap transisi keadaan sel stelata serta evaluasi klinis yang ketat.
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1. Duo H, You J, Du S, Yu M, Wu S, Yue P, et al. Liver cirrhosis in 2021: Global burden of disease study. PLoS One. 2025;20(7):e0328493. doi:10.1371/journal.pone.0328493.
2. Li Q, Ding C, Cao M, Yang F, Yan X, He S, et al. Global epidemiology of liver cancer 2022: an emphasis on geographic disparities. Chin Med J (Engl). 2024;137(19):2334–42. doi:10.1097/CM9.0000000000003264.
3. Tham EKJ, Tan DJH, Danpanichkul P, Ng CH, Syn N, Koh B, et al. The Global burden of cirrhosis and other chronic liver diseases in 2021. Liver Int. 2025;45(3):e70001. doi:10.1111/liv.70001.
4. FDA approves first treatment for patients with liver scarring due to fatty liver disease. U.S. Food and Drug Administration. FDA. 2024 [cited 2026 Apr 24]. Available from: https://www.fda.gov/news-events/pressannouncements/
fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease.
5. FDA approves treatment for serious liver disease Known as ‘MASH’. U.S. Food & Drug Administration. 2025 [cited 2026 Jun 8]. Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approvestreatment-serious-liver-disease-known-mash
6. Sundari N, Soetikno V, Louisa M, Wardhani BW, Tjandrawinata RR. Protective effect of Phaleria macrocarpa water extract (Proliverenol) against carbon tetrachloride-induced liver fibrosis in rats: role of TNF-α and TGF-β1. J Toxicol. 2018;2018:2642714. doi:10.1155/2018/2642714.
7. Andriani Y, Tengku-Muhammad TS, Mohamad H, Saidin J, Syamsumir DF, Chew GS, et al. Phaleria macrocarpa Boerl. (Thymelaeaceae) leaves increase SR-BI expression and reduce cholesterol levels in rats fed a high cholesterol diet. Molecules. 2015;20(3):4410–29. doi:10.3390/molecules20034410.
8. Nurkolis F, Dama A, Gorica E, Santini A, Tjandrawinata RR. Phytochemical profiling and pharmacoinformatics reveal Proliverenol from Phaleria macrocarpa as a multi-target hepatoprotective modulator of MAFLD. Pharmaceuticals (Basel). 2026;19(3):491. doi:10.3390/ph19030491.
9. Oshimi S, Zaima K, Matsuno Y, Hirasawa Y, Iizuka T, Studiawan H, et al. Studies on the constituents from the fruits of Phaleria macrocarpa. J Nat Med. 2008;62(2):207–10. doi:10.1007/s11418-007-0209-9.
10. Lay MM, Karsani SA, Mohajer S, Abd Malek SN. Phytochemical constituents, nutritional values, phenolics, flavonols, flavonoids, antioxidant and cytotoxicity studies on Phaleria macrocarpa (Scheff.) Boerl fruits. BMC Complement Altern Med. 2014;14:152. doi:10.1186/1472-6882-14-152.
11. El-Lakkany NM, El-Maadawy WH, Seif El-Din SH, Saleh S, Safar MM, Ezzat SM, et al. Antifibrotic effects of gallic acid on hepatic stellate cells: In vitro and in vivo mechanistic study. J Tradit Complement Med. 2018;9(1):45-53. doi:10.1016/j.jtcme.2018.01.010.
12. Li L, Dong Y, Liu X, Wang M. Mangiferin for the management of liver diseases: a review. Foods. 2023;12(13):2469. doi:10.3390/foods12132469.
13. Zhang SY, Zhang QH, Zhao W, Zhang X, Zhang Q, Bi YF, et al. Isolation, characterization and cytotoxic activity of benzophenone glucopyranosides from Mahkota Dewa (Phaleria macrocarpa (Scheff.) Boerl). Bioorg Med Chem Lett. 2012;22(22):6862–6. doi:10.1016/j.bmcl.2012.09.038.
14. Saufi A, von Heimendahl CBI, Alfermann AW, Fuss E. Stereochemistry of lignans in Phaleria macrocarpa (Scheff.) Boerl. Z Naturforsch C. 2008;63(1–2):13–6. doi:10.1515/znc-2008-1-203.
15. Szabo G, Petrasek J. Gut-liver axis and sterile signals in the development of alcoholic liver disease. Alcohol Alcohol. 2017;52(4):414–24. doi:10.1093/alcalc/agx025.
16. Wobser H, Dorn C, Weiss TS, Amann T, Bollheimer C, Büttner R, et al. Lipid accumulation in hepatocytes induces fibrogenic activation of hepatic stellate cells. Cell Res. 2009;19(8):996–1005. doi:10.1038/cr.2009.73.
17. Schoemaker MH, Rots MG, Beljaars L, Ypma AY, Jansen PLM, Poelstra K, et al. PDGF-receptor betatargeted adenovirus redirects gene transfer from hepatocytes to activated stellate cells. Mol Pharm. 2008;5(3):399–406. doi:10.1021/mp700118p.
18. Dewidar B, Meyer C, Dooley S, Meindl-Beinker AN. TGF-β in hepatic stellate cell activation and liver fibrogenesis-updated 2019. Cells. 2019;8(11):1419. doi:10.3390/cells8111419.
19. Dooley S, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, et al. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology. 2003;125(1):178–91. doi:10.1016/s0016-5085(03)00666-8.
20. Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2011;8(2):108–18. doi:10.1038/nrgastro.2010.213.
21. Wang F, Chen L, Kong D, Zhang X, Xia S, Liang B, et al. Canonical Wnt signaling promotes HSC glycolysis and liver fibrosis through an LDH-A/HIF-1α transcriptional complex. Hepatology. 2024;79(3):606–23. doi:10.1097/HEP.0000000000000569.
22. Mejias M, Gallego J, Naranjo-Suarez S, Ramirez M, Pell N, Manzano A, et al. CPEB4 increases expression of PFKFB3 to induce glycolysis and activate mouse and human hepatic stellate cells, promoting liver fibrosis. Gastroenterology. 2020;159(1):273–88. doi:10.1053/j.gastro.2020.03.008.
23. Robert S, Gicquel T, Bodin A, Lagente V, Boichot E. Characterization of the MMP/TIMP imbalance and collagen production induced by IL-1β or TNF-α release from human hepatic stellate cells. PLoS One. 2016;11(4):e0153118. doi:10.1371/journal.pone.0153118
24. Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non-parenchymal cells of rat liver: regulation by TNF-alpha and TGFbeta1. J Hepatol. 1999;30(1):48–60. doi:10.1016/s0168-8278(99)80007-5.
25. Berlian G, Tandrasasmita OM, Tjandrawinata RR. Standardized bioactive fraction of Phaleria macrocarpa (Proliverenol) prevents ethanol-induced hepatotoxicity via down-regulation of NF-κB-TNFα-caspase-8 pathway. Asian Pac J Trop Biomed. 2016;6(8):686–91. doi:10.1016/j.apjtb.2016.06.007.
26. Wardhani BWK, Sundari N, Tjandrawinata RR, Jusuf AA, Soetikno V, Louisa M. Antifibrotic activity of Phaleria macrocarpa extract in rat liver-fibrosis model: focus on oxidative stress markers, TGF-β1 and MMP-13. Open Access Maced J Med Sci. 2020;8(A):555–62. doi:10.3889/oamjms.2020.4929.
27. Hasan I, Nababan SHH, Tjandrawinata RR, Yunaidi DA, Susanto LW. The effect of Phaleria macrocarpa bioactive fraction (Proliverenol) supplementation on liver damage in patients with non-alcoholic fatty liver disease (NAFLD). MEDICINUS. 2025;38(7):7–20. doi:10.56951/a4ba3z37.
28. Yu J, Zhang S, Chu ESH, Go MYY, Lau RHY, Zhao J, et al. Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro. Int J Biochem Cell Biol. 2010;42(6):948–57. doi:10.1016/j.biocel.2010.02.006.
29. Xie J, Su S, Wu J, Yang X, Zhang Q, Shen X, et al. Unlocking mangiferin: a therapeutic candidate revolutionizing liver disease therapy. Nutrients. 2025;17(21):3401. doi:10.3390/nu17213401.
30. Shang Y, Tian J, Zhang Z, Luo L, Saeheng S, Qiu S, et al. Mangiferin: Sources, anti-inflammatory activities, and molecular mechanisms. J Agric Food Chem. 2025;73(43):27145–60. doi:10.1021/acs.jafc.5c06234.
31. Ciceu A, Fenyvesi F, Hermenean A, Ardelean S, Dumitra S, Puticiu M. Advancements in plant-based therapeutics for hepatic fibrosis: molecular mechanisms and nanoparticulate drug delivery systems. Int J Mol Sci. 2024;25(17):9346. doi:10.3390/ijms25179346.
32. Kashyap R. Herbal isolates and their role in the treatment of liver fibrosis: an updated review. International Journal of Medical, Pharmaceutical and Health Sciences. 2025;2(4):435–46. doi:10.62946/ijmphs/2.4.435-446.
33. Kim HY, Rosenthal SB, Liu X, Miciano C, Hou X, Miller M, et al. Multi-modal analysis of human hepatic stellate cells identifies novel therapeutic targets for metabolic dysfunction-associated steatotic liver disease. J Hepatol. 2025;82(5):882–97. doi:10.1016/j.jhep.2024.10.044.
34. Sharma P, Asediya V, Kalra G, Sultana S, Purohit N, Kibitlewska K, et al. Hepatoprotective effect of silymarin herb in prevention of liver dysfunction using pig as animal model. Nutrients. 2025;17(20):3278. doi:10.3390/nu17203278.
35. Qin L, Qin J, Zhen X, Yang Q, Huang L. Curcumin protects against hepatic stellate cells activation and migration by inhibiting the CXCL12/CXCR4 biological axis in liver fibrosis: a study in vitro and in vivo. Biomed Pharmacother. 2018;101:599–607. doi:10.1016/j.biopha.2018.02.091.
36. Clichici S, Olteanu D, Nagy AL, Oros A, Filip A, Mircea PA. Silymarin inhibits the progression of fibrosis in the early stages of liver injury in CCl₄-treated rats. J Med Food. 2015;18(3):290–8. doi:10.1089/jmf.2013.0179.
37. Rachmawati H, Novel MA, Nisa RM, Berlian G, Tandrasasmita OM, Rahma A, et al. Co-delivery of curcumin-loaded nanoemulsion and Phaleria macrocarpa extract to NIH 3T3 cell for antifibrosis. J Drug Deliv Sci Technol. 2017;39:123–30. doi:10.1016/j.jddst.2017.03.015.
38. Chen P, Zou F, Liu W. Recent advancement in prevention against hepatotoxicity, molecular mechanisms, and bioavailability of gallic acid, a natural phenolic compound: challenges and perspectives. Front Pharmacol. 2025;16:1549526. doi:10.3389/fphar.2025.1549526.
39. Shaikenov RO, Klimshina VI, Morozkina SN, Snetkov PP. Polymeric matrices for mangiferin delivery: ways to enhance bioavailability and therapeutic effect. In: The 5th International Electronic Conference on Applied Sciences. Basel Switzerland: MDPI; 2025. p. 78. doi:10.3390/engproc2025087078.
40. Hou S, Wang F, Li Y, Li Y, Wang M, Sun D, et al. Pharmacokinetic study of mangiferin in human plasma after oral administration. Food Chem. 2012;132(1):289–94. doi:10.1016/j.foodchem.2011.10.079.
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