سامانه مدیریت نشریات علمی دانشگاه علوم پزشکی مشهد

Naraki, Gol Afrouz, Fazeli Kakhki, Homa, Qoorchi Moheb Seraj, Farid, Naraki, Karim, Ghasemzadeh Rahbardar, Mahboobeh. (1404). Effect of Crocus sativus L. (saffron) and Rosmarinus officinalis L. (rosemary) in hepatocellular carcinoma: A narrative review of current evidence and prospects. , 28(8), 986-1003. doi: 10.22038/ijbms.2025.84172.18204
Gol Afrouz Naraki; Homa Fazeli Kakhki; Farid Qoorchi Moheb Seraj; Karim Naraki; Mahboobeh Ghasemzadeh Rahbardar. "Effect of Crocus sativus L. (saffron) and Rosmarinus officinalis L. (rosemary) in hepatocellular carcinoma: A narrative review of current evidence and prospects". , 28, 8, 1404, 986-1003. doi: 10.22038/ijbms.2025.84172.18204
Naraki, Gol Afrouz, Fazeli Kakhki, Homa, Qoorchi Moheb Seraj, Farid, Naraki, Karim, Ghasemzadeh Rahbardar, Mahboobeh. (1404). 'Effect of Crocus sativus L. (saffron) and Rosmarinus officinalis L. (rosemary) in hepatocellular carcinoma: A narrative review of current evidence and prospects', , 28(8), pp. 986-1003. doi: 10.22038/ijbms.2025.84172.18204
Naraki, Gol Afrouz, Fazeli Kakhki, Homa, Qoorchi Moheb Seraj, Farid, Naraki, Karim, Ghasemzadeh Rahbardar, Mahboobeh. Effect of Crocus sativus L. (saffron) and Rosmarinus officinalis L. (rosemary) in hepatocellular carcinoma: A narrative review of current evidence and prospects. , 1404; 28(8): 986-1003. doi: 10.22038/ijbms.2025.84172.18204

Effect of Crocus sativus L. (saffron) and Rosmarinus officinalis L. (rosemary) in hepatocellular carcinoma: A narrative review of current evidence and prospects

Iranian Journal of Basic Medical Sciences
مقاله 2، دوره 28، شماره 8، آبان 2025، صفحه 986-1003    اصل مقاله (646.51 K)
نوع مقاله: Review Article
شناسه دیجیتال (DOI): 10.22038/ijbms.2025.84172.18204
نویسندگان
Gol Afrouz Naraki1؛ Homa Fazeli Kakhki2؛ Farid Qoorchi Moheb Seraj3؛ Karim Naraki2؛ Mahboobeh Ghasemzadeh Rahbardar* 4
1Department of Orthotics and Prosthetics, School of Rehabilitation Science, Shiraz University of Medical Sciences, Shiraz, Iran
2Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
3Endovascular Section, Neurosurgical Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
4Clinical Research Development Unit, Shahid Hasheminejad Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
چکیده
Hepatocellular carcinoma (HCC) is a considerable worldwide health concern that requires novel therapeutic approaches. Herbal therapy, with its rich historical origins and diverse pharmacological properties, provoked interest in its possible involvement in HCC treatment. Crocus sativus L. (saffron) and Rosmarinus officinalis L. (rosemary) are two frequently employed herbs in traditional Persian medicine for hepatoprotective properties. As a result, this review article aims to investigate the present landscape of therapies using saffron and rosemary, as well as their main components in the management of HCC. A thorough search was undertaken on Google Scholar, PubMed, and Web of Science for in vivo and in vitro studies on the effects of these two herbs on HCC. No time limitations were imposed, with the search extending until December 2024. Saffron and rosemary have shown promising anticancer activities against HCC through several mechanisms for instance, increasing apoptosis, adenosine monophosphate-activated protein kinase (AMPK) activation, decreasing colony formation, nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, reducing the activity of Janus kinases (JAK)1, JAK2, protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, as well as lowering vascular endothelial growth factor (VEGF) amounts in preclinical fields. While research into saffron, rosemary, and their main components in controlling HCC shows promise, it is critical to note that the belief that herbal therapy is always safe can be misleading. Caution is recommended while evaluating these approaches, as their effects and interactions with standard treatments may differ. More thorough clinical studies are needed to evaluate the safety and efficacy profiles of these herbal medicines in HCC thoroughly. 
کلیدواژه‌ها
Apoptosis؛ Carcinogenesis؛ Carnosol؛ Cell proliferation؛ Crocin؛ Liver neoplasms؛ Phytotherapy؛ Rosmarinic acid؛ Safranal
مراجع
1. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2016; 2:16018-16070.
2. Villanueva A. Hepatocellular carcinoma. N Engl J Med 2019; 380:1450-1462.
3. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Primers 2021; 7:6.
4. Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, et al. The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: Results from the global burden of disease study 2015. JAMA Oncol 2017; 3:1683-1691.
5. Kanwal F, Kramer J, Asch SM, Chayanupatkul M, Cao Y, El-Serag HB. Risk of hepatocellular cancer in HCV patients treated with direct-acting antiviral agents. Gastroenterology 2017; 153:996-1005.e1001.
6. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology 2018; 67:123-133.
7. Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet 2015; 47:505-511.
8. Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, et al. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol 2019; 25:2279-2293.
9. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68:7-30.
10. Dimitroulis D, Damaskos C, Valsami S, Davakis S, Garmpis N, Spartalis E, et al. From diagnosis to treatment of hepatocellular carcinoma: An epidemic problem for both developed and developing world. World J Gastroenterol 2017; 23:5282-5294.
11. Daher S, Massarwa M, Benson AA, Khoury T. Current and future treatment of hepatocellular carcinoma: An updated comprehensive review. J Clin Transl Hepatol 2018; 6:69-78.
12. Golabi P, Fazel S, Otgonsuren M, Sayiner M, Locklear CT, Younossi ZM. Mortality assessment of patients with hepatocellular carcinoma according to underlying disease and treatment modalities. Medicine 2017; 96:e5904.
13. Ikeda M, Morizane C, Ueno M, Okusaka T, Ishii H, Furuse J. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Jpn J Clin Oncol 2018; 48:103-114.
14. Keating GM. Sorafenib: A review in hepatocellular carcinoma. Target Oncol 2017; 12:243-253.
15. Personeni N, Pressiani T, Santoro A, Rimassa L. Regorafenib in hepatocellular carcinoma: Latest evidence and clinical implications. Drugs Context 2018; 7:212533.
16. Spallanzani A, Orsi G, Andrikou K, Gelsomino F, Rimini M, Riggi L, et al. Lenvatinib as a therapy for unresectable hepatocellular carcinoma. Expert Rev Anticancer Ther 2018; 18:1069-1076.
17. Hosseini M, Pkan P, Rakhshandeh H, Aghaie A, Sadeghnia HR, Rahbardar MG. The effect of hydro-alcoholic extract of citrus flower on pentylenetetrazole and maximal electroshock-induced seizures in mice. World Appl Sci J 2011; 15:1104-1109.
18. Jalali J, Ghasemzadeh Rahbardar M. Ameliorative effects of Portulaca oleracea L. (purslane) and its active constituents on nervous system disorders: A review. Iran J Basic Med Sci 2023; 26:2-12.
19. Sharma AN, Dewangan HK, Upadhyay PK. Comprehensive review on herbal medicine: emphasis on current therapy and role of phytoconstituents for cancer treatment. Chem Biodivers 2024; 21:e202301468.
20. Ali M, Wani SUD, Salahuddin M, Manjula S, Mruthunjaya K, Dey T, et al. Recent advance of herbal medicines in cancer-a molecular approach. Heliyon 2023; 9:e13684.
21. Park MN, Rahman MA, Rahman MH, Kim JW, Choi M, Kim JW, et al. Potential therapeutic implication of herbal medicine in mitochondria-mediated oxidative stress-related liver diseases. Antioxidants 2022; 11:2041-2065.
22. Fadishei M, Ghasemzadeh Rahbardar M, Imenshahidi M, Mohajeri A, Razavi BM, Hosseinzadeh H. Effects of Nigella sativa oil and thymoquinone against bisphenol A-induced metabolic disorder in rats. Phytother Res 2021; 35:2005-2024.
23. Emadi SA, Ghasemzadeh Rahbardar M, Mehri S, Hosseinzadeh H. A review of therapeutic potentials of milk thistle (Silybum marianum L.) and its main constituent, silymarin, on cancer, and their related patents. Iran J Basic Med Sci 2022; 25:1166-1176.
24. Mohammadi Zonouz A, Ghasemzadeh Rahbardar M, Hosseinzadeh H. The molecular mechanisms of ginkgo (Ginkgo biloba) activity in signaling pathways: A comprehensive review. Phytomedicine 2024; 126:155352.
25. Ghasemzadeh Rahbardar M, Hosseinzadeh H. The ameliorative effect of turmeric (Curcuma longa Linn) extract and its major constituent, curcumin, and its analogs on ethanol toxicity. Phytother Res 2024; 38:2165-2181.
26. Ardakanian A, Ghasemzadeh Rahbardar M, Omidkhoda F, Razavi BM, Hosseinzadeh H. Effect of alpha-mangostin on olanzapine-induced metabolic disorders in rats. Iran J Basic Med Sci 2022; 25:198-207.
27. Salehsari A, Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Investigating the effect of zeaxanthin on olanzapine-induced metabolic disorders in rats. Avicenna J Phytomed 2024; 14:653-665.
28. Panneerselvam S, Wilson C, Kumar P, Abirami D, Pamarthi J, Reddy MS, et al. Overview of hepatocellular carcinoma: from molecular aspects to future therapeutic options. Cell Adh Migr 2023; 17:1-21.
29. Liao X, Bu Y, Jia Q. Traditional Chinese medicine as supportive care for the management of liver cancer: Past, present, and future. Genes Dis 2020; 7:370-379.
30. Li M, Liu Y, Zhang H, Liu Y, Wang W, You S, et al. Anti-cancer potential of polysaccharide extracted from Polygonatum sibiricum on HepG2 cells via cell cycle arrest and apoptosis. Front Nutr 2022; 9:938290.
31. Kaewnoonual N, Itharat A, Pongsawat S, Nilbu-Nga C, Kerdput V, Pradidarcheep W. Anti-angiogenic and anti-proliferative effects of Benja-ummarit extract in rats with hepatocellular carcinoma. Biomed Rep 2020; 12:109-120.
32.Sahu N, Rakshit S, Bhaskar LVKS. Chapter 3 - Risk factors and pathogenic mechanism–associated hepatocellular carcinoma. In: Nagaraju GP, Peela S, editors. Theranostics and Precision Medicine for the Management of Hepatocellular Carcinoma: Academic Press; 2022. p. 33-49.
33. Seung KY. Molecular mechanism of hepatocellular carcinoma. Hepatoma Res 2018; 4:42.
34. Li Y, Yu Y, Yang L, Wang R. Insights into the role of oxidative stress in hepatocellular carcinoma development. Front Biosci (Landmark Ed) 2023; 28:286.
35. Refolo MG, Messa C, Guerra V, Carr BI, D’Alessandro R. Inflammatory mechanisms of HCC development. Cancers 2020; 12:641-663.
36. Borgia M, Dal Bo M, Toffoli G. Role of virus-related chronic inflammation and mechanisms of cancer immune-suppression in pathogenesis and progression of hepatocellular carcinoma. Cancers 2021; 13:4387-4415.
37. Bishayee A. The role of inflammation and liver cancer. Adv Exp Med Biol 2014; 816:401-435.
38. Villanueva A, Luedde T. The transition from inflammation to cancer in the liver. Clin Liver Dis (Hoboken) 2016; 8:89-93.
39. Alqahtani A, Khan Z, Alloghbi A, S. Said Ahmed T, Ashraf M, M. Hammouda D. Hepatocellular carcinoma: Molecular mechanisms and targeted therapies. Medicina 2019; 55:526-547.
40. Ramakrishna G, Rastogi A, Trehanpati N, Sen B, Khosla R, Sarin SK. From cirrhosis to hepatocellular carcinoma: New molecular insights on inflammation and cellular senescence. Liver Cancer 2013; 2:367-383.
41. Luedde T, Schwabe RF. NF-κB in the liver--linking injury, fibrosis and hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2011; 8:108-118.
42. Soukupova J, Malfettone A, Hyroššová P, Hernández-Alvarez MI, Peñuelas-Haro I, Bertran E, et al. Role of the transforming growth factor-β in regulating hepatocellular carcinoma oxidative metabolism. Sci Rep 2017; 7:12486-12500.
43. Aravalli RN, Steer CJ, Cressman EN. Molecular mechanisms of hepatocellular carcinoma. Hepatology 2008; 48:2047-2063.
44. Waly Raphael S, Yangde Z, Yuxiang C. Hepatocellular carcinoma: Focus on different aspects of management. ISRN Oncol 2012; 2012:421673.
45. Chen C, Wang G. Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy. World J Hepatol 2015; 7:1964-1970.
46. Bertino G, Demma S, Ardiri A, Proiti M, Gruttadauria S, Toro A, et al. Hepatocellular carcinoma: Novel molecular targets in carcinogenesis for future therapies. Biomed Res Int 2014; 2014:203693.
47. Cha C, Dematteo RP. Molecular mechanisms in hepatocellular carcinoma development. Best Pract Res Clin Gastroenterol 2005; 19:25-37.
48. Kudo M. Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma. Dig Dis 2011; 29:289-302.
49. Roberts LR, Gores GJ. Hepatocellular carcinoma: Molecular pathways and new therapeutic targets. Semin Liver Dis 2005; 25:212-225.
50. Dawson SP. Hepatocellular carcinoma and the ubiquitin-proteasome system. Biochim Biophys Acta 2008; 1782:775-784.
51. Zolfaghari Farajerdi M, Rajabian F, Razavi BM, Ghasemzadeh Rahbardar M, Khajavi Rad A, Amoueian S, et al. Evaluating the effect of crocin on contrast-induced nephropathy in rats. Avicenna J Phytomed  2025; 15:920-932.
52. Javadi B, Sahebkar A, Emami SA. A survey on saffron in major islamic traditional medicine books. Iran J Basic Med Sci 2013; 16:1-11.
53. Jiang H, Huang X, Wang J, Zhou Y, Ren C, Zhou T, et al. Hepatoprotective effect of medicine food homology flower saffron against CCl(4)-induced liver fibrosis in mice via the Akt/HIF-1α/VEGF signaling pathway. Molecules 2023; 28:7238-7255.
54. Ghasemzadeh Rahbardar M, Hosseinzadeh H. A review of how the saffron (Crocus sativus) petal and its main constituents interact with the Nrf2 and NF-κB signaling pathways. Naunyn Schmiedebergs Arch Pharmacol 2023; 396:1879-1909.
55. Naraki K, Ghasemzadeh Rahbardar M, Razavi BM, Aminifar T, Khajavi Rad A, Amoueian S, et al. The power of trans-sodium crocetinate: exploring its renoprotective effects in a rat model of colistin-induced nephrotoxicity. Naunyn Schmiedebergs Arch Pharmacol 2024; 397:10155-10174.
56. Rajabian F, Mehri S, Razavi BM, Khajavirad A, Ghasemzadeh Rahbardar M, Hosseinzadeh H. Effect of trans-sodium crocetinate on contrast-induced cytotoxicity in HEK-293 cells. Iran J Basic Med Sci 2023; 26:148-156.
57. Vafaeipour Z, Ghasemzadeh Rahbardar M, Hosseinzadeh H. Effect of saffron, black seed, and their main constituents on inflammatory cytokine response (mainly TNF-α) and oxidative stress status: an aspect on pharmacological insights. Naunyn Schmiedebergs Arch Pharmacol 2023; 396:2241-2259.
58. Ghasemzadeh Rahbardar M, Ferns GA, Ghayour Mobarhan M. Assessing the efficacy of herbal supplements for managing obesity: A comprehensive review of global clinical trials. Iran J Basic Med Sci 2025; 28:691-709.
59. Aminifard T, Mehri S, Ghasemzadeh Rahbardar M, Rajabian F, Khajavi Rad A, Hosseinzadeh H. Trans-sodium crocetinate suppresses apoptotic and oxidative response following myoglobin-induced cytotoxicity in HEK-293 cells. Iran J Basic Med Sci 2024; 27:768-774.
60. Boskabady MH, Ghasemzadeh Rahbardar M, Nemati H, Esmaeilzadeh M. Inhibitory effect of Crocus sativus (saffron) on histamine (H1) receptors of guinea pig tracheal chains. Pharmazie 2010; 65:300-305.
61. Boskabady MH, Rahbardar MG, Jafari Z. The effect of safranal on histamine (H(1)) receptors of guinea pig tracheal chains. Fitoterapia 2011; 82:162-167.
62. Rajabalizadeh R, Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Renoprotective effects of crocin against colistin-induced nephrotoxicity in a rat model. Iran J Basic Med Sci 2024; 27:151-156.
63. Rajabian F, Razavi BM, Mehri S, Amouian S, Ghasemzadeh Rahbardar M, Khajavi Rad A, et al. Evaluation of pathways involved in the protective effect of trans sodium crocetinate against contrast-induced nephropathy in rats. Naunyn Schmiedebergs Arch Pharmacol 2025; 398:5373-5387.
64. Mohammadzadeh L, Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Crocin protects malathion-induced striatal biochemical deficits by inhibiting apoptosis and increasing α-synuclein in rats’ striatum. J Mol Neurosci 2022; 72:983-993.
65. Parizadeh MR, Ghafoori Gharib F, Abbaspour AR, Tavakol Afshar J, Ghayour - Mobarhan M. Effects of aqueous saffron extract on nitric oxide production by two human carcinoma cell lines: Hepatocellular carcinoma (HepG2) and laryngeal carcinoma (Hep2). Avicenna J Phytomed 2011; 1:43-50.
66. Amin A, Hamza AA, Bajbouj K, Ashraf SS, Daoud S. Saffron: A potential candidate for a novel anticancer drug against hepatocellular carcinoma. Hepatology 2011; 54:857-867.
67. Liu T, Tian L, Fu X, Wei L, Li J, Wang T. Saffron inhibits the proliferation of hepatocellular carcinoma via inducing cell apoptosis. Panminerva Med 2020; 62:7-12.
68. Mohan CD, Kim C, Siveen KS, Manu KA, Rangappa S, Chinnathambi A, et al. Crocetin imparts antiproliferative activity via inhibiting STAT3 signaling in hepatocellular carcinoma. IUBMB Life 2021; 73:1348-1362.
69. Ibrahim S, Baig B, Hisaindee S, Darwish H, Abdel-Ghany A, El-Maghraby H, et al. Development and evaluation of crocetin-functionalized pegylated magnetite nanoparticles for hepatocellular carcinoma. Molecules 2023; 28:2882-2899.
70. Noureini SK, Wink M. Antiproliferative effects of crocin in HepG2 cells by telomerase inhibition and hTERT down-regulation. Asian Pac J Cancer Prev 2012; 13:2305-2309.
71. Amin A, Hamza AA, Daoud S, Khazanehdari K, Hrout AA, Baig B, et al. Saffron-based crocin prevents early lesions of liver cancer: In vivo, in vitro and network analyses. Recent Pat Anticancer Drug Discov 2016; 11:121-133.
72. El-Kharrag R, Amin A, Hisaindee S, Greish Y, Karam SM. Development of a therapeutic model of precancerous liver using crocin-coated magnetite nanoparticles. Int J Oncol 2017; 50:212-222.
73. Yao C, Liu BB, Qian XD, Li LQ, Cao HB, Guo QS, et al. Crocin induces autophagic apoptosis in hepatocellular carcinoma by inhibiting Akt/mTOR activity. Onco Targets Ther 2018; 11:2017-2028.
74. Kim B, Park B. Saffron carotenoids inhibit STAT3 activation and promote apoptotic progression in IL-6-stimulated liver cancer cells. Oncol Rep 2018; 39:1883-1891.
75. Abdu S, Juaid N, Amin A, Moulay M, Miled N. Therapeutic effects of crocin alone or in combination with sorafenib against hepatocellular carcinoma: In vivo & in vitro insights. Antioxidants 2022; 11:1645-1665.
76. Basuony NS, Mohamed TM, Beltagy DM, Massoud AA, Elwan MM. Therapeutic effects of crocin nanoparticles alone or in combination with doxorubicin against hepatocellular carcinoma in vitro. Anticancer Agents Med Chem 2025; 25:194-206.
77. Al-Hrout Aa, Chaiboonchoe A, Khraiwesh B, Murali C, Baig B, El-Awady R, et al. Safranal induces DNA double-strand breakage and ER-stress-mediated cell death in hepatocellular carcinoma cells. Sci Rep 2018; 8:16951-16965.
78. Abdalla A, Murali C, Amin A. Safranal inhibits angiogenesis via targeting HIF-1α/VEGF machinery: In vitro and ex vivo insights. Front Oncol 2022; 11:789172.
79. Abdalla Y, Abdalla A, Hamza AA, Amin A. Safranal prevents liver cancer through inhibiting oxidative stress and alleviating inflammation. Front Pharmacol 2021; 12:777500.
80. Nelson DR, Hrout AaA, Alzahmi AS, Chaiboonchoe A, Amin A, Salehi-Ashtiani K. Molecular mechanisms behind safranal’s toxicity to HepG2 cells from dual omics. Antioxidants 2022; 11:1125-1139.
81. Zein N. The effect of Saffron aqueous extract on hepatocellular carcinoma rat model. Biochem Lett 2017; 13:49-63.
82. Fikry R, Zein N, Faozan A. Properties of Crocus sativus saffron on DEN-induced hepatocellular carcinoma in rats. Biochem Lett 2018; 14:171-179.
83. Thamer NA. Green synthesized silver nanoparticles using Crocus sativus L extract after reduces prehepatocellular carcinoma in rats. Iraqi J Cancer Med Genet 2016; 9:181-185.
84. Elsherbiny NM, Eisa NH, El-Sherbiny M, Said E. Chemo-preventive effect of crocin against experimentally-induced hepatocarcinogenesis via regulation of apoptotic and Nrf2 signaling pathways. Environ Toxicol Pharmacol 2020; 80:103494.
85. Awad B, Hamza AA, Al-Maktoum A, Al-Salam S, Amin A. Combining crocin and sorafenib improves their tumor-inhibiting effects in a rat model of diethylnitrosamine-induced cirrhotic-hepatocellular carcinoma. Cancers 2023; 15:4063-4081.
86. Ghasemzadeh Rahbardar M, Hosseinzadeh H. Therapeutic effects of rosemary (Rosmarinus officinalis L.) and its active constituents on nervous system disorders. Iran J Basic Med Sci 2020; 23:1100-1112.
87. Ghasemzadeh Rahbardar M, Amin B, Mehri S, Mirnajafi-Zadeh SJ, Hosseinzadeh H. Anti-inflammatory effects of ethanolic extract of Rosmarinus officinalis L. and rosmarinic acid in a rat model of neuropathic pain. Biomed Pharmacother 2017; 86:441-449.
88. Rašković A, Milanović I, Pavlović N, Ćebović T, Vukmirović S, Mikov M. Anti-oxidant activity of rosemary (Rosmarinus officinalis L.) essential oil and its hepatoprotective potential. BMC Complement Altern Med 2014; 14:225-233.
89. Ghasemzadeh Rahbardar M, Hosseinzadeh H. Therapeutic potential of hypnotic herbal medicines: A comprehensive review. Phytother Res 2024; 38:3037-3059.
90. Nakisa N, Ghasemzadeh Rahbardar M. Therapeutic potential of rosemary (Rosmarinus officinalis L.) on sports injuries: A review of patents. J Pharmacogn Res 2022; 9:71-83.
91. Rahbardar MG, Amin B, Mehri S, Mirnajafi-Zadeh SJ, Hosseinzadeh H. Rosmarinic acid attenuates development and existing pain in a rat model of neuropathic pain: An evidence of anti-oxidative and anti-inflammatory effects. Phytomedicine 2018; 40:59-67.
92. Nakisa N, Rahbardar MG. Action mechanisms of antirheumatic herbal medicines.  Rheumatoid Arthritis 2021; 1-15
93. Alavi MS, Fanoudi S, Ghasemzadeh Rahbardar M, Mehri S, Hosseinzadeh H. An updated review of protective effects of rosemary and its active constituents against natural and chemical toxicities. Phytother Res 2021; 35:1313-1328.
94. Ghasemzadeh MR, Amin B, Mehri S, Mirnajafi-Zadeh SJ, Hosseinzadeh H. Effect of alcoholic extract of aerial parts of Rosmarinus officinalis L. on pain, inflammation and apoptosis induced by chronic constriction injury (CCI) model of neuropathic pain in rats. J Ethnopharmacol 2016; 194:117-130.
95. Ghasemzadeh Rahbardar M, Eisvand F, Rameshrad M, Razavi BM, Tabatabaee Yazdi A, Hosseinzadeh H. Carnosic acid mitigates doxorubicin-induced cardiac toxicity: Evidence from animal and cell model investigations. Iran J Basic Med Sci 2024; 27:425-438.
96. Rahbardar MG, Eisvand F, Rameshrad M, Razavi BM, Hosseinzadeh H. In vivo and in vitro protective effects of rosmarinic acid against doxorubicin-induced cardiotoxicity. Nutr Cancer 2022; 74:747-760.
97.Rahbardar MG, Hosseinzadeh H. Chapter 47 - Mechanisms of action of herbal antidepressants. In: Martin CR, Hunter L-A, Patel VB, Preedy VR, Rajendram R, editors. The Neuroscience of Depression: Academic Press; 2021. p. 503-518.
98. Ghasemzadeh Rahbardar M, Hemadeh B, Razavi BM, Eisvand F, Hosseinzadeh H. Effect of carnosic acid on acrylamide induced neurotoxicity: In vivo and in vitro experiments. Drug Chem Toxicol 2022; 45:1528-1535.
99. Ghasemzadeh Rahbardar M, Hosseinzadeh H. Toxicity and safety of rosemary (Rosmarinus officinalis): A comprehensive review. Naunyn Schmiedebergs Arch Pharmacol 2025; 398:9-23.
100. Wei FX, Liu JX, Wang L, Li HZ, Luo JB. [Expression of bcl-2 and bax genes in the liver cancer cell line HepG2 after apoptosis induced by essential oils from Rosmarinus officinalis]. Zhong Yao Cai 2008; 31:877-879.
101. Melušová M, Jantová S, Horváthová E. Carvacrol and rosemary oil at higher concentrations induce apoptosis in human hepatoma HepG2 cells. Interdiscip Toxicol 2014; 7:189-194.
102. Tu Z, Moss-Pierce T, Ford P, Jiang TA. Rosemary (Rosmarinus officinalis L.) extract regulates glucose and lipid metabolism by activating AMPK and PPAR pathways in HepG2 cells. J Agric Food Chem 2013; 61:2803-2810.
103. Tong XP, Ma YX, Quan DN, Zhang L, Yan M, Fan XR. Rosemary extracts upregulate Nrf2, Sestrin2, and MRP2 protein level in human hepatoma HepG2 cells. Evid Based Complement Alternat Med 2017; 2017:7359806.
104. Rodenak-Kladniew B, Castro A, Stärkel P, Galle M, Crespo R. 1,8-Cineole promotes G0/G1 cell cycle arrest and oxidative stress-induced senescence in HepG2 cells and sensitizes cells to anti-senescence drugs. Life Sci 2020; 243:117271.
105. Wang T, Takikawa Y, Tabuchi T, Satoh T, Kosaka K, Suzuki K. Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway. J Gastroenterol 2012; 47:805-813.
106. Hu Y, Zhang N, Fan Q, Lin M, Zhang C, Fan G, et al. Protective efficacy of carnosic acid against hydrogen peroxide induced oxidative injury in HepG2 cells through the SIRT1 pathway. Can J Physiol Pharmacol 2015; 93:625-631.
107. Xiang Q, Ma Y, Dong J, Shen R. Carnosic acid induces apoptosis associated with mitochondrial dysfunction and Akt inactivation in HepG2 cells. Int J Food Sci Nutr 2015; 66:76-84.
108. Zhang X, Chen Y, Cai G, Li X, Wang D. Carnosic acid induces apoptosis of hepatocellular carcinoma cells via ROS-mediated mitochondrial pathway. Chem Biol Interact 2017; 277:91-100.
109. Wang X, Gupta P, Jramne Y, Danilenko M, Liu D, Studzinski GP. Carnosic acid increases sorafenib-induced inhibition of ERK1/2 and STAT3 signaling which contributes to reduced cell proliferation and survival of hepatocellular carcinoma cells. Oncotarget 2020; 11:3129-3143.
110. Wu Q, Wang X, Pham K, Luna A, Studzinski GP, Liu C. Enhancement of sorafenib-mediated death of Hepatocellular carcinoma cells by Carnosic acid and Vitamin D2 analog combination. J Steroid Biochem Mol Biol 2020; 197:105524.
111. Hasei S, Yamamotoya T, Nakatsu Y, Ohata Y, Itoga S, Nonaka Y, et al. Carnosic acid and carnosol activate AMPK, suppress expressions of gluconeogenic and lipogenic genes, and inhibit proliferation of HepG2 cells. Int J Mol Sci 2021; 22:4040-4050.
112. Wu W, Li Y, Wu X, Liang J, You W, He X, et al. Carnosic acid nanocluster-based framework combined with PD-1 inhibitors impeded tumorigenesis and enhanced immunotherapy in hepatocellular carcinoma. Funct Integr Genomics 2024; 24:5.
113. Kong S, Xiao W, Ma T, Chen Y, Shi H, Tu J, et al. Carnosol inhibits the proliferation, migration, and invasion of hepatocellular carcinoma cells in vitro by regulating the AMPK signaling pathway. Anticancer Agents Med Chem 2025; doi: 10.2174/1871520623666230418093254.
114. Ma ZJ, Yan H, Wang YJ, Yang Y, Li XB, Shi AC, et al. Proteomics analysis demonstrating rosmarinic acid suppresses cell growth by blocking the glycolytic pathway in human HepG2 cells. Biomed Pharmacother 2018; 105:334-349.
115. Huang Y, Cai Y, Huang R, Zheng X. Rosmarinic acid combined with adriamycin induces apoptosis by triggering mitochondria-mediated signaling pathway in HepG2 and Bel-7402 cells. Med Sci Monit 2018; 24:7898-7908.
116. Wang L, Yang H, Wang C, Shi X, Li K. Rosmarinic acid inhibits proliferation and invasion of hepatocellular carcinoma cells SMMC 7721 via PI3K/AKT/mTOR signal pathway. Biomed Pharmacother 2019; 120:109443.
117. Jerard C, Michael BP, Chenicheri S, Vijayakumar N, Ramachandran R. Rosmarinic acid-rich fraction from Mentha arvensis synchronizes Bcl/Bax expression and induces Go/G1 arrest in hepatocarcinoma cells. Proc Natl Acad Sci India Sect B Biol Sci 2020; 90:515-522.
118. Ozgun GS, Ozgun E. The cytotoxic concentration of rosmarinic acid increases MG132-induced cytotoxicity, proteasome inhibition, autophagy, cellular stresses, and apoptosis in HepG2 cells. Hum Exp Toxicol 2020; 39:514-523.
119. Jin B, Liu J, Gao D, Xu Y, He L, Zang Y, et al. Detailed studies on the anticancer action of rosmarinic acid in human Hep-G2 liver carcinoma cells: Evaluating its effects on cellular apoptosis, caspase activation and suppression of cell migration and invasion. J Buon 2020; 25:1383-1389.
120. Chen C, Liu Y, Shen Y, Zhu L, Yao L, Wang X, et al. Rosmarinic acid, the active component of Rubi Fructus, induces apoptosis of SGC-7901 and HepG2 cells through mitochondrial pathway and exerts anti-tumor effect. Naunyn Schmiedebergs Arch Pharmacol 2023; 396:3743-3755.
121. Elafify HS, Algendy FE, Said AM. The possible impacts of rosemary and hops ethanolic extracts on hepatocellular carcinoma experimentally induced in rats. Benha Vet Med J 2023; 43:10-14.
122. Abdallah HMI, El Awdan SA, Abdel-Rahman RF, Farrag ARH, Allam RM. 1,8 cineole and ellagic acid inhibit hepatocarcinogenesis via upregulation of MiR-122 and suppression of TGF-β1, FSCN1, Vimentin, VEGF, and MMP-9. PLoS One 2022; 17:e0258998.
123. Cao W, Hu C, Wu L, Xu L, Jiang W. Rosmarinic acid inhibits inflammation and angiogenesis of hepatocellular carcinoma by suppression of NF-κB signaling in H22 tumor-bearing mice. J Pharmacol Sci 2016; 132:131-137.
124. Cao W, Mo K, Wei S, Lan X, Zhang W, Jiang W. Effects of rosmarinic acid on immunoregulatory activity and hepatocellular carcinoma cell apoptosis in H22 tumor-bearing mice. Korean J Physiol Pharmacol 2019; 23:501-508.
125. Cao W, Pan J, Mo K, Wang Z, Wei S, Yin Y, et al. Effects of gene silencing of indoleamine 2,3-dioxygenase 1 combined with rosmarinic acid on tumor immune microenvironment in H22 tumor-bearing mice. Int Immunopharmacol 2023; 119:110193.
126. Abdullaev FI, Riverón-Negrete L, Caballero-Ortega H, Manuel Hernández J, Pérez-López I, Pereda-Miranda R, et al. Use of in vitro assays to assess the potential antigenotoxic and cytotoxic effects of saffron (Crocus sativus L.). Toxicol In Vitro 2003; 17:731-736.
127. Li Y, Darwish WS, Chen Z, Tan H, Wu Y, Suzuki H, et al. Identification of lead-produced lipid hydroperoxides in human HepG2 cells and protection using rosmarinic and ascorbic acids with a reference to their regulatory roles on Nrf2-Keap1 anti-oxidant pathway. Chem Biol Interact 2019; 314:108847.

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