Letter to the editor

Recent insights into luteolin and its biological and pharmacological activities

Priscilla Nadalin¹, Jae Kwang Kim², Sang Un Park¹[*]^,3,4

EXCLI J 2024;23:Doc787



Luteolin (LUT), or 3',4',5,7-tetrahydroxyflavone, is a flavonoid generally found in glycosylated form in a wide range of plants such as medicinal herbs, fruits and vegetables (Arampatzis et al., 2023[2]). Chinese traditional medicine makes extensive use of LUT to treat numerous conditions, particularly inflammatory disorders, hypertension, and cancer (Lin et al., 2008[30]). According to IUPAC chemical nomenclature, LUT is named 2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4H-chromen-4-one. This compound was first isolated in its pure form in 1829 by a French chemist Michel Eugène Chevreul (Jain and Tiwari, 2020[19]).

LUT exerts a range of beneficial effects on human health, with the following being reported in many studies: antiallergic, anti-inflammatory, antidiabetic, neuroprotective, and anticancer. Due to their chemical nature, LUT and its glycosides also display antioxidant properties, scavenging free radicals derived from oxidation and chelating metal ions (Cai et al., 1997[3]; Choi et al., 2007[8]; Muruganathan et al., 2022[33]). In recent years, LUT has attracted much attention from the pharmaceutical, food, and cosmetic industries for its plethora of biological and pharmacological activities. Herein, we present a summary of recent key studies performed to evaluate the biological and pharmacological activities of LUT (Table 1(Tab. 1); References in Table 1: Aljohani et al., 2023[1]; Arampatzis et al., 2023[2]; Chang et al., 2023[4]; Chen et al., 2022[6], 2023[5]; Cheng et al., 2022[7]; Ding et al., 2023[9]; Dong et al., 2023[10]; Eddy et al., 2024[11]; Fu et al., 2024[12]; Guo et al., 2024[13]; Han et al., 2022[14]; Hao et al., 2023[15]; He et al., 2023[16]; Huang et al., 2023[17][18]; Jang et al., 2022[20]; Ji et al., 2022[21]; Jia et al., 2023[22]; Jiang et al., 2022[23]; Kahksha et al., 2023[24]; Kariu et al., 2023[25]; Kim et al., 2023[26]; Li et al., 2022[27][28], 2023[29]; Liu et al., 2023[31]; Mousavi et al., 2022[32]; Nishiguchi et al., 2024[34]; Pan et al., 2022[35]; Qi et al., 2022[36]; Qiao et al., 2023[37]; Qin et al., 2022[38]; Ramadan et al., 2023[39]; Ren et al., 2024[40]; Rudin et al., 2023[41]; Song et al., 2022[42]; Sudhakaran et al., 2023[43][44]; Sur and Lee, 2022[45]; Tráj et al., 2023[46]; Wang et al., 2023[47]; Wen et al., 2024[48]; Xia et al., 2024[49]; Xie et al., 2022[50]; Xu et al., 2023[51]; Xue et al., 2023[52]; Yajie et al., 2023[53]; Yang et al., 2023[54]; Ye et al., 2023[55]; Yoon et al., 2023[56]; Yuan et al., 2023[57]; Zaki et al., 2023[58]; Zhang et al., 2023[59]; Zheng et al., 2023[60]; Zhou et al., 2022[61]; Zhu et al., 2022[62]).

Notes

Priscilla Nadalin and Jae Kwang Kim contributed equally as first author.

Declaration

Acknowledgments

This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Korean government (MSIT) (No. 2022M3E5E6018649) and this work was also supported by the Institute of Information & Communications Technology Planning & Evaluation (IITP) grant funded by the Korea government (MSIT) (No.RS-202200155857, Artificial Intelligence Convergence Innovation Human Resources Development (Chungnam National University)).

Conflict of interest

The authors declare no conflict of interest.

References

1. Aljohani H, Khodier AE, Al-Gayyar MM, Khodier A. Antitumor activity of luteolin against Ehrlich solid carcinoma in rats via blocking Wnt/β-catenin/Smad4 pathway. Cureus. 2023;15(5):e39789

2. Arampatzis AS, Pampori A, Droutsa E, Laskari M, Karakostas P, Tsalikis L, et al. Occurrence of luteolin in the greek flora, isolation of luteolin and its action for the treatment of periodontal diseases. Molecules. 2023;28(23):7720

3. Cai Q, Rahn RO, Zhang R. Dietary flavonoids, quercetin, luteolin and genistein, reduce oxidative DNA damage and lipid peroxidation and quench free radicals. Cancer Lett. 1997;119(1):99-107

4. Chang X, Tamauchi S, Yoshida K, Yoshihara M, Yokoi A, Shimizu Y, et al. Downregulating vaccinia-related kinase 1 by luteolin suppresses ovarian cancer cell proliferation by activating the p53 signaling pathway. Gynecol Oncol. 2023;173:31-40

5. Chen L, Yu T, Zhai Y, Nie H, Li X, Ding Y. Luteolin enhances transepithelial sodium transport in the lung alveolar model: integrating network pharmacology and mechanism study. Int J Mol Sci. 2023;24(12):10122

6. Chen YF, Wu S, Li X, Chen M, Liao HF. Luteolin suppresses three angiogenesis modes and cell interaction in uveal melanoma in vitro. Curr Eye Res. 2022;47:1590-9

7. Cheng Y, Wang X, Yu Y, Gu J, Zhao M, Fu Q, et al. Noise induced depression-like behavior, neuroinflammation and synaptic plasticity impairments: the protective effects of luteolin. Neurochem Res. 2022;47:3318-30

8. Choi CW, Jung HA, Kang SS, Choi JS. Antioxidant constituents and a new triterpenoid glycoside from Flos Lonicerae. Arch Pharm Res. 2007;30(1):1-7

9. Ding T, Yi T, Li Y, Zhang W, Wang X, Liu J, et al. Luteolin attenuates lupus nephritis by regulating macrophage oxidative stress via HIF-1α pathway. Eur J Pharm. 2023;953:175823

10. Dong M, Luo Y, Lan Y, He Q, Xu L, Pei Z. Luteolin reduces cardiac damage caused by hyperlipidemia in Sprague-Dawley rats. Heliyon. 2023;9(6):e17613

11. Eddy AC, Rajakumar A, Spradley FT, Granger JP, Rana S. Luteolin prevents TNF-α-induced NF-κB activation and ROS production in cultured human placental explants and endothelial cells. Placenta. 2024;145:65-71

12. Fu W, Xu L, Chen Y, Zhang Z, Chen S, Li Q, et al. Luteolin induces ferroptosis in prostate cancer cells by promoting TFEB nuclear translocation and increasing ferritinophagy. Prostate. 2024;84:223-36

13. Guo F, Guo Y, Zhang D, Fu Z, Han S, Wan Y, et al. Luteolin inhibits the JAK/STAT pathway to alleviate auditory cell apoptosis of acquired sensorineural hearing loss based on network pharmacology, molecular docking, molecular dynamics simulation, and experiments in vitro. Toxicol Appl Pharmacol. 2024;482:116790

14. Han S, Lin F, Qi Y, Liu C, Zhou L, Xia Y, et al. HO-1 contributes to luteolin-triggered ferroptosis in clear cell renal cell carcinoma via increasing the labile iron pool and promoting lipid peroxidation. Oxid Med Cell Longev. 2022;2022:3846217

15. Hao X, Zu M, Ning J, Zhou X, Gong Y, Han X, et al. Antitumor effect of luteolin proven by patient‐derived organoids of gastric cancer. Phytother Res. 2023;37:5315-27

16. He Z, Li X, Wang Z, Cao Y, Han S, Li N, et al. Protective effects of luteolin against amyloid beta-induced oxidative stress and mitochondrial impairments through peroxisome proliferator-activated receptor γ-dependent mechanism in Alzheimer's disease. Redox Biol. 2023;66:102848

17. Huang CY, Chen HW, Lo CW, Wang YR, Li CC, Liu KL, et al. Luteolin ameliorates palmitate-induced lipotoxicity in hepatocytes by mediating endoplasmic reticulum stress and autophagy. Food Chem Toxicol. 2023;171:113554

18. Huang G, Liu X, Jiang T, Cao Y, Sang M, Song X, et al. Luteolin overcomes acquired resistance to osimertinib in non-small cell lung cancer cells by targeting the HGF-MET-Akt pathway. Am J Cancer Res. 2023;13:4145-62

19. Jain R, Tiwari A. Monograph: Luteolin. Matrix Sci Med. 2020;4(3):88-9

20. Jang CH, Moon N, Lee J, Kwon MJ, Oh J, Kim JS. Luteolin synergistically enhances antitumor activity of oxaliplatin in colorectal carcinoma via AMPK inhibition. Antioxidants (Basel). 2022;11(4):626

21. Ji L, Su S, Xin M, Zhang Z, Nan X, Li Z, et al. Luteolin ameliorates hypoxia-induced pulmonary hypertension via regulating HIF-2α-Arg-NO axis and PI3K-AKT-eNOS-NO signaling pathway. Phytomedicine. 2022;104:154329

22. Jia Q, Wen J, Yang Q, Liu S, Zhang J, Wang T, et al. Lonicera japonica Thunb extract ameliorates lipopolysaccharide-induced acute lung injury associated with luteolin-mediated suppression of NF-κB signaling pathway. J Inflamm (Lond). 2023;20(1):44

23. Jiang J, Zhu F, Zhang H, Sun T, Fu F, Chen X, et al. Luteolin suppresses the growth of colon cancer cells by inhibiting the IL-6/STAT3 signaling pathway. J Gastrointest Oncol. 2022;13:1722-32

24. Kahksha, Alam O, Al-Keridis LA, Khan J, Naaz S, Alam A, et al. Evaluation of antidiabetic effect of luteolin in stz induced diabetic rats: molecular docking, molecular dynamics, in vitro and in vivo studies. J Funct Biomater. 2023;14(3):126

25. Kariu T, Hamada N, Lakshmyya K. Luteolin inhibits Porphyromonas gingivalis growth and alleviates alveolar bone destruction in experimental murine periodontitis. Biosci Biotechnol Biochem. 2023;88(1):37-43

26. Kim JW, Shin SK, Kwon EY. Luteolin protects against obese sarcopenia in mice with high‐fat diet‐induced obesity by ameliorating inflammation and protein degradation in muscles. Mol Nutr Food Res. 2023;67(6):e2200729

27. Li F, Wei R, Huang M, Chen J, Li P, Ma Y, et al. Luteolin can ameliorate renal interstitial fibrosis-induced renal anaemia through the SIRT1/FOXO3 pathway. Food Funct. 2022;13:11896-914

28. Li L, Pan G, Fan R, Li D, Guo L, Ma L, et al. Luteolin alleviates inflammation and autophagy of hippocampus induced by cerebral ischemia/reperfusion by activating PPAR gamma in rats. BMC Complement Med Ther. 2022;22(1):176

29. Li M, Wang H, Lu Y, Cai J. Luteolin suppresses inflammation and oxidative stress in chronic obstructive pulmonary disease through inhibition of the NOX4‐mediated NF‐κB signaling pathway. Immun Inflamm Dis. 2023;11(4):e820

30. Lin Y, Shi R, Wang X, Shen HM. Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets. 2008;8:634-46

31. Liu X, Zuo J, Teng J, Yang L, Guo J, Liu L, et al. Antibiofilm potential of luteolin against multidrug-resistant Staphylococcus aureus isolated from dairy goats and farm environments. Environ Pollut. 2023;335:122274

32. Mousavi L, Zadeh-Hashem E, Imani M. β-Cyfluthrin-mediated cytotoxicity of cultured rat primary hepatocytes ameliorated by cotreatment with luteolin. Evid Based Complement Alternat Med. 2022;2022:3647988

33. Muruganathan N, Dhanapal AR, Baskar V, Muthuramalingam P, Selvaraj D, Aara H, et al. Recent updates on source, biosynthesis, and therapeutic potential of natural flavonoid luteolin: A review. Metabolites. 2022;12(11):1145

34. Nishiguchi H, Omura T, Sato A, Kitahiro Y, Yamamoto K, Kunimasa J, et al. Luteolin protects against 6-hydoroxydopamine-induced cell death via an upregulation of HRD1 and SEL1L. Neurochem Res. 2024;49:117-28

35. Pan Q, Liu Y, Ma W, Kan R, Zhu H, Li D. Cardioprotective effects and possible mechanisms of Luteolin for myocardial ischemia-reperfusion injury: a systematic review and meta-analysis of preclinical evidence. Front Cardiovasc Med. 2022;9:685998

36. Qi Y, Fu S, Pei D, Fang Q, Xin W, Yuan X, et al. Luteolin attenuated cisplatin-induced cardiac dysfunction and oxidative stress via modulation of Keap1/Nrf2 signaling pathway. Free Radic Res. 2022;56:209-21

37. Qiao XR, Feng T, Zhang D, Zhi LL, Zhang JT, Liu XF, et al. Luteolin alleviated neutrophilic asthma by inhibiting IL-36γ secretion-mediated MAPK pathways. Pharm Biol. 2023;61:165-76

38. Qin T, Zhu W, Kan X, Li L, Wu D. Luteolin attenuates the chemoresistance of osteosarcoma through inhibiting the PTN/β-catenin/MDR1 signaling axis by upregulating miR-384. J Bone Oncol. 2022;34:100429

39. Ramadan A, Mohammed A, Elnour AA, Sadeq A, Al Mazrouei N, Alkaabi M, et al. The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells. Saudi Pharm J. 2023;31(12):101871

40. Ren Y, Li G, Li E, Deng K, Lian J, Gao Q, et al. Luteolin blocks the ROS/PI3K/AKT pathway to inhibit mesothelial-mesenchymal transition and reduce abdominal adhesions. Eur J Pharmacol. 2024;964:176272

41. Rudin L, Roth N, Kneubühler J, Dubey BN, Bornstein MM, Shyp V. Inhibitory effect of natural flavone luteolin on Streptococcus mutans biofilm formation. Microbiol Spectr. 2023;11(5):e0522322

42. Song Y, Yu J, Li L, Wang L, Dong L, Xi G, et al. Luteolin impacts deoxyribonucleic acid repair by modulating the mitogen-activated protein kinase pathway in colorectal cancer. Bioengineered. 2022;13:10998-1011

43. Sudhakaran G, Selvam M, Sreekutty A, Chandran A, Almutairi BO, Arokiyaraj S, et al. Luteolin photo-protects zebrafish from environmental stressor ultraviolet radiation (UVB). J Toxicol Environ Health A. 2023;86:720-34

44. Sudhakaran G, Sreekutty A, Subramaniyan S, Madesh S, Priya PS, Pachaiappan R, et al. Skeletal and neurological risks demonstrated in zebrafish due to second-hand cigarette smoke and the neutralization of luteolin. Tissue Cell. 2023;85:102259

45. Sur B, Lee B. Luteolin reduces fear, anxiety, and depression in rats with post-traumatic stress disorder. Anim Cells Syst (Seoul). 2022;26:174-82

46. Tráj P, Sebők C, Mackei M, Kemény Á, Farkas O, Kákonyi Á, et al. Luteolin: a phytochemical to mitigate s. typhimurium flagellin-induced inflammation in a chicken in vitro hepatic model. Animals (Basel). 2023;13(8):1410

47. Wang W, Yang C, Xia J, Li N, Xiong W. Luteolin is a potential inhibitor of COVID-19: An in silico analysis. Medicine (Baltimore). 2023;102(38):e35029

48. Wen D, Han W, Chen Q, Qi G, Gao M, Guo P, et al. Integrating network pharmacology and experimental validation to explore the mechanisms of luteolin in alleviating fumonisin B1–induced intestinal inflammatory injury. Toxicon. 2024;237:107531

49. Xia Y, Tan W, Yuan F, Lin M, Luo H. Luteolin attenuates oxidative stress and colonic hypermobility in water avoidance stress rats by activating the Nrf2 signaling pathway. Mol Nutr Food Res. 2024;68(1):e2300126

50. Xie T, Yuan J, Mei L, Li P, Pan R. Luteolin suppresses TNF‑α‑induced inflammatory injury and senescence of nucleus pulposus cells via the Sirt6/NF‑κB pathway. Exp Ther Med. 2022;24(1):469

51. Xu X, Fan X, Wu X, Xia R, Liang J, Gao F, et al. Luteolin ameliorates necroptosis in Glucocorticoid-induced osteonecrosis of the femoral head via RIPK1/RIPK3/MLKL pathway based on network pharmacology analysis. Biochem Biophys Res Commun. 2023;661:108-18

52. Xue L, Jin X, Ji T, Li R, Zhuge X, Xu F, et al. Luteolin ameliorates DSS-induced colitis in mice via suppressing macrophage activation and chemotaxis. Int Immunopharmacol. 2023;124:110996

53. Yajie D, Feng L, Zhaoyan L, Xu Y, Nida C, Zhang G, et al. Efficacy of luteolin on the human gastric cancer cell line MKN45 and underlying mechanism. J Tradit Chin Med. 2023;43(1):34-41

54. Yang K, Yin J, Yue X, Bieber K, Riemekasten G, Ludwig RJ, et al. Luteolin peracetate and gossypolone inhibit immune complex-mediated neutrophil activation in vitro and dermal-epidermal separation in an ex vivo model of epidermolysis bullosa acquisita. Front Immunol. 2023;14:1196116

55. Ye Y, Yang L, Wang H, Li L, Chai S, Meng Z. Luteolin inhibits GPVI-mediated platelet activation, oxidative stress, and thrombosis. Front Pharmacol. 2023;14:1255069

56. Yoon HJ, Kang DH, Jin F, Bang JS, Sohn UD, Je HD. The effect of luteolin on the modulation of vascular contractility via ROCK and CPI-17 inactivation. Biomol Ther (Seoul). 2023;31:193-9

57. Yuan X, Ouyang J, Long C. Effects and mechanism of luteolin on proliferation and apoptosis of glioma. Altern Ther Health Med. 2023;2023:AT8550

58. Zaki MSA, Abadi AM, El-Kott AF, Mohamed G, Alrashdi BM, Eid RA, et al. Protective efficacy of luteolin against aflatoxinB1-induced toxicity, oxidative damage, and apoptosis in the rat liver. Environ Sci Pollut Res Int. 2023;30:52358-68

59. Zhang C, Zhang Y, Hu X, Zhao Z, Chen Z, Wang X, et al. Luteolin inhibits subretinal fibrosis and epithelial-mesenchymal transition in laser-induced mouse model via suppression of Smad2/3 and YAP signaling. Phytomedicine. 2023;116:154865

60. Zheng Y, Li L, Chen H, Zheng Y, Tan X, Zhang G, et al. Luteolin exhibits synergistic therapeutic efficacy with erastin to induce ferroptosis in colon cancer cells through the HIC1-mediated inhibition of GPX4 expression. Free Radic Biol Med. 2023;208:530-44

61. Zhou YS, Cui Y, Zheng JX, Quan YQ, Wu SX, Xu H, et al. Luteolin relieves lung cancer-induced bone pain by inhibiting NLRP3 inflammasomes and glial activation in the spinal dorsal horn in mice. Phytomedicine. 2022;96:153910

62. Zhu Q, Meng P, Han Y, Yang H, Yang Q, Liu Z, et al. Luteolin induced hippocampal neuronal pyroptosis inhibition by regulation of miR-124-3p/TNF-α/TRAF6 axis in mice affected by breast-cancer-related depression. Evid Based Complement Alternat Med. 2022;2022:2715325

 

 

 

Table 1: Recent studies on the biological and pharmacological activities of luteolin

[*] Corresponding Author:

Sang Un Park, Department of Crop Science, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Korea; Tel.: +82-42-821-5730, Fax: +82-42-822-2631, eMail: supark@cnu.ac.kr