SavedAdd your journal

Journals / Turkish Journal of Kinesiology / 2026 / Volume: 12 Issue: 3

An in silico investigation of hesperidin as a modulator of the irisin/AMPK axis: Implications for exercise-mimetic signaling

Yasin Sepil(Rectorate Unit, Atatürk University, Erzurum, Türkiye.)0009-0007-9709-016X
Azizeh Shadidizaji(Department of Plant Biotechnology, Faculty of Agriculture and Coordination Office of Computer-Based Modeling and Simulation of Biological Systems, Ataturk University, Erzurum, Türkiye.)0009-0007-5573-1360
Yusuf Buzdağlı(Department of Coaching Education, Faculty of Sport Sciences, Erzurum Technical University, Erzurum, Türkiye.)0000-0003-1809-5194
Erdinç Şıktar(Department of Coaching Education, Faculty of Sport Sciences, Atatürk University, Erzurum, Türkiye.)0000-0003-0387-3969
Ahmet Hacımüftüoğlu(Vaccine Development Application and Research Center, Ataturk University, Erzurum, Türkiye.)0000-0002-9658-3313
Pages
—
Publication Date
2026-06-30
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Rather than establishing biological efficacy, the results furnish a mechanistic platform for prioritizing future experimental studies, including cellular validation of AMPK activation and well-controlled human intervention trials examining performance, metabolic biomarkers, and supplementation timing.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:Exercise-induced metabolic adaptations are orchestrated by energy-sensing signaling networks centered on 5′-AMP-activated protein kinase (AMPK).
📊
Key Findings & Data:The aim of the present study was therefore to investigate potential interactions between hesperidin and the catalytic α1 subunit of human AMPK (PRKAA1) using an integrated in silico approach and to evaluate the resulting structural insights within a mechanistic framework capable of guiding future experimental research on exercise-mimetic signaling.
💡
Conclusion & Impact:Rather than establishing biological efficacy, the results furnish a mechanistic platform for prioritizing future experimental studies, including cellular validation of AMPK activation and well-controlled human intervention trials examining performance, metabolic biomarkers, and supplementation timing.
🔬Design:Review
📍Scope:Comprehensive Sample
⚙️Variables:AMP-activated protein kinase · hesperidin · molecular docking

Abstract

Exercise-induced metabolic adaptations are orchestrated by energy-sensing signaling networks centered on 5′-AMP-activated protein kinase (AMPK). Dietary polyphenols, including the citrus flavanone glycoside hesperidin, have been proposed to influence pathways overlapping with those activated during physical activity. However, atomic-level structural evidence describing how hesperidin may interact with AMPK and how such interactions could be positioned within the irisin–AMPK axis remains limited. The aim of the present study was therefore to investigate potential interactions between hesperidin and the catalytic α1 subunit of human AMPK (PRKAA1) using an integrated in silico approach and to evaluate the resulting structural insights within a mechanistic framework capable of guiding future experimental research on exercise-mimetic signaling. An integrated in silico workflow was applied to investigate interactions between hesperidin and the catalytic α1 subunit of human AMPK (PRKAA1). Molecular docking was used to predict binding orientations and energetics within defined binding pockets, followed by binding-site characterization and interaction profiling. The predicted complexes were evaluated in the context of signaling pathways associated with the irisin–AMPK axis to generate mechanistically grounded hypotheses for subsequent experimental validation. Hesperidin adopted structurally compatible binding poses within AMPKα1 and formed extensive interaction networks involving residues located in druggable regions of the protein. Docking scores suggested energetically favorable ligand accommodation, supporting the plausibility of a direct molecular interface between hesperidin and a central metabolic regulator. These findings provide atomic-level insight into how citrus-derived flavanones might engage energy-sensing pathways relevant to exercise physiology. The present in silico analyses identify a structurally coherent interaction between hesperidin and human AMPKα1 and situate this interaction within metabolic signaling frameworks linked to exercise adaptation. Rather than establishing biological efficacy, the results furnish a mechanistic platform for prioritizing future experimental studies, including cellular validation of AMPK activation and well-controlled human intervention trials examining performance, metabolic biomarkers, and supplementation timing.

🔖

Cite This Article

Sepil, Y., Shadidizaji, A., Buzdağlı, Y., Şıktar, E., Hacımüftüoğlu, A. (2026). An in silico investigation of hesperidin as a modulator of the irisin/AMPK axis: Implications for exercise-mimetic signaling. Turkish Journal of Kinesiology, Volume: 12 Issue: 3. https://doi.org/10.31459/turkjkin.1909093

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (59)

  1. Ahmad, S., Jose da Costa Gonzales, L., Bowler-Barnett, E. H., Rice, D. L., Kim, M., Wijerathne, S., Luciani, A., Kandasaamy, S., Luo, J., Watkins, X., Turner, E., Martin, M. J., & UniProt Consortium (2025). The UniProt website API: facilitating programmatic access to protein knowledge. Nucleic Acids Res, 53(W1), W547–W553. doi: 10.1093/nar/gkaf394
  2. Al‐Ibraheem, A. M. T., Hameed, A. T. A. Z., Marsool, M. D. M., Jain, H., Prajjwal, P., Khazmi, I.,. Razzaq, M. (2024). Exercise‐Induced cytokines, diet, and inflammation and their role in adipose tissue metabolism. Health Sci Rep, 7(9), e70034. doi: 10.1002/hsr2.70034
  3. Albrecht, E., Schering, L., Buck, F., Vlach, K., Schober, H.-C., Drevon, C. A., & Maak, S. (2020). Irisin: Still chasing shadows. Mol Metab, 34, 124-135. doi: 10.1016/j.molmet.2020.01.016
  4. Bojarczuk, A., & Dzitkowska-Zabielska, M. (2022). Polyphenol supplementation and antioxidant status in athletes: a narrative review. Nutrients, 15(1), 158. doi: 10.3390/nu15010158
  5. Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C.,. Long, J. Z. (2012). A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481(7382), 463-468. doi: 10.1038/nature10777
  6. Buzdağlı, Y., Eyipınar, C. D., Kacı, F. N., & Tekin, A. (2023). Effects of hesperidin on anti-inflammatory and antioxidant response in healthy people: a meta-analysis and meta-regression. Int J Environ Health Res, 33(12), 1390-1405. doi: 10.1080/09603123.2022.2093841
  7. Cao, G., Zuo, J., Wu, B., & Wu, Y. (2024). Polyphenol supplementation boosts aerobic endurance in athletes: Systematic review. Front Physiol, 15, 1369174. doi: 10.3389/fphys.2024.1369174
  8. Chen, N., Li, Q., Liu, J., & Jia, S. (2016). Irisin, an exercise‐induced myokine as a metabolic regulator: an updated narrative review. Diabetes Metab Res Rev, 32(1), 51-59. doi: 10.1002/dmrr.2660
  9. Egan, B., & Sharples, A. P. (2023). Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training. Physiol Rev, 103(3), 2057-2170. doi: 10.1152/physrev.00054.2021
  10. Egan, B., & Zierath, J. R. (2013). Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab, 17(2), 162-184. doi: 10.1016/j.cmet.2012.12.012
  11. Estruel-Amades, S., Massot-Cladera, M., Garcia-Cerdà, P., Pérez-Cano, F. J., Franch, À., Castell, M., & Camps-Bossacoma, M. (2019). Protective effect of hesperidin on the oxidative stress induced by an exhausting exercise in intensively trained rats. Nutrients, 11(4), 783. doi: 10.3390/nu11040783
  12. Garg, A., Garg, S., Zaneveld, L., & Singla, A. (2001). Chemistry and pharmacology of the citrus bioflavonoid hesperidin. Phytother Res, 15(8), 655-669. doi: 10.1002/ptr.1074
  13. Genheden, S., & Ryde, U. (2015). The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov, 10(5), 449-461. doi: 10.1517/17460441.2015.1032936
  14. Göransson, O., Kopietz, F., & Rider, M. H. (2023). Metabolic control by AMPK in white adipose tissue. Trends Endocrinol Metab, 34(11), 704-717. doi: 10.1016/j.tem.2023.08.011
  15. Hardie, D. G. (2011). AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function. Genes Dev, 25(18), 1895-1908. doi: 10.1101/gad.17420111
  16. Hardie, D. G. (2022). AMP-activated protein kinase—a journey from 1 to 100 downstream targets. Biochem J, 479(22), 2327-2343. doi: 10.1042/BCJ20220255
  17. Hawley, J. A., Hargreaves, M., Joyner, M. J., & Zierath, J. R. (2014). Integrative biology of exercise. Cell, 159(4), 738-749. doi: 10.1016/j.cell.2014.10.029
  18. Herzig, S., & Shaw, R. J. (2018). AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol, 19(2), 121-135. doi: 10.1038/nrm.2017.95
  19. Hollingsworth, S. A., & Dror, R. O. (2018). Molecular dynamics simulation for all. Neuron, 99(6), 1129-1143. doi: 10.1016/j.neuron.2018.08.011
  20. Huang, J., Zhou, Y., Wan, B., Wang, Q., & Wan, X. (2017). Green tea polyphenols alter lipid metabolism in the livers of broiler chickens through increased phosphorylation of AMP-activated protein kinase. PLoS One, 12(10), e0187061. doi: 10.1371/journal.pone.0187061
  21. Huh, J. Y., Panagiotou, G., Mougios, V., Brinkoetter, M., Vamvini, M. T., Schneider, B. E., & Mantzoros, C. S. (2012). FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism, 61(12), 1725-1738. doi: 10.1016/j.metabol.2012.09.002
  22. Imperatrice, M., Cuijpers, I., Troost, F. J., & Sthijns, M. M. (2022). Hesperidin functions as an ergogenic aid by increasing endothelial function and decreasing exercise-induced oxidative stress and inflammation, thereby contributing to improved exercise performance. Nutrients, 14(14), 2955. doi: 10.3390/nu14142955
  23. Jedrychowski, M. P., Wrann, C. D., Paulo, J. A., Gerber, K. K., Szpyt, J., Robinson, M. M.,. Spiegelman, B. M. (2015). Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab, 22(4), 734-740. doi: 10.1016/j.cmet.2015.08.001
  24. Jørgensen, S. B., Richter, E. A., & Wojtaszewski, J. F. (2006). Role of AMPK in skeletal muscle metabolic regulation and adaptation in relation to exercise. J Physiol, 574(1), 17-31. doi: 10.1113/jphysiol.2006.109942
  25. Karplus, M., & McCammon, J. A. (2002). Molecular dynamics simulations of biomolecules. Nat Struct Biol, 9(9), 646-652. doi: 10.1038/nsb0902-646
  26. Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S.,. Yu, B. (2025). PubChem 2025 update. Nucleic Acids Res, 53(D1), D1516-D1525. doi: 10.1093/nar/gkae1059
  27. Kumar, S., Chhabra, V., Shenoy, S., Daksh, R., Ravichandiran, V., Swamy, R. S., & Kumar, N. (2024). Role of flavonoids in modulation of mitochondria dynamics during oxidative stress. Mini Rev Med Chem, 24(9), 908-919. doi: 10.2174/0113895575259219230920093214
  28. Laurindo, L. F., Rodrigues, V. D., Laurindo, L. F., Cherain, L. M. A., de Lima, E. P., Boaro, B. L.,. dos Santos Haber, J. F. (2025). Targeting AMPK with Irisin: Implications for metabolic disorders, cardiovascular health, and inflammatory conditions—A systematic review. Life Sci, 360, 123230. doi: 10.1016/j.lfs.2024.123230
  29. Li, H., Wang, F., Yang, M., Sun, J., Zhao, Y., & Tang, D. (2021). The effect of irisin as a metabolic regulator and its therapeutic potential for obesity. Int J Endocrinol, 2021(1), 6572342. doi: 10.1155/2021/6572342
  30. Maak, S., Norheim, F., Drevon, C. A., & Erickson, H. P. (2021). Progress and challenges in the biology of FNDC5 and irisin. Endocr Rev, 42(4), 436-456. doi: 10.1210/endrev/bnab003
  31. Mahgoub, M. O., D’Souza, C., Al Darmaki, R. S., Baniyas, M. M., & Adeghate, E. (2018). An update on the role of irisin in the regulation of endocrine and metabolic functions. Peptides, 104, 15-23. doi: 10.1016/j.peptides.2018.03.018
  32. Martínez-Noguera, F. J., Alcaraz, P. E., Carlos-Vivas, J., & Marín-Pagán, C. (2022). Chronic supplementation of 2S-hesperidin improves acid-base status and decreases lactate at FatMax, at ventilatory threshold 1 and 2 and after an incremental test in amateur cyclists. Biology (Basel), 11(5), 736. doi: 10.3390/biology11050736
  33. Martínez-Noguera, F. J., Alcaraz, P. E., Carlos-Vivas, J., & Marín-Pagán, C. (2023). 8 weeks of 2S-hesperidin prevents a decrease in pO2 at submaximal intensity in amateur cyclists in off-season: randomized controlled trial. Food Function, 14(6), 2750-2767. doi: 10.1039/D2FO03007A
  34. Martínez-Noguera, F. J., Marín-Pagán, C., Carlos-Vivas, J., Rubio-Arias, J. A., & Alcaraz, P. E. (2019). Acute effects of hesperidin in oxidant/antioxidant state markers and performance in amateur cyclists. Nutrients, 11(8), 1898. doi: 10.3390/nu11081898
  35. Narkar, V. A., Downes, M., Ruth, T. Y., Embler, E., Wang, Y.-X., Banayo, E.,. Juguilon, H. (2008). AMPK and PPARδ agonists are exercise mimetics. Cell, 134(3), 405-415. doi: 10.1016/j.cell.2008.06.051
  36. Parhiz, H., Roohbakhsh, A., Soltani, F., Rezaee, R., & Iranshahi, M. (2015). Antioxidant and anti‐inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res, 29(3), 323-331. doi: 10.1002/ptr.5256
  37. Perakakis, N., Triantafyllou, G. A., Fernández-Real, J. M., Huh, J. Y., Park, K. H., Seufert, J., & Mantzoros, C. S. (2017). Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol, 13(6), 324-337. doi: 10.1038/nrendo.2016.221
  38. Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004). UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem, 25(13), 1605-1612. doi: 10.1002/jcc.20084
  39. Pires, D. E., Blundell, T. L., & Ascher, D. B. (2015). pkCSM: predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem, 58(9), 4066-4072. doi: 10.1021/acs.jmedchem.5b00104
  40. Pyrzynska, K. (2022). Hesperidin: A review on extraction methods, stability and biological activities. Nutrients, 14(12), 2387.
  41. Rodríguez-González, G. L., Vargas-Hernández, L., Reyes-Castro, L. A., Ibáñez, C. A., Bautista, C. J., Lomas-Soria, C.,. Flores-Pliego, A. (2022). Resveratrol supplementation in obese pregnant rats improves maternal metabolism and prevents increased placental oxidative stress. Antioxidants (Basel), 11(10), 1871. doi: 10.3390/antiox11101871
  42. Roohbakhsh, A., Parhiz, H., Soltani, F., Rezaee, R., & Iranshahi, M. (2015). Molecular mechanisms behind the biological effects of hesperidin and hesperetin for the prevention of cancer and cardiovascular diseases. Life Sci, 124(1), 64-74. doi: 10.1016/j.lfs.2014.12.030
  43. Schake, P., Bolz, S. N., Linnemann, K., & Schroeder, M. (2025). PLIP 2025: introducing protein–protein interactions to the protein–ligand interaction profiler. Nucleic Acids Res, 53(1), 463-465. doi: 10.1093/nar/gkaf361
  44. Schrödinger, L., & DeLano, W. (2020). PyMOL. Retrieved from http://www.pymol.org/pymol
  45. Silla, A., Punzo, A., Caliceti, C., Barbalace, M. C., Hrelia, S., & Malaguti, M. (2025). The role of antioxidant compounds from citrus waste in modulating neuroinflammation: a sustainable solution. Antioxidants, 14(5), 581. doi: 10.3390/antiox14050581
  46. Steinberg, G. R., & Kemp, B. E. (2009). AMPK in health and disease. Physiol Rev, 89(3), 1025-1078. doi: 10.1152/physrev.00011.2008
  47. Trepiana, J., Milton-Laskibar, I., Gómez-Zorita, S., Eseberri, I., González, M., Fernández-Quintela, A., & Portillo, M. P. (2018). Involvement of 5′ AMP-activated protein kinase (AMPK) in the effects of resveratrol on liver steatosis. Int J Mol Sci, 19(11), 3473. doi: 10.3390/ijms19113473
  48. Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M.,. Andreelli, F. (2010). AMPK inhibition in health and disease. Crit Rev Biochem Mol Biol, 45(4), 276-295. doi: 10.3109/10409238.2010.488215
  49. Xu, G., Huang, K., & Zhou, J. (2018). Hepatic AMP kinase as a potential target for treating nonalcoholic fatty liver disease: evidence from studies of natural products. Curr Med Chem, 25(8), 889-907. doi: 10.2174/0929867324666170404142450
  50. Xu, Y., Wang, S., Hu, Q., Gao, S., Ma, X., Zhang, W.,. Pei, J. (2018). CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction. Nucleic Acids Res, 46(W1), W374-W379. doi: 10.1093/nar/gky380
  51. Al‐Ibraheem, A. M. T., Hameed, A. T. A. Z., Marsool, M. D. M., Jain, H., Prajjwal, P., Khazmi, I.,. Razzaq, M. (2024). Exercise‐Induced cytokines, diet, and inflammation and their role in adipose tissue metabolism. Health Sci Rep, 7(9), e70034. doi: 10.1002/hsr2.70034
  52. Boström, P., Wu, J., Jedrychowski, M. P., Korde, A., Ye, L., Lo, J. C.,. Long, J. Z. (2012). A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature, 481(7382), 463-468. doi: 10.1038/nature10777
  53. Jedrychowski, M. P., Wrann, C. D., Paulo, J. A., Gerber, K. K., Szpyt, J., Robinson, M. M.,. Spiegelman, B. M. (2015). Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab, 22(4), 734-740. doi: 10.1016/j.cmet.2015.08.001
  54. Kim, S., Chen, J., Cheng, T., Gindulyte, A., He, J., He, S.,. Yu, B. (2025). PubChem 2025 update. Nucleic Acids Res, 53(D1), D1516-D1525. doi: 10.1093/nar/gkae1059
  55. Laurindo, L. F., Rodrigues, V. D., Laurindo, L. F., Cherain, L. M. A., de Lima, E. P., Boaro, B. L.,. dos Santos Haber, J. F. (2025). Targeting AMPK with Irisin: Implications for metabolic disorders, cardiovascular health, and inflammatory conditions—A systematic review. Life Sci, 360, 123230. doi: 10.1016/j.lfs.2024.123230
  56. Narkar, V. A., Downes, M., Ruth, T. Y., Embler, E., Wang, Y.-X., Banayo, E.,. Juguilon, H. (2008). AMPK and PPARδ agonists are exercise mimetics. Cell, 134(3), 405-415. doi: 10.1016/j.cell.2008.06.051
  57. Rodríguez-González, G. L., Vargas-Hernández, L., Reyes-Castro, L. A., Ibáñez, C. A., Bautista, C. J., Lomas-Soria, C.,. Flores-Pliego, A. (2022). Resveratrol supplementation in obese pregnant rats improves maternal metabolism and prevents increased placental oxidative stress. Antioxidants (Basel), 11(10), 1871. doi: 10.3390/antiox11101871
  58. Viollet, B., Horman, S., Leclerc, J., Lantier, L., Foretz, M., Billaud, M.,. Andreelli, F. (2010). AMPK inhibition in health and disease. Crit Rev Biochem Mol Biol, 45(4), 276-295. doi: 10.3109/10409238.2010.488215
  59. Xu, Y., Wang, S., Hu, Q., Gao, S., Ma, X., Zhang, W.,. Pei, J. (2018). CavityPlus: a web server for protein cavity detection with pharmacophore modelling, allosteric site identification and covalent ligand binding ability prediction. Nucleic Acids Res, 46(W1), W374-W379. doi: 10.1093/nar/gky380