{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T23:42:54Z","timestamp":1780098174652,"version":"3.54.0"},"reference-count":59,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Peking University Medical-Qingyan Boshi Joint Laboratory for Skin Nutrition and Anti-Aging","award":["L202206"],"award-info":[{"award-number":["L202206"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Ovarian aging represents a critically important aspect of female senescence. It not only denotes the loss of fertility but is also accompanied by a series of physiological changes and the aging of other organs. Hydroxytyrosol (HT), a natural polyphenolic phytocompound, has been demonstrated to exhibit remarkable effects in regulating autophagy, inflammation, and the aging process. However, the relationship between HT and ovarian aging, as well as the specific underlying mechanisms, remains poorly understood. Methods: In this study, network pharmacology, molecular docking, and molecular dynamics simulation were employed to explore the regulatory effect of HT on ovarian inflammaging via autophagy-targeted mechanisms. Results: Through network pharmacology analysis, this study successfully identified 10 hub genes associated with ovarian aging regulation. Notably, four out of the top five hub genes were found to be closely related to autophagy regulatory pathways. Further investigation revealed the pivotal role of ATG7: HT may regulate ovarian inflammaging through activating the FIP200 (focal adhesion kinase family interacting protein of 200 kD)-dependent non-canonical selective autophagy pathway. The results of molecular docking indicated that ATG7 has a strong binding ability with HT. Molecular dynamics simulation further verified the binding stability between the two. Conclusions: By analysis, a possible pathway for HT to regulate ovarian inflammaging via non-canonical selective autophagy was explored, providing cues for further research.<\/jats:p>","DOI":"10.3390\/nu17091421","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T08:26:43Z","timestamp":1745396803000},"page":"1421","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Exploring the Regulatory Effect of Hydroxytyrosol on Ovarian Inflammaging Through Autophagy-Targeted Mechanisms: A Bioinformatics Approach"],"prefix":"10.3390","volume":"17","author":[{"given":"Xiaoyang","family":"An","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7201-6982","authenticated-orcid":false,"given":"Meihong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing 100191, China"},{"name":"Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1210\/er.2009-0006","article-title":"Ovarian Aging: Mechanisms and Clinical Consequences","volume":"30","author":"Broekmans","year":"2009","journal-title":"Endocr. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1113\/jphysiol.2014.282665","article-title":"Physiological geroscience: Targeting function to increase healthspan and achieve optimal longevity","volume":"594","author":"Seals","year":"2016","journal-title":"J. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1749-6632.2000.tb06651.x","article-title":"Inflamm-aging. An evolutionary perspective on immunosenescence","volume":"908","author":"Franceschi","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"38","DOI":"10.4103\/0019-5278.82996","article-title":"Night work and inflammatory markers","volume":"15","author":"Khosro","year":"2011","journal-title":"Indian. J. Occup. Environ. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1093\/gerona\/glu057","article-title":"Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases","volume":"69","author":"Franceschi","year":"2014","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2706","DOI":"10.1016\/j.fertnstert.2009.02.038","article-title":"The variable expression of lectin-like oxidized low-density lipoprotein receptor (LOX-1) and signs of autophagy and apoptosis in freshly harvested human granulosa cells depend on gonadotropin dose, age, and body weight","volume":"93","author":"Vilser","year":"2010","journal-title":"Fertil. Steril."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1080\/15548627.2021.1933742","article-title":"Autophagy in metabolism and quality control: Opposing, complementary or interlinked functions?","volume":"18","author":"Deretic","year":"2022","journal-title":"Autophagy"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e16166","DOI":"10.1111\/jog.16166","article-title":"Exploring potential pathways from oxidative stress to ovarian aging","volume":"51","author":"Kobayashi","year":"2025","journal-title":"J. Obs. Gynaecol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.molimm.2018.09.010","article-title":"The role of mitochondria in NLRP3 inflammasome activation","volume":"103","author":"Liu","year":"2018","journal-title":"Mol. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"166","DOI":"10.18632\/aging.100444","article-title":"Inflammaging: Disturbed interplay between autophagy and inflammasomes","volume":"4","author":"Salminen","year":"2012","journal-title":"Aging"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101468","DOI":"10.1016\/j.arr.2021.101468","article-title":"Autophagy and the hallmarks of aging","volume":"72","author":"Kaushik","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1080\/15548627.2022.2029234","article-title":"The RB1CC1 Claw-binding motif: A new piece in the puzzle of autophagy regulation","volume":"18","author":"Popelka","year":"2022","journal-title":"Autophagy"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.molcel.2019.01.035","article-title":"FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates","volume":"74","author":"Turco","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1038\/s41467-021-21874-1","article-title":"Phosphorylation regulates the binding of autophagy receptors to FIP200 Claw domain for selective autophagy initiation","volume":"12","author":"Zhou","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1080\/15548627.2023.2197760","article-title":"LC3-independent autophagy is vital to prevent TNF cytotoxicity","volume":"19","author":"Priem","year":"2023","journal-title":"Autophagy"},{"key":"ref_16","unstructured":"Nutrition and Allergies EFSA Panel on Dietetic Products (2011). Scientific Opinion on the Substantiation of Health Claims Related to Polyphenols in Olive and Protection of LDL Particles from Oxidative Damage (ID 1313, 1333, 1638, 1639, 1696, 2865) Pursuant to Article 13(1) of Regulation (EC) No 1924\/2006, European Food Safety Authority (EFSA)."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/S0014-5793(00)01216-3","article-title":"Olive oil phenolics are dose-dependently absorbed in humans","volume":"468","author":"Visioli","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.foodres.2017.11.053","article-title":"Hydroxytyrosol: Bioavailability, toxicity, and clinical applications","volume":"105","author":"Quiles","year":"2018","journal-title":"Food Res. Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4258","DOI":"10.7150\/ijbs.97263","article-title":"The PI3K\/Akt-Nrf2 Signaling Pathway and Mitophagy Synergistically Mediate Hydroxytyrosol to Alleviate Intestinal Oxidative Damage","volume":"20","author":"Wen","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5043","DOI":"10.1021\/jf0703710","article-title":"Hydroxytyrosol-rich olive mill wastewater extract protects brain cells in vitro and ex vivo","volume":"55","author":"Schaffer","year":"2007","journal-title":"J. Agric. Food Chem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Velotti, F., and Bernini, R. (2023). Hydroxytyrosol Interference with Inflammaging via Modulation of Inflammation and Autophagy. Nutrients, 15.","DOI":"10.3390\/nu15071774"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1016\/j.jnutbio.2009.09.006","article-title":"Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells","volume":"21","author":"Zhu","year":"2010","journal-title":"J. Nutr. Biochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.phrs.2019.03.005","article-title":"Hydroxytyrosol protects from aging process via AMPK and autophagy; a review of its effects on cancer, metabolic syndrome, osteoporosis, immune-mediated and neurodegenerative diseases","volume":"143","author":"Cano","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"111579","DOI":"10.1016\/j.nut.2021.111579","article-title":"Hydroxytyrosol alleviates dextran sodium sulfate-induced colitis by inhibiting NLRP3 inflammasome activation and modulating gut microbiota in vivo","volume":"97","author":"Miao","year":"2022","journal-title":"Nutrition"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1093\/humupd\/dmm048","article-title":"Cellular and molecular aspects of ovarian follicle ageing","volume":"14","author":"Tatone","year":"2008","journal-title":"Hum. Reprod. Update"},{"key":"ref_26","first-page":"6455","article-title":"Hydroxytyrosol suppresses LPS-induced intrahepatic inflammatory responses via inhibition of ERK signaling pathway activation in acute liver injury","volume":"24","author":"Yu","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"W55","DOI":"10.1093\/nar\/gkn307","article-title":"SuperPred: Drug classification and target prediction","volume":"36","author":"Dunkel","year":"2008","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D1633","DOI":"10.1093\/nar\/gkae1075","article-title":"BindingDB in 2024: A FAIR knowledgebase of protein-small molecule binding data","volume":"53","author":"Liu","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"D1328","DOI":"10.1093\/nar\/gkae883","article-title":"Comparative Toxicogenomics Database\u2019s 20th anniversary: Update 2025","volume":"53","author":"Davis","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"D1144","DOI":"10.1093\/nar\/gkaa1084","article-title":"Integration of the Drug-Gene Interaction Database (DGIdb 4.0) with open crowdsource efforts","volume":"49","author":"Freshour","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1758-2946-6-13","article-title":"TCMSP: A database of systems pharmacology for drug discovery from herbal medicines","volume":"6","author":"Ru","year":"2014","journal-title":"J. Cheminform."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s13321-018-0289-4","article-title":"HAMdb: A database of human autophagy modulators with specific pathway and disease information","volume":"10","author":"Wang","year":"2018","journal-title":"J. Cheminform."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1080\/15548627.2023.2247737","article-title":"AutophagyNet: High-resolution data source for the analysis of autophagy and its regulation","volume":"20","author":"Csabai","year":"2024","journal-title":"Autophagy"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"D701","DOI":"10.1093\/nar\/gkab909","article-title":"SignaLink3: A multi-layered resource to uncover tissue-specific signaling networks","volume":"50","author":"Csabai","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"D368","DOI":"10.1093\/nar\/gkad1011","article-title":"AlphaFold Protein Structure Database in 2024: Providing structure coverage for over 214 million protein sequences","volume":"52","author":"Varadi","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.molcel.2011.08.034","article-title":"Atg8 transfer from Atg7 to Atg3: A distinctive E1-E2 architecture and mechanism in the autophagy pathway","volume":"44","author":"Taherbhoy","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.18632\/aging.101325","article-title":"Targeted elimination of senescent Ras-transformed cells by suppression of MEK\/ERK pathway","volume":"9","author":"Kochetkova","year":"2017","journal-title":"Aging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"613","DOI":"10.3892\/ijmm.2012.891","article-title":"ERK and Akt signaling pathways are involved in advanced glycation end product-induced autophagy in rat vascular smooth muscle cells","volume":"29","author":"Hu","year":"2012","journal-title":"Int. J. Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Pokharel, S.M., Shil, N.K., and Bose, S. (2016). Autophagy, TGF-\u03b2, and SMAD-2\/3 Signaling Regulates Interferon-\u03b2 Response in Respiratory Syncytial Virus Infected Macrophages. Front. Cell Infect. Microbiol., 6.","DOI":"10.3389\/fcimb.2016.00174"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eabn4395","DOI":"10.1126\/scisignal.abn4395","article-title":"Coordinated activation of TGF-\u03b2 and BMP pathways promotes autophagy and limits liver injury after acetaminophen intoxication","volume":"15","author":"Stavropoulos","year":"2022","journal-title":"Sci. Signal."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"332","DOI":"10.2203\/dose-response.10-013.Yeager","article-title":"Cortisol exerts bi-phasic regulation of inflammation in humans","volume":"9","author":"Yeager","year":"2011","journal-title":"Dose Response"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"7476","DOI":"10.1158\/1538-7445.AM2024-7476","article-title":"Abstract 7476: Obtusifolin attenuates LPS-induced inflammation and NLRP3 inflammasome activation by suppressing the MAPK\/NF-\u03baB signaling pathway and ROS production in BV2 cells","volume":"84","author":"Lin","year":"2024","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1002\/ptr.8071","article-title":"Oral administration of punicalagin attenuates imiquimod-induced psoriasis by reducing ROS generation and inflammation via MAPK\/ERK and NF-\u03baB signaling pathways","volume":"38","author":"Wang","year":"2024","journal-title":"Phytother. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.4049\/jimmunol.0803851","article-title":"Inhibition of ERK MAPK suppresses IL-23- and IL-1-driven IL-17 production and attenuates autoimmune disease","volume":"183","author":"Brereton","year":"2009","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Wu, Z., Yu, Y., Niu, L., Fei, A., and Pan, S. (2016). IGF-1 protects tubular epithelial cells during injury via activation of ERK\/MAPK signaling pathway. Sci. Rep., 6.","DOI":"10.1038\/srep28066"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"E955","DOI":"10.1210\/jc.2015-1431","article-title":"Up-regulation of Bcl-2 by CD147 Through ERK Activation Results in Abnormal Cell Survival in Human Endometriosis","volume":"100","author":"Wang","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"109031","DOI":"10.1016\/j.intimp.2022.109031","article-title":"EphA10 drives tumor progression and immune evasion by regulating the MAPK\/ERK cascade in lung adenocarcinoma","volume":"110","author":"Zhao","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/s12985-023-02166-0","article-title":"DENV-2 NS1 promotes AMPK-LKB1 interaction to activate AMPK\/ERK\/mTOR signaling pathway to induce autophagy","volume":"20","author":"Wu","year":"2023","journal-title":"Virol. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s12672-024-01167-x","article-title":"Autophagy-related biomarkers in hepatocellular carcinoma and their relationship with immune infiltration","volume":"15","author":"Li","year":"2024","journal-title":"Discov. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8615","DOI":"10.18632\/aging.204360","article-title":"IGF1 gene therapy in middle-aged female rats delays reproductive senescence through its effects on hypothalamic GnRH and kisspeptin neurons","volume":"14","author":"Dolcetti","year":"2022","journal-title":"Aging"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.18632\/aging.203857","article-title":"A comprehensive analysis of age-related metabolomics and transcriptomics reveals metabolic alterations in rat bone marrow mesenchymal stem cells","volume":"14","author":"Yu","year":"2022","journal-title":"Aging"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Tracz-Gaszewska, Z., and Dobrzyn, P. (2019). Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer. Cancers, 11.","DOI":"10.3390\/cancers11070948"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"19062","DOI":"10.1074\/jbc.M500566200","article-title":"Persistent nuclear factor-kappa B activation in Ucp2-\/- mice leads to enhanced nitric oxide and inflammatory cytokine production","volume":"280","author":"Bai","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1038\/s41419-021-04188-4","article-title":"An interplay between UCP2 and ROS protects cells from high-salt-induced injury through autophagy stimulation","volume":"12","author":"Forte","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"107072","DOI":"10.1016\/j.foodhyd.2021.107072","article-title":"Study of the binding mechanism between hydroxytyrosol and bovine serum albumin using multispectral and molecular docking","volume":"122","author":"Lv","year":"2022","journal-title":"Food Hydrocoll."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"138813","DOI":"10.1016\/j.foodchem.2024.138813","article-title":"Interaction of soy protein isolate with hydroxytyrosol based on an alkaline method: Implications for structural and functional properties","volume":"446","author":"Gu","year":"2024","journal-title":"Food Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1007\/s00217-015-2614-8","article-title":"In vitro investigation on the antiglycative and carbonyl trapping activities of hydroxytyrosol","volume":"242","author":"Navarro","year":"2016","journal-title":"Eur. Food Res. Technol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1421\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:20:06Z","timestamp":1760030406000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/9\/1421"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,23]]},"references-count":59,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["nu17091421"],"URL":"https:\/\/doi.org\/10.3390\/nu17091421","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,23]]}}}