{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T15:54:47Z","timestamp":1790610887649,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China (NSFC) Young Scientists Fund, Category B","award":["82522002"],"award-info":[{"award-number":["82522002"]}]},{"name":"National Natural Science Foundation of China (NSFC) General Program","award":["82470119"],"award-info":[{"award-number":["82470119"]}]},{"DOI":"10.13039\/501100003453","name":"Guangdong Natural Science Foundation","doi-asserted-by":"crossref","award":["2024B1515020016"],"award-info":[{"award-number":["2024B1515020016"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Photoaging is an extrinsic skin aging process caused by chronic ultraviolet (UV) radiation. A core pathological feature of photoaging is excessive oxidative stress, which can further induce ferroptosis. The HSP70 family plays a critical role in this stress response by protecting the key antioxidant enzyme GPX4. In this study, we established UV-induced photoaging models in cultured cells and 3D skin organoids. UPLC-MS\/MS analysis of Chenpi transdermal permeate (prepared by in vitro transdermal penetration of Chenpi extract through mouse skin) identified hesperidin as the primary bioactive compound of Chenpi (dried peel of the plant Citrus reticulata Blanco after the aging process). The efficacy of hesperidin was validated in human keratinocytes (HaCaTs), fibroblasts (HSFs), and skin organoids. Mechanistically, transcriptomic and metabolomics analysis indicated that ferroptosis is a key pathway through which hesperidin ameliorates photoaging. Limited proteolysis mass spectrometry (LiP-MS), transcriptomics, and molecular dynamics simulation results demonstrated that hesperidin directly binds to the molecular chaperone HSPA1L. By upregulating HSPA1L expression, hesperidin enhanced the stability of GPX4 and suppressed UV-triggered ferroptosis. Our findings identify the HSPA1L\/GPX4 axis as a critical redox regulatory pathway targeted by hesperidin, providing a mechanistic foundation for anti-photoaging therapies.<\/jats:p>","DOI":"10.3390\/antiox15040484","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T10:29:08Z","timestamp":1776162548000},"page":"484","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Hesperidin from Chenpi Ameliorates Skin Photoaging by Targeting HSPA1L to Stabilize GPX4 and Suppress Ferroptosis"],"prefix":"10.3390","volume":"15","author":[{"given":"Xiaoyu","family":"Guo","sequence":"first","affiliation":[{"name":"Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengyao","family":"Wu","sequence":"additional","affiliation":[{"name":"Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxing","family":"Li","sequence":"additional","affiliation":[{"name":"Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlang","family":"He","sequence":"additional","affiliation":[{"name":"Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjie","family":"Ma","sequence":"additional","affiliation":[{"name":"Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taizhi","family":"Su","sequence":"additional","affiliation":[{"name":"Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changzheng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Hematology, Guangzhou Medical University, Guangzhou 511436, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[{"name":"Research Centre of Basic Integrative Medicine, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou 510006, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1016\/j.jaad.2021.02.048","article-title":"Visible light. Part I: Properties and cutaneous effects of visible light","volume":"84","author":"Austin","year":"2021","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1016\/j.jaad.2012.02.009","article-title":"The role of antioxidants in photoprotection: A critical review","volume":"67","author":"Chen","year":"2012","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1196\/annals.1395.029","article-title":"Proteasome and Photoaging","volume":"1100","author":"Bulteau","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_4","first-page":"632","article-title":"UVB-Induced Senescence of Human Dermal Fibroblasts Involves Impairment of Proteasome and Enhanced Autophagic Activity","volume":"72","author":"Cavinato","year":"2016","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s43630-025-00691-1","article-title":"Emerging role of ferroptosis in ultraviolet radiation-driven skin photoaging: A narrative review","volume":"24","author":"Teng","year":"2025","journal-title":"Photochem. Photobiol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3147","DOI":"10.2147\/CCID.S433071","article-title":"Variation of Ferroptosis-Related Markers in HaCaT Cell Photoaging Models Induced by UVB","volume":"16","author":"Zhang","year":"2023","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e15018","DOI":"10.1111\/exd.15018","article-title":"Ferrostatin 1 ameliorates UVB-induced damage of HaCaT cells by regulating ferroptosis","volume":"33","author":"Teng","year":"2024","journal-title":"Exp. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102143","DOI":"10.1016\/j.redox.2021.102143","article-title":"Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure","volume":"47","author":"Vats","year":"2021","journal-title":"Redox Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"112948","DOI":"10.1016\/j.jphotobiol.2024.112948","article-title":"ATG5-mediated keratinocyte ferroptosis promotes M1 polarization of macrophages to aggravate UVB-induced skin inflammation","volume":"257","author":"Xiao","year":"2024","journal-title":"J. Photochem. Photobiol. B Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"188890","DOI":"10.1016\/j.bbcan.2023.188890","article-title":"GPX4: The hub of lipid oxidation, ferroptosis, disease and treatment","volume":"1878","author":"Liu","year":"2023","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_12","first-page":"495","article-title":"Selenomethionine in gelatin methacryloyl hydrogels: Modulating ferroptosis to attenuate skin aging","volume":"35","author":"Sun","year":"2024","journal-title":"Bioact. Mater."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"124360","DOI":"10.1016\/j.carbpol.2025.124360","article-title":"Bletilla striata polysaccharide protects against UVA-induced skin damage by activating Nrf2\/HO-1 signaling and inhibiting ferroptosis","volume":"370","author":"Wang","year":"2025","journal-title":"Carbohydr. Polym."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1172\/JCI117800","article-title":"Heat shock protein 70 overexpression affects the response to ultraviolet light in murine fibroblasts. Evidence for increased cell viability and suppression of cytokine release","volume":"95","author":"Simon","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Batsukh, S., Oh, S., Lee, J.M., Joo, J.H.J., Son, K.H., and Byun, K. (2024). Extracellular Vesicles from Ecklonia cava and Phlorotannin Promote Rejuvenation in Aged Skin. Mar. Drugs, 22.","DOI":"10.3390\/md22050223"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/s42003-021-01902-y","article-title":"A Vaspin\u2013HSPA1L complex protects proximal tubular cells from organelle stress in diabetic kidney disease","volume":"4","author":"Nakatsuka","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1002\/jcsm.13459","article-title":"The regulation of MFG-E8 on the mitophagy in diabetic sarcopenia via the HSPA1L-Parkin pathway and the effect of D-pinitol","volume":"15","author":"Zhao","year":"2024","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1186\/s12944-017-0546-y","article-title":"Protective effects of orange (Citrus sinensis L.) peel aqueous extract and hesperidin on oxidative stress and peptic ulcer induced by alcohol in rat","volume":"16","author":"Selmi","year":"2017","journal-title":"Lipids Health Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"135952","DOI":"10.1016\/j.jhazmat.2024.135952","article-title":"Low-dose deoxynivalenol exposure triggers hepatic excessive ferritinophagy and mitophagy mitigated by hesperidin modulated O-GlcNAcylation","volume":"480","author":"Chen","year":"2024","journal-title":"J. Hazard. Mater."},{"key":"ref_20","unstructured":"Chen, X. (2015). Study on Protective Effects of Phlegm Mechanisms Against Skin Photoaging. [Master\u2019s Thesis, Guangzhou University of Chinese Medicine]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"tkaf016","DOI":"10.1093\/burnst\/tkaf016","article-title":"Advances in engineered organoid models of skin for biomedical research","volume":"13","author":"Zeng","year":"2025","journal-title":"Burn. Trauma"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41586-020-2352-3","article-title":"Hair-bearing human skin generated entirely from pluripotent stem cells","volume":"582","author":"Lee","year":"2020","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4162","DOI":"10.7150\/ijbs.97422","article-title":"FGF7 and FGF10 Promote Fate Transition of Human Epidermal Cell-derived Organoids to an Eccrine Gland Phenotype","volume":"20","author":"Zhao","year":"2024","journal-title":"Int. J. Biol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"611","DOI":"10.18063\/ijb.v8i4.611","article-title":"Recombinant Human Collagen-Based Bioinks for the 3D Bioprinting of Full-thickness Human Skin Equivalent","volume":"8","author":"Yang","year":"2022","journal-title":"Int. J. Bioprinting"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E7101","DOI":"10.1073\/pnas.1700475114","article-title":"Self-organization process in newborn skin organoid formation inspires strategy to restore hair regeneration of adult cells","volume":"114","author":"Lei","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1038\/s41467-025-57055-7","article-title":"Keratinocyte-driven dermal collagen formation in the axolotl skin","volume":"16","author":"Ohashi","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/j.molcel.2022.03.022","article-title":"Ferroptosis at the intersection of lipid metabolism and cellular signaling","volume":"82","author":"Liang","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/s41586-020-2732-8","article-title":"Plasticity of ether lipids promotes ferroptosis susceptibility and evasion","volume":"585","author":"Zou","year":"2020","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.cell.2017.09.021","article-title":"Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease","volume":"171","author":"Stockwell","year":"2017","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"101274","DOI":"10.1016\/j.drup.2025.101274","article-title":"ZNF207-driven PRDX1 lactylation and NRF2 activation in regorafenib resistance and ferroptosis evasion","volume":"82","author":"Yang","year":"2025","journal-title":"Drug Resist. Updates"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5848","DOI":"10.1074\/jbc.M109.063453","article-title":"Prevention of UVB Radiation-induced Epidermal Damage by Expression of Heat Shock Protein 70","volume":"285","author":"Matsuda","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1056\/NEJM199711133372003","article-title":"Pathophysiology of Premature Skin Aging Induced by Ultraviolet Light","volume":"337","author":"Fisher","year":"1997","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4774","DOI":"10.1016\/j.molcel.2024.10.044","article-title":"The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo","volume":"84","author":"Vind","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S55","DOI":"10.1016\/S0190-9622(98)70446-3","article-title":"Photoaging therapy with topical tretinoin: An evidence-based analysis","volume":"39","author":"Kang","year":"1998","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1\u201319; quiz 20-2","DOI":"10.1067\/mjd.2003.16","article-title":"Cutaneous photodamage, oxidative stress, and topical antioxidant protection","volume":"48","author":"Pinnell","year":"2003","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_36","first-page":"154","article-title":"The biological effect of recombinant humanized collagen on damaged skin induced by UV-photoaging: An in vivo study","volume":"11","author":"Wang","year":"2022","journal-title":"Bioact. Mater."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1016\/j.jaad.2021.12.019","article-title":"Photoprotection for skin of all color: Consensus and clinical guidance from an expert panel","volume":"86","author":"Rigel","year":"2022","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2412581","DOI":"10.1002\/advs.202412581","article-title":"Bioactive Glycyrrhizic Acid Ionic Liquid Self-Assembled Nanomicelles for Enhanced Transdermal Delivery of Anti-Photoaging Signal Peptides","volume":"12","author":"Wang","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1186\/s12951-022-01657-6","article-title":"Exosome-like nanovesicles derived from Phellinus linteus inhibit Mical2 expression through cross-kingdom regulation and inhibit ultraviolet-induced skin aging","volume":"20","author":"Han","year":"2022","journal-title":"J. Nanobiotechnol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"0098","DOI":"10.34133\/bmr.0098","article-title":"Polygonum multiflorum Extracellular Vesicle-Like Nanovesicle for Skin Photoaging Therapy","volume":"28","author":"He","year":"2024","journal-title":"Biomater. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"152887","DOI":"10.1016\/j.phymed.2019.152887","article-title":"Therapeutic potential of hesperidin and its aglycone hesperetin: Cell cycle regulation and apoptosis induction in cancer models","volume":"73","author":"Santos","year":"2020","journal-title":"Phytomedicine"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"108426","DOI":"10.1016\/j.jnutbio.2020.108426","article-title":"Citrus reticulata Blanco peel extract ameliorates hepatic steatosis, oxidative stress and inflammation in HF and MCD diet-induced NASH C57BL\/6 J mice","volume":"83","author":"Ke","year":"2020","journal-title":"J. Nutr. Biochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1007\/s00394-016-1207-z","article-title":"Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells","volume":"56","author":"Hagenlocher","year":"2017","journal-title":"Eur. J. Nutr."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bellavite, P., and Imbriano, A. (2025). Skin Photoaging and the Biological Mechanism of the Protective Effects of Hesperidin and Derived Molecules. Antioxidants, 14.","DOI":"10.3390\/antiox14070788"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pyrzynska, K. (2022). Hesperidin: A Review on Extraction Methods, Stability and Biological Activities. Nutrients, 14.","DOI":"10.3390\/nu14122387"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Herath, H.M.U.L., Piao, M.J., Kang, K.A., Zhen, A.X., Fernando, P.D.S.M., Kang, H.K., Yi, J.M., and Hyun, J.W. (2022). Hesperidin Exhibits Protective Effects against PM2.5-Mediated Mitochondrial Damage, Cell Cycle Arrest, and Cellular Senescence in Human HaCaT Keratinocytes. Molecules, 27.","DOI":"10.3390\/molecules27154800"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1702","DOI":"10.1111\/andr.13814","article-title":"Therapeutic potential of hesperidin in diabetes mellitus-induced erectile dysfunction through Nrf2-mediated ferroptosis and oxidative stress","volume":"13","author":"Xin","year":"2024","journal-title":"Andrology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1080\/15548627.2023.2165323","article-title":"Copper-dependent autophagic degradation of GPX4 drives ferroptosis","volume":"19","author":"Xue","year":"2023","journal-title":"Autophagy"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1158\/0008-5472.CAN-16-1979","article-title":"HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells","volume":"77","author":"Zhu","year":"2017","journal-title":"Cancer Res."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/484\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T04:17:31Z","timestamp":1776313051000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/15\/4\/484"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["antiox15040484"],"URL":"https:\/\/doi.org\/10.3390\/antiox15040484","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]}}}