Academic Journal
Προβολή σε EDS
Συνδεδεμένο Πλήρες Κείμενο

Emodin alleviates radiation-induced pulmonary fibrosis by targeting cellular senescence via the mtDNA-cGAS-STING axis.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Emodin alleviates radiation-induced pulmonary fibrosis by targeting cellular senescence via the mtDNA-cGAS-STING axis.
Συγγραφείς: Duan W; Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China., Sha Y; 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan, People's Republic of China., Tang X; Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China., Liu R; Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China., Su B; 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan, People's Republic of China., Huang M; 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan, People's Republic of China., Xun X; 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan, People's Republic of China., Ye Y; 920th Hospital of Joint Logistics Support Force, PLA, Kunming, Yunnan, People's Republic of China. ye_yfei@163.com.
Πηγή: Biogerontology [Biogerontology] 2026 Jul 06; Vol. 27 (4). Date of Electronic Publication: 2026 Jul 06.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Kluwer Academic Country of Publication: Netherlands NLM ID: 100930043 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-6768 (Electronic) Linking ISSN: 13895729 NLM ISO Abbreviation: Biogerontology Subsets: MEDLINE
Imprint Name(s): Original Publication: Dordrecht ; Boston : Kluwer Academic, c2000-
Ιατρικοί όροι (MeSH): Cellular Senescence*/drug effects , Cellular Senescence*/radiation effects , Emodin*/pharmacology , DNA, Mitochondrial*/metabolism , Membrane Proteins*/metabolism , Nucleotidyltransferases*/metabolism , Pulmonary Fibrosis*/drug therapy , Pulmonary Fibrosis*/etiology , Pulmonary Fibrosis*/metabolism , Radiation Pneumonitis*/pathology , Radiation Pneumonitis*/metabolism , Radiation Pneumonitis*/drug therapy, Signal Transduction/drug effects ; Mitochondria/drug effects ; Mitochondria/metabolism ; Animals ; cGAS-STING Signaling Pathway ; STING Protein ; Mice ; Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase ; Mice, Inbred C57BL ; Male
Περίληψη: Radiation-induced pulmonary fibrosis (RIPF) is a severe complication of thoracic radiotherapy with limited effective treatment options. Cellular senescence has emerged as a critical driver of age-related tissue fibrosis; however, its role in RIPF and potential as a therapeutic target are underexplored. In this study, we investigated whether emodin, a natural compound with known anti-aging properties, alleviates RIPF by suppressing radiation-induced cellular senescence. In a mouse model exposed to 16 Gy thoracic irradiation, emodin treatment significantly attenuated pulmonary fibrosis, reduced collagen deposition, and downregulated fibrotic markers. Notably, emodin markedly suppressed radiation-induced senescence in pulmonary epithelial cells, accompanied by reduced secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, emodin preserved mitochondrial integrity, curbed mitochondrial reactive oxygen species (mtROS) accumulation, and prevented mitochondrial DNA (mtDNA) leakage into the cytoplasm, thereby inhibiting the cGAS-STING-NF-κB signaling pathway, a key pro-inflammatory axis in senescent cells. Importantly, knockdown of cGAS or treatment with the mitochondrial uncoupler CCCP attenuated the anti-senescent effects of emodin, underscoring the centrality of mitochondrial dysfunction and the mtDNA-cGAS-STING axis in senescence-driven fibrosis. Collectively, these findings identify emodin as a novel senescence-targeting agent that mitigates RIPF by alleviating mitochondrial dysfunction and disrupting the mtDNA-cGAS-STING pathway, highlighting its therapeutic potential in age-related fibrotic diseases.
(© 2026. The Author(s), under exclusive licence to Springer Nature B.V.)
Competing Interests: Declarations. Competing Interests: The authors declare no competing interests. Ethical approval: The study protocol was approved by the Ethics Committee of Jingzhou Hospital Affiliated to Yangtze University. All animal experiments were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the university.
References: Ahn SM et al (2016) Emodin from polygonum multiflorum ameliorates oxidative toxicity in HT22 cells and deficits in photothrombotic ischemia. J Ethnopharmacol 188:13–20. https://doi.org/10.1016/j.jep.2016.04.058. (PMID: 10.1016/j.jep.2016.04.05827151150)
Algieri C et al (2025) Mitochondrial dysfunction acts as a modulator of the immunometabolic route for activating the cytosolic DNA sensor pathway in triggering innate immunosurveillance. J Transl Med 23(1):1321. https://doi.org/10.1186/s12967-025-07392-4. (PMID: 10.1186/s12967-025-07392-44125782812628636)
Alipour-Khezri E et al (2025) Cytosolic DNA sensing pathway in senescence and aging: underlying mechanisms and targeted interventions. Biomed Pharmacother 193:118790. https://doi.org/10.1016/j.biopha.2025.118790. (PMID: 10.1016/j.biopha.2025.11879041273929)
Bryant JD et al (2022) Assessing mitochondrial DNA release into the cytosol and subsequent activation of innate immune-related pathways in mammalian cells. Curr Protoc 2(2):e372. Erratum in: Curr Protoc 4(7):e1106. https://doi.org/10.1002/cpz1.372.
Bai J et al (2020) Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a. Invest New Drugs 38(2):229–245. https://doi.org/10.1007/s10637-019-00777-5. (PMID: 10.1007/s10637-019-00777-530976957)
Blasiak J (2020) Senescence in the pathogenesis of age-related macular degeneration. Cell Mol Life Sci 77(5):789–805. https://doi.org/10.1007/s00018-019-03420-x. (PMID: 10.1007/s00018-019-03420-x3189754311105088)
Chang S et al (2024) Pathogenic mechanisms and latest therapeutic approaches for radiation-induced lung injury: a narrative review. Crit Rev Oncol Hematol 202:104461. https://doi.org/10.1016/j.critrevonc.2024.104461. (PMID: 10.1016/j.critrevonc.2024.10446139103129)
Chen C, Xu P (2023) Cellular functions of cGAS-STING signaling. Trends Cell Biol 33(8):630–648. https://doi.org/10.1016/j.tcb.2022.11.001. (PMID: 10.1016/j.tcb.2022.11.00136437149)
Chen B et al (2017) Ethyl pyruvate alleviates radiation-induced lung injury in mice. Biomed Pharmacother 92:468–478. https://doi.org/10.1016/j.biopha.2017.05.111. (PMID: 10.1016/j.biopha.2017.05.11128570981)
Chen Z et al (2019) Advances in molecular mechanisms and treatment of radiation-induced pulmonary fibrosis. Transl Oncol. 12(1):162–169. https://doi.org/10.1016/j.tranon.2018.09.009. (PMID: 10.1016/j.tranon.2018.09.00930342294)
Cheng DW et al (2022) Emodin alleviates arthritis pain through reducing spinal inflammation and oxidative stress. Mol Pain. 18:17448069221146398. https://doi.org/10.1177/17448069221146398. (PMID: 10.1177/17448069221146398364743089772972)
Cravereau O et al (2025) AFSOS-SFRO guidelines on radiation-induced lung injury. Clin Lung Cancer 26(7):527–540. https://doi.org/10.1016/j.cllc.2025.07.008. (PMID: 10.1016/j.cllc.2025.07.00840796462)
Feng L et al (2024) Emodin improves renal fibrosis in chronic kidney disease by regulating mitochondrial homeostasis through the mediation of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α). Eur J Histochem 68(2):3917. https://doi.org/10.4081/ejh.2024.3917. (PMID: 10.4081/ejh.2024.39173874240311128849)
Frediani E et al (2022) Olive phenols preserve lamin B1 expression reducing cGAS/STING/NFκB-mediated SASP in ionizing radiation-induced senescence. J Cell Mol Med 26(8):2337–2350. https://doi.org/10.1111/jcmm.17255. (PMID: 10.1111/jcmm.17255352780368995441)
Gao R et al (2017) Emodin suppresses TGF-β1-induced epithelial-mesenchymal transition in alveolar epithelial cells through notch signaling pathway. Toxicol Appl Pharmacol 318:1–7. https://doi.org/10.1016/j.taap.2016.12.009. (PMID: 10.1016/j.taap.2016.12.00927989784)
Gao M et al (2020) cGAS/STING: novel perspectives of the classic pathway. Mol Biomed 1(1):7. https://doi.org/10.1186/s43556-020-00006-z. (PMID: 10.1186/s43556-020-00006-z350064298603984)
Han L et al (2025) TMEM131-mediated soluble TRAIL triggered type II alveolar epithelial cell senescence in radiation-induced lung injury. Adv Sci (Weinh) 2025:e09973. https://doi.org/10.1002/advs.202509973. (PMID: 10.1002/advs.202509973)
Hanania AN et al (2019) Radiation-induced lung injury: assessment and management. Chest 156(1):150–162. https://doi.org/10.1016/j.chest.2019.03.033. (PMID: 10.1016/j.chest.2019.03.033309989088097634)
Hao X et al (2022) Chromatin basis of the senescence-associated secretory phenotype. Trends Cell Biol 32(6):513–526. https://doi.org/10.1016/j.tcb.2021.12.003. (PMID: 10.1016/j.tcb.2021.12.003350128499106822)
Jin H et al (2020) Radiationinduced lung fibrosis: preclinical animal models and therapeutic strategies. Cancers (Basel). 12(6):1561. https://doi.org/10.3390/cancers12061561. (PMID: 10.3390/cancers12061561325456747352529)
Li H et al (2022) Kanglexin delays heart aging by promoting mitophagy. Acta Pharmacol Sin 43(3):613–623. https://doi.org/10.1038/s41401-021-00686-5. (PMID: 10.1038/s41401-021-00686-534035486)
Li X et al (2023) Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther 8(1):239. https://doi.org/10.1038/s41392-023-01502-8. (PMID: 10.1038/s41392-023-01502-83729110510248351)
Liu S et al (2026) Rhapontigenin alleviates cellular senescence and physiological aging by upregulating sirt1 and promoting autophagy. Chin Med 21(1):22. https://doi.org/10.1186/s13020-025-01319-3. (PMID: 10.1186/s13020-025-01319-34150812112784611)
Loo TM et al (2020) Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer. Cancer Sci 111(2):304–311. https://doi.org/10.1111/cas.14266. (PMID: 10.1111/cas.1426631799772)
Lu L et al (2025) Emodin inhibits AIM2 inflammasome activation via modulating K27-linked polyubiquitination to attenuate renal fibrosis. Phytother Res 39(2):551–563. https://doi.org/10.1002/ptr.8390. (PMID: 10.1002/ptr.839039558552)
Mebratu YA et al (2023) The aged extracellular matrix and the profibrotic role of senescence-associated secretory phenotype. Am J Physiol Cell Physiol 325(3):C565–C579. https://doi.org/10.1152/ajpcell.00124.2023. (PMID: 10.1152/ajpcell.00124.20233748606510511170)
Meziani L et al (2018) CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages. Eur Respir J 51(3):1702120. https://doi.org/10.1183/13993003.02120-2017. (PMID: 10.1183/13993003.02120-201729496785)
Ni J et al (2023) STING signaling activation modulates macrophage polarization via CCL2 in radiation-induced lung injury. J Transl Med 21(1):590. https://doi.org/10.1186/s12967-023-04446-3. (PMID: 10.1186/s12967-023-04446-33766731710476398)
Parimon T et al (2023) Senescence of alveolar epithelial progenitor cells: a critical driver of lung fibrosis. Am J Physiol Cell Physiol 325(2):C483–C495. https://doi.org/10.1152/ajpcell.00239.2023. (PMID: 10.1152/ajpcell.00239.20233745843710511168)
Roy S et al (2021) Biology of radiation-induced lung injury. Semin Radiat Oncol 2021(31):155–161. https://doi.org/10.1016/j.semradonc.2020.11.006. (PMID: 10.1016/j.semradonc.2020.11.006)
Schafer MJ et al (2017) Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8:14532. https://doi.org/10.1038/ncomms14532. (PMID: 10.1038/ncomms14532282300515331226)
Shen G et al (2025) Emodin protects against severe acute pancreatitis-associated acute lung injury by activating Nrf2/HO-1/GPX4 signal and inhibiting ferroptosis in vivo and in vitro. BMC Gastroenterol 25(1):57. https://doi.org/10.1186/s12876-025-03660-1. (PMID: 10.1186/s12876-025-03660-13991046411800461)
Wang Y et al (2022) Emodin prevents renal ischemia-reperfusion injury via suppression of CAMKII/DRP1-mediated mitochondrial fission. Eur J Pharmacol 916:174603. https://doi.org/10.1016/j.ejphar.2021.174603. (PMID: 10.1016/j.ejphar.2021.17460334793771)
Zhang L et al (2023) Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS J. 290(5):1362–1383. https://doi.org/10.1111/febs.16350. (PMID: 10.1111/febs.1635035015337)
Zhang X et al (2025) Pathological mechanisms of radiation-induced lung injury and novel nano-drug delivery therapeutic strategies. Int J Nanomed 20:12431–12465. https://doi.org/10.2147/IJN.S551477. (PMID: 10.2147/IJN.S551477)
Zhao X et al (2025) The role of cGAS-STING pathway in the development of radiation-induced lung injury. J Cancer Res Clin Oncol 151(2):48. https://doi.org/10.1007/s00432-025-06088-y. (PMID: 10.1007/s00432-025-06088-y3985646411761121)
Zhu J et al (2024) TNKS1BP1 mediates AECII senescence and radiation induced lung injury through suppressing EEF2 degradation. Respir Res 25(1):299. https://doi.org/10.1186/s12931-024-02914-y. (PMID: 10.1186/s12931-024-02914-y3911301811308570)
Grant Information: chmdf2025-xrky11-05 Medical Research Projects of China Medical and Health Development Foundation; JM2025110199 Beijing Chen Jumei Public Welfare Foundation
Contributed Indexing: Keywords: CGAS–STING pathway; Cellular senescence; Emodin; Mitochondrial dysfunction; RIPF
Substance Nomenclature: KA46RNI6HN (Emodin)
0 (DNA, Mitochondrial)
0 (STING Protein)
EC 2.7.7.86 (Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase)
0 (Membrane Proteins)
EC 2.7.7.- (Nucleotidyltransferases)
EC 2.7.7.- (cGAS protein, mouse)
0 (Sting1 protein, mouse)
Entry Date(s): Date Created: 20260706 Date Completed: 20260706 Latest Revision: 20260706
Update Code: 20260706
DOI: 10.1007/s10522-026-10472-7
PMID: 42405973
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1573-6768
DOI:10.1007/s10522-026-10472-7