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Here, we identify Foenumoside B (FSB), a natural saponin from\n                    <jats:italic>Lysimachia foenum\u2010graecum<\/jats:italic>\n                    , as a dual\u2010action modulator that preserves mitochondrial quality and restores systemic redox homeostasis to attenuate RILI. In a murine total lung irradiation model (20\u2009Gy), oral FSB (10\u2009mg\/kg\/day) mitigated inflammation and fibrotic remodeling, improved pulmonary mechanics and arterial blood gases, and exhibited no overt hepatorenal toxicity. Mechanistically, FSB activated PINK1\/Parkin\u2010dependent mitophagy in alveolar epithelial cells. Pharmacologic autophagy blockade (3\u2010MA) or PINK1 silencing abrogated these benefits, increasing mtROS, \u03b3H2AX foci, comet tail moments, and p16\/p21 expression, and reducing cell viability, thereby confirming mitophagy as indispensable for FSB's cytoprotection. Molecular docking analysis demonstrates that FSB binds to the catalytic \u03b11 and \u03b12 subunits of AMPK, thereby significantly increasing the p\u2010AMPK\/AMPK ratio. Upon pharmacologic inhibition of AMPK, the FSB\u2010mediated improvements in mitophagy, mitochondrial function, redox homeostasis, and tissue protection are markedly attenuated, indicating that FSB's biological effects rely on AMPK activation. FSB also restored Nrf2\/HO\u20101 signaling and antioxidant capacity. Co\u2010IP\/ChIP showed AMPK directly associates with Nrf2, enhances its phosphorylation and ARE binding at the HO\u20101 promoter, and weakens Keap1\u2010mediated degradation. Overall, FSB suppresses reactive oxygen species at their mitochondrial source and, through AMPK\u2010driven mitophagy and Nrf2 activation, enhances endogenous antioxidant defenses, providing a translatable strategy to preserve alveolar architecture during radiotherapy.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501880r","type":"journal-article","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T07:51:27Z","timestamp":1763193087000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["An\n                    <scp>AMPK<\/scp>\n                    \u2010Centric Strategy: Foenumoside B Coordinates\n                    <scp>PINK1<\/scp>\n                    \/Parkin\u2010Mediated Mitophagy With Nrf2\/\n                    <scp>HO<\/scp>\n                    \u20101 Antioxidant Signaling to Resolve Oxidative Stress in Radiation\u2010Induced Lung Injury"],"prefix":"10.1096","volume":"39","author":[{"given":"Xiaoyu","family":"Pu","sequence":"first","affiliation":[{"name":"Jilin Provincial Key Laboratory of Radiation Oncology &amp; Therapy, Department of Radiation Oncology &amp; Therapy The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1070-1308","authenticated-orcid":false,"given":"Bohao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery The First Hospital of Jilin University  Changchun China"},{"name":"Department of Cell Fate and Diseases, Jilin Provincial Key Laboratory of Women's Reproductive Health, Jilin Provincial Clinical Research Center for Birth Defect and Rare Disease The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery The First Hospital of Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,14]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2023.10.044"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2019.03.033"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2019.03.006"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.999600"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.388"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-10386-8"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1909"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.95"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345221148983"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.28778"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-05281-y"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1042\/CS20211156"},{"key":"e_1_2_11_14_1","first-page":"164","article-title":"\u03b2\u2010Aminoisobutyrics 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