An <scp>AMPK</scp> ‐Centric Strategy: Foenumoside B Coordinates <scp>PINK1</scp> /Parkin‐Mediated Mitophagy With Nrf2/ <scp>HO</scp> ‐1 Antioxidant Signaling to Resolve Oxidative Stress in Radiation‐Induced Lung Injury

Radiation-induced lung injury (RILI) is a dose-limiting toxicity of thoracic radiotherapy driven by mitochondrial damage-mediated oxidative stress, persistent DNA damage, and senescence, which together destabilize the alveolar-interstitial niche and promote fibrosis. Here, we identify Foenumoside B (FSB), a natural saponin from Lysimachia foenum-graecum, as a dual-action modulator that preserves mitochondrial quality and restores systemic redox homeostasis to attenuate RILI. In a murine total lung irradiation model (20 Gy), oral FSB (10 mg/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-dependent mitophagy in alveolar epithelial cells. Pharmacologic autophagy blockade (3-MA) or PINK1 silencing abrogated these benefits, increasing mtROS, γH2AX 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 α1 and α2 subunits of AMPK, thereby significantly increasing the p-AMPK/AMPK ratio. Upon pharmacologic inhibition of AMPK, the FSB-mediated 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-1 signaling and antioxidant capacity. Co-IP/ChIP showed AMPK directly associates with Nrf2, enhances its phosphorylation and ARE binding at the HO-1 promoter, and weakens Keap1-mediated degradation. Overall, FSB suppresses reactive oxygen species at their mitochondrial source and, through AMPK-driven mitophagy and Nrf2 activation, enhances endogenous antioxidant defenses, providing a translatable strategy to preserve alveolar architecture during radiotherapy.