Soybean Lecithin–Gallic Acid Complex Sensitizes Lung Cancer Cells to Radiation Through Ferroptosis Regulated by Nrf2/SLC7A11/GPX4 Pathway

<b>Background</b>: Radioresistance remains a significant obstacle in lung cancer radiotherapy, necessitating novel strategies to enhance therapeutic efficacy. This study investigated the radiosensitizing potential of a soybean lecithin-gallic acid complex (SL-GAC) in non-small cell lung cancer (NSCLC) cells and explored its underlying ferroptosis-related mechanisms. SL-GAC was synthesized to improve the bioavailability of gallic acid (GA), a polyphenol with anticancer properties. <b>Methods</b>: NSCLC cell lines (A549 and H1299) and normal bronchial epithelial cells (BEAS-2B) were treated with SL-GAC, ionizing radiation (IR), or their combination. Through a series of in vitro experiments, including cell viability assays, scratch healing assays, flow cytometry, and Western blot analysis, we comprehensively evaluated the effects of SL-GAC on NSCLC cell proliferation, migration, oxidative stress, and ferroptosis induction. <b>Results</b>: SL-GAC combined with IR synergistically suppressed NSCLC cell proliferation and migration, exacerbated oxidative stress via elevated ROS and malondialdehyde levels, and induced mitochondrial dysfunction marked by reduced membrane potential and structural damage, whereas no significant ROS elevation was observed in BEAS-2B cells. Mechanistically, the combination triggered ferroptosis in NSCLC cells, evidenced by iron accumulation and downregulation of Nrf2, SLC7A11, and GPX4, alongside upregulated ACSL4. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, reversed these effects and restored radiosensitivity. <b>Conclusions</b>: Our findings demonstrate that SL-GAC enhances NSCLC radiosensitivity by promoting ferroptosis via the Nrf2/SLC7A11/GPX4 axis, highlighting its potential as a natural radiosensitizer for clinical translation.