Main Session
Sep
28
PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology
2673 - The HPD-HGA Metabolic Axis Promotes Radioresistance by Suppressing Ferroptosis in Lung Cancer
Presenter(s)
Jiaqi Zhai, MD - State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science, Beijing,
J. Zhai1, R. Xu1, X. Xu1, S. Wang2, and M. Deng1; 1State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, 2State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, China
Purpose/Objective(s):
Radiotherapy is a major treatment modality for lung cancer, but adaptive metabolic rewiring can limit treatment response. Ferroptosis, a form of iron-dependent lipid peroxidation-driven cell death, is an important component of radiation-induced tumor killing. Our preliminary analyses showed that 4-hydroxyphenylpyruvate dioxygenase (HPD) is highly expressed in lung cancer and associated with poor prognosis. We hypothesized that HPD promotes homogentisic acid (HGA) accumulation, which suppresses radiation-induced ferroptosis by altering intracellular iron availability and lipid peroxidation, thereby driving radioresistance.Materials/Methods:
HPD expression and its prognostic relevance were examined in public datasets and lung cancer tissue specimens. Lung cancer cell lines with HPD overexpression or knockdown were established, and intracellular HGA was quantified by LC-MS. After ionizing radiation (IR), radiosensitivity was evaluated by CCK-8 and clonogenic assays. Ferroptosis-related changes were assessed by C11-BODIPY flow cytometry, MDA/4-HNE measurements, and transmission electron microscopy of mitochondrial morphology. Intracellular iron status was measured with FerroOrange and Fe²?/total iron assays. To define mechanism, we performed exogenous HGA supplementation, iron add-back (FAS/FAC), and rescue experiments using ferroptosis inhibitors (Ferrostatin-1, Liproxstatin-1, DFO) and non-ferroptotic cell death inhibitors (Z-VAD, Nec-1). GPX4, SLC7A11, and FSP1 were evaluated by immunoblotting. Xenograft models were used for in vivo validation of radiotherapy response with or without HPD targeting.Results:
HPD expression was elevated in lung cancer tissues and cell lines, and higher HPD levels were associated with worse clinical outcomes. HPD overexpression increased intracellular HGA and improved clonogenic survival after IR, whereas HPD knockdown lowered HGA and increased radiosensitivity. In mechanistic assays, HPD overexpression or exogenous HGA reduced the labile iron pool, decreased C11-BODIPY oxidation and MDA/4-HNE accumulation, and lessened IR-induced mitochondrial shrinkage, supporting inhibition of ferroptosis. Iron add-back partially reversed the radioprotective effect of HGA. Ferrostatin-1 and DFO produced similar protective effects, while Z-VAD and Nec-1 had little impact, indicating a ferroptosis-predominant mechanism. In xenograft models, HPD inhibition enhanced radiation-induced tumor growth delay, and exogenous HGA partially restored radioresistance.Conclusion:
These findings support a model in which the HPD-HGA metabolic axis promotes radioresistance in lung cancer by suppressing radiation-induced ferroptosis, at least in part through reducing labile iron availability and lipid peroxidation. Targeting HPD-HGA signaling may represent a novel metabolic radiosensitization strategy for lung cancer.