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2',4'-dihydroxychalcone induces ferroptosis through ERO1A/GPX4 regulatory axis in cholangiocarcinoma
Tong Wang1, Xuebing Zhou2, Nanmiao Wang2
1Department of Gynecology ,Yanbian University Hospital, Yanji, 133000, Jilin Province, China; Department of Pathology & Cancer Research Center, Yanbian University Medical College, Yanji, China; Key Laboratory of Pathobiology, State Ethnic Affairs Commission & Central Laboratory, Yanbian University Hospital,Yanji, China.
Background:
Cholangiocarcinoma (CCA) , an aggressive cancer often detected late, carries a grim prognosis. 2',4'-Dihydroxychalcone (2',4'-DHC), a flavonoid monomer isolated from Empetrum nigrum, has demonstrated notable anti-tumor activity in multiple cancer types. However, its therapeutic mechanism in cholangiocarcinoma remains poorly understood, especially regarding the regulation of ferroptosis, a mechanism that has not yet been fully elucidated in this disease.
Purpose:
This study reveals that 2',4'-DHC induces ferroptosis through modulation of the ERO1A/GPX4 signaling axis, thereby suppressing the progression of cholangiocarcinoma. These findings provide novel mechanistic insights and propose a potential therapeutic strategy for this highly refractory malignancy.
Methods:
Proliferation, migration, and epithelial-mesenchymal transition assays were employed to determine the effects of 2',4'-DHC and ERO1A on CCA cells. Electron microscopy and ferroptosis markers confirmed the involvement of ferroptosis. Molecular docking and molecular dynamics simulations established direct targeting between 2',4'-DHC and ERO1A. Ubiquitination assays validated ferroptosis potentiation. The anti-tumor efficacy of 2',4'-DHC was assessed in murine xenograft models.
Results:
In our study, we first demonstrated that 2',4'-DHC inhibited the proliferation, migration and EMT progression of CCA cells, by inducing ferroptosis, Mechanistically, 2',4'-DHC targeted ERO1A, leading to GPX4 ubiquitination and subsequent proteasomal degradation. In vivo, 2',4'-DHC suppressed tumor growth and significantly enhanced the therapeutic efficacy of oxaliplatin, without causing evident toxicity to major organs.
Conclusion:
2',4'-DHC induces ferroptosis in CCA cells through the ERO1A/GPX4 axis and inhibits malignant progression. 2',4'-DHC drug-adjuvant therapy may enhance the efficacy of current anticancer treatments. It also holds promise as a prognostic molecular marker and therapeutic target in CCA.
