Abstract
Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.
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Data availability
The RNA-Seq data are available at the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra/), accession number: PRJNA1000259.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (82372818 to Xiao-dong Zhang; 82103066 to Guang Yang; 82302887 to Hong-feng Yuan; 82303210 to Yu-fei Wang).
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XDZ, GY, and CYH concepted and designed the project; YHS and HFY Developed the methodology; CYH acquired the data Acquisition of data (provided animals, provided facilities, etc.); CYH, LNZ, YFW, HHZ, LLS, JS, WL and PL analyzed and interpreted the data (e.g., statistical analysis, biostatistics, computational analysis); CYH, NNZ and XDZ written, reviewed, and/or revised of the manuscript.
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Hou, Cy., Suo, Yh., Lv, P. et al. Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis. Acta Pharmacol Sin 46, 208–221 (2025). https://doi.org/10.1038/s41401-024-01354-0
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DOI: https://doi.org/10.1038/s41401-024-01354-0
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