蛇床子酸劫持p53促进肝癌细胞增长，通过抑制铁死亡作用
Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis
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影响因子:8.4
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2025 Jan
作者:
Chun-Yu Hou, Yu-Hong Suo, Pan Lv, Hong-Feng Yuan, Li-Na Zhao, Yu-Fei Wang, Hui-Hui Zhang, Jiao Sun, Lin-Lin Sun, Wei Lu, Ning-Ning Zhang, Guang Yang, Xiao-Dong Zhang
DOI:
10.1038/s41401-024-01354-0
摘要
蛇床子酸（AAs）已被证实为肝细胞癌（HCC）的重要风险因素。铁死亡是一种调控性细胞死亡方式，参与肿瘤发生。在本研究中，我们探讨了AAs增强HCC生长的分子机制。通过生物信息学和RNA-Seq分析发现，AAs与铁死亡密切相关。在HepG2细胞中验证了p53与AAs的物理相互作用，结合SPR分析确定了p53的结合位点，包括Pro92、Arg174、Asp207、Phe212和His214。基于与AAs相互作用的结合位点，我们设计了突变体并进行了RNA-Seq分析。结果显示，该结合位点调控铁死亡相关基因GADD45A、NRF2和SLC7A11。功能性研究表明，AAs的结合破坏p53与GADD45A或NRF2启动子区域的结合，减弱了p53促进GADD45A表达和抑制NRF2的作用；突变体未表现出相同效应。结果导致GADD45A下调、NRF2上调，最终抑制铁死亡，暗示AAs劫持p53以下调GADD45A和上调NRF2，从而促进肿瘤生长。总结而言，AAs通过劫持p53调控GADD45A/NRF2/SLC7A11轴抑制铁死亡，增强肿瘤生长。这一机制揭示了AAs增强HCC的潜在途径及p53在肝癌中的新作用，为肝癌治疗提供新靶点，特别是肿瘤促基因NRF2具有潜在的临床应用价值。
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.