天津医科大学张晓东等研究人员合作发现，马兜铃酸劫持p53通过抑制铁死亡促进肝癌细胞生长。该研究于2024年8月1日在线发表于国际一流学术期刊《中国药理学报》。

研究人员探讨了马兜铃酸（AA）增强肝细胞癌（HCC）生长的分子机制。通过生物信息学和RNA-Seq分析，研究人员发现AA与铁死亡密切相关。在HepG2细胞中，通过生物信息学分析和SPR分析验证了p53与AA的物理相互作用，结合位点包含p53的Pro92、Arg174、Asp207、Phe212和His214。基于与AA相互作用的结合位点，研究人员设计了突变体并进行了RNA-Seq分析。研究发现，该结合位点对铁死亡、GADD45A、NRF2和SLC7A11具有重要作用。

功能上，这种相互作用干扰了p53与GADD45A或NRF2启动子的结合，减弱了p53在增强GADD45A和抑制NRF2中的作用；而突变体未表现出相同效果。因此，这一事件下调了GADD45A，上调了NRF2，最终抑制了铁死亡，这表明AA劫持了p53以下调GADD45A和上调NRF2，从而在HepG2细胞中抑制铁死亡。

总之，AA酸通过p53/GADD45A/NRF2/SLC7A11轴抑制铁死亡，进而增强肿瘤生长。该研究揭示了AA酸增强HCC的潜在机制，并提供了p53在肝癌中的新见解。从治疗角度看，癌基因NRF2是肝癌的一个有前景的靶点。

据悉，AA被认为是HCC的一个重要危险因素。铁死亡是一种涉及肿瘤发展的调控性细胞死亡形式。

附：英文原文

Title: Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis

Author: Hou, Chun-yu, Suo, Yu-hong, Lv, Pan, Yuan, Hong-feng, Zhao, Li-na, Wang, Yu-fei, Zhang, Hui-hui, Sun, Jiao, Sun, Lin-lin, Lu, Wei, Zhang, Ning-ning, Yang, Guang, Zhang, Xiao-dong

Issue&Volume: 2024-08-01

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.

DOI: 10.1038/s41401-024-01354-0

Source: https://www.nature.com/articles/s41401-024-01354-0