Zhang Jiaxin, Liu Zuojia, Zhao Wenjing, Li Chang, Liu Fei, Wang Jin
State Key Laboratory of Electroanalytical Chemistry Chinese Academy of Sciences Changchun Institute of Applied Chemistry Changchun China.
School of Chinese Medicine Hong Kong Traditional Chinese Medicine Phenome Research Center Hong Kong Baptist University Hong Kong China.
Smart Med. 2025 May 6;4(2):e70005. doi: 10.1002/smmd.70005. eCollection 2025 Jun.
Oncogenic KRAS, a notorious driver of cancer progression, remains a therapeutic challenge. In hepatocellular carcinoma (HCC), KRAS overexpression correlates with tumor aggressiveness. Here, we demonstrate that NSC48160 induces HCC cell death by suppressing KRAS expression. Metabolomic profiling revealed that NSC48160 significantly enhances intracellular tricarboxylic acid (TCA) cycle activity and fructose metabolism, disrupting redox homeostasis, and triggering ferroptosis. Combining NSC48160 with the SLC7A11 inhibitor HG106 synergistically eliminated HCC cells in vitro and suppressed tumor growth in vivo. Mechanistically, NSC48160 indirectly inhibits the Nrf2-SLC7A11-GPX4 axis, as evidenced by ferroptosis-pathway array assays. Specifically, NSC48160 downregulates Nrf2 expression, thereby suppressing its downstream targets GPX4 and SLC7A11, ultimately promoting ferroptosis. Our findings establish NSC48160 as a novel KRAS inhibitor that induces ferroptosis through metabolic and redox reprogramming, offering a promising therapeutic strategy for KRAS-driven HCC.
致癌性KRAS是癌症进展中臭名昭著的驱动因素，仍然是一个治疗挑战。在肝细胞癌（HCC）中，KRAS过表达与肿瘤侵袭性相关。在此，我们证明NSC48160通过抑制KRAS表达诱导HCC细胞死亡。代谢组学分析显示，NSC48160显著增强细胞内三羧酸（TCA）循环活性和果糖代谢，破坏氧化还原稳态，并引发铁死亡。将NSC48160与SLC7A11抑制剂HG106联合使用可在体外协同消除HCC细胞，并在体内抑制肿瘤生长。机制上，铁死亡途径阵列分析表明，NSC48160间接抑制Nrf2-SLC7A11-GPX4轴。具体而言，NSC48160下调Nrf2表达，从而抑制其下游靶点GPX4和SLC7A11，最终促进铁死亡。我们的研究结果确立了NSC48160作为一种新型KRAS抑制剂，它通过代谢和氧化还原重编程诱导铁死亡，为KRAS驱动的HCC提供了一种有前景的治疗策略。
