The induction of ferroptosis is promising for cancer therapy. However, the mechanisms enabling cancer cells to evade ferroptosis, particularly in low-cystine environments, remain elusive. Our study delves into the intricate regulatory mechanisms of Activating transcription factor 3 (ATF3) on Cystathionine β-synthase (CBS) under cystine deprivation stress, conferring resistance to ferroptosis in colorectal cancer (CRC) cells. Additionally, our findings establish a positively correlation between this signaling axis and CRC progression, suggesting its potential as a therapeutic target. Mechanistically, ATF3 positively regulates CBS to resist ferroptosis under cystine deprivation stress. In contrast, the suppression of CBS sensitizes CRC cells to ferroptosis through targeting the mitochondrial tricarboxylic acid (TCA) cycle. Notably, our study highlights that the ATF3-CBS signaling axis enhances ferroptosis-based CRC cancer therapy. Collectively, the findings reveal that the ATF3-CBS signaling axis is the primary feedback pathway in ferroptosis, and blocking this axis could be a potential therapeutic approach for colorectal cancer.

中文翻译：

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ATF3-CBS 信号轴协调结直肠癌中的铁死亡和肿瘤发生


铁死亡的诱导对于癌症治疗来说是有希望的。然而，使癌细胞逃避铁死亡的机制，特别是在低胱氨酸环境中，仍然难以捉摸。我们的研究深入探讨了在胱氨酸剥夺应激下激活转录因子 3 (ATF3) 对胱硫醚 β-合酶 (CBS) 的复杂调节机制，从而赋予结直肠癌 (CRC) 细胞对铁死亡的抵抗力。此外，我们的研究结果表明该信号轴与 CRC 进展之间呈正相关，表明其作为治疗靶点的潜力。从机制上讲，ATF3 正向调节 CBS 以抵抗胱氨酸剥夺应激下的铁死亡。相比之下，CBS 的抑制通过靶向线粒体三羧酸 (TCA) 循环，使 CRC 细胞对铁死亡敏感。值得注意的是，我们的研究强调 ATF3-CBS 信号轴增强了基于铁死亡的 CRC 癌症治疗。总的来说，研究结果表明 ATF3-CBS 信号轴是铁死亡的主要反馈途径，阻断该轴可能是结直肠癌的潜在治疗方法。