Li Miaomiao, Wang Yi, Li Xinyan, Xu Jiayi, Yan Liangwen, Tang Shenkang, Liu Chenyue, Shi Mengjiao, Liu Rongrong, Zhao Yaping, Zhang Yi, Yang Lan, Zhang Yinggang, Wang Gang, Li Zongfang, Guo Ying, Feng Yetong, Liu Pengfei
Department of Critical Care Medicine, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Cell Death Dis. 2025 Apr 6;16(1):257. doi: 10.1038/s41419-025-07581-5.
Protein tyrosine phosphatase mitochondrial 1 (PTPMT1), is a member of the protein tyrosine phosphatase superfamily localized on the mitochondrial inner membrane, and regulates the biosynthesis of cardiolipin. Given the important position of PTPMT1 in mitochondrial function and metabolism, pharmacological targeting of PTPMT1 is considered a promising manner in disease treatments. In this study, we mainly investigated the role of PTPMT1 in hepatocellular carcinoma (HCC) ferroptosis, a new type of cell death accompanied by significant iron accumulation and lipid peroxidation. Herein, the pharmacological inhibition of PTPMT1 was induced by alexidine dihydrochloride (AD, a dibiguanide compound). Human HCC cell lines with PTPMT1 knockout and PTPMT1 overexpression were established using CRISPR/Cas9 and lentiviral transduction methods, respectively. The position of PTPMT1 in regulating HCC ferroptosis was evaluated in vitro and in vivo. Our results indicated that pharmacological inhibition of PTPMT1, facilitated by AD treatment, heightens the susceptibility of HCC to cystine deprivation-ferroptosis, and AD treatment promoted the conversion from ferritin-bound Fe to free Fe, which contributed to the labile iron pool in cytoplasm. Meanwhile, pharmacological inhibition of PTPMT1 also induced the formation of both swollen mitochondria and donut mitochondria, and enhanced the metabolism process form succinate to fumarate in mitochondrial tricarboxylic acid (TCA) cycle, which increased the sensitivity of HCC cells to cystine deprivation-induced ferroptosis. In total, our work reveals the close association of PTPMT1 with cysteine deprivation-induced ferroptosis, providing a novel insight into chemotherapy strategies against human HCC.
蛋白酪氨酸磷酸酶线粒体1（PTPMT1）是位于线粒体内膜上的蛋白酪氨酸磷酸酶超家族的成员，可调节心磷脂的生物合成。鉴于PTPMT1在线粒体功能和代谢中的重要地位，对PTPMT1进行药物靶向治疗被认为是一种很有前景的疾病治疗方式。在本研究中，我们主要研究了PTPMT1在肝细胞癌（HCC）铁死亡中的作用，铁死亡是一种新型细胞死亡，伴有大量铁蓄积和脂质过氧化。在此，通过二盐酸阿来西定（AD，一种双胍类化合物）诱导对PTPMT1的药理抑制。分别使用CRISPR/Cas9和慢病毒转导方法建立了PTPMT1基因敲除和PTPMT1过表达的人肝癌细胞系。在体外和体内评估了PTPMT1在调节HCC铁死亡中的作用。我们的结果表明，AD处理促进的PTPMT1药理抑制增强了HCC对胱氨酸剥夺诱导的铁死亡的敏感性，并且AD处理促进了铁蛋白结合的铁向游离铁的转化，这有助于细胞质中不稳定铁池的形成。同时，PTPMT1的药理抑制还诱导了肿胀线粒体和环形线粒体的形成，并增强了线粒体三羧酸（TCA）循环中从琥珀酸到延胡索酸的代谢过程，这增加了HCC细胞对胱氨酸剥夺诱导的铁死亡的敏感性。总之，我们的工作揭示了PTPMT1与半胱氨酸剥夺诱导的铁死亡密切相关，为针对人类HCC的化疗策略提供了新的见解。
