2. Academic Validation
  3. Mitochondrial GCN5L1 acts as a novel regulator for iron homeostasis to promote sorafenib sensitivity in hepatocellular carcinoma

Mitochondrial GCN5L1 acts as a novel regulator for iron homeostasis to promote sorafenib sensitivity in hepatocellular carcinoma

  • J Transl Med. 2024 Jun 25;22(1):593. doi: 10.1186/s12967-024-05404-3.
Xiuya Hu # 1,  Peiyu Zhang # 1,  Sai Li 2,  Jiaqi Zhang 1,  Danni Wang 2,  Zihan Wang 2,  Lu Zhu 3 4 5,  Lingdi Wang 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Main Bldg., R1306 22 Qixiangtai Rd, Tianjin, 300070, China.
  • 2 The Province and Ministry co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 3 State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Main Bldg., R1306 22 Qixiangtai Rd, Tianjin, 300070, China. zhulu@tmu.edu.cn.
  • 4 The Province and Ministry co-sponsored Collaborative Innovation Center for Medical Epigenetics, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. zhulu@tmu.edu.cn.
  • 5 Department of Gynecology and Obstetrics, Tianjin Medical University General Hospital, Tianjin, China. zhulu@tmu.edu.cn.
  • 6 State Key Laboratory of Experimental Hematology, Tianjin Key Laboratory of Inflammatory Biology, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Tianjin Medical University, Main Bldg., R1306 22 Qixiangtai Rd, Tianjin, 300070, China. wanglingdi@tmu.edu.cn.
  • # Contributed equally.
PMID: 38918793 DOI: 10.1186/s12967-024-05404-3
Abstract

Background: Sorafenib resistance is becoming increasingly common and disadvantageous for hepatocellular carcinoma (HCC) treatment. Ferroptosis is an iron dependent programmed cell death underlying the mechanism of sorafenib. Iron is crucial for synthesis of cofactors essential to mitochondrial Enzymes and necessary for HCC proliferation, while mitochondrial iron overload and oxidative stress are associated with sorafenib induced Ferroptosis. However, the crosstalk among iron homeostasis and sorafenib resistance is unclear.

Methods: We conducted bioinformatics analysis of sorafenib treated HCC datasets to analyze GCN5L1 and iron related gene expression with sorafenib resistance. GCN5L1 deleted HCC cell lines were generated by CRISPR technology. Sorafenib resistant HCC cell line was established to validate dataset analysis and evaluate the effect of potential target.

Results: We identified GCN5L1, a regulator of mitochondrial acetylation, as a modulator in sorafenib-induced Ferroptosis via affecting mitochondrial iron homeostasis. GCN5L1 deficiency significantly increased sorafenib sensitivity in HCC cells by down-regulating mitochondrial iron transporters CISD1 expression to induce iron accumulation. Mitochondrial iron accumulation leads to an acceleration in cellular and lipid ROS. Sorafenib resistance is related to CISD1 overexpression to release mitochondrial iron and maintaining mitochondrial homeostasis. We combined CISD1 inhibitor NL-1 with sorafenib, which significantly enhanced sorafenib-induced Ferroptosis by promoting mitochondrial iron accumulation and lipid peroxidation. The combination of NL-1 with sorafenib enhanced sorafenib efficacy in vitro and in vivo.

Conclusions: Our findings demonstrate that GCN5L1/CISD1 axis is crucial for sorafenib resistance and would be a potential therapeutic strategy for sorafenib resistant HCC.

Keywords

CISD1; GCN5L1; Hepatocellular carcinoma; Mitochondrial ROS; Mitochondrial iron; Sorafenib.

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