FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner

Cell Death Dis. 2023 Aug 26;14(8):567. doi: 10.1038/s41419-023-06070-x.

Jong Woo Kim ^# ¹ ², Min-Ju Kim ^# ³, Tae-Hee Han ⁴ ⁵, Ji-Yoon Lee ¹, Sangok Kim ⁶, Hyerin Kim ⁶, Kyoung-Jin Oh ¹ ², Won Kon Kim ¹ ², Baek-Soo Han ² ⁷, Kwang-Hee Bae ¹ ², Hyun Seung Ban ⁴ ⁵, Soo Han Bae ⁸ ⁹, Sang Chul Lee ¹⁰ ¹¹, Haeseung Lee ¹², Eun-Woo Lee ¹³ ¹⁴ ¹⁵

Affiliations

1 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
2 Department of Functional Genomics, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
3 Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea.
4 Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
5 Department of Biomolecular Science, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea.
6 Korea Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
7 Biodefense Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea.
8 Severance Biomedical Science Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
9 Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
10 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea. lesach@kirbb.re.kr.
11 Department of Functional Genomics, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea. lesach@kirbb.re.kr.
12 Department of Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan, 46241, Republic of Korea. haeseung@pusan.ac.kr.
13 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Republic of Korea. ewlee@kribb.re.kr.
14 Department of Functional Genomics, University of Science and Technology (UST), Daejeon, 34113, Republic of Korea. ewlee@kribb.re.kr.
15 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. ewlee@kribb.re.kr.
# Contributed equally.

PMID: 37633973 DOI: 10.1038/s41419-023-06070-x

Abstract

Ferroptosis, a type of cell death induced by lipid peroxidation, has emerged as a novel anti-cancer strategy. Cancer cells frequently acquire resistance to Ferroptosis. However, the underlying mechanisms are poorly understood. To address this issue, we conducted a thorough investigation of the genomic and transcriptomic data derived from hundreds of human Cancer cell lines and primary tissue samples, with a particular focus on non-small cell lung carcinoma (NSCLC). It was observed that mutations in Kelch-like ECH-associated protein 1 (KEAP1) and subsequent nuclear factor erythroid 2-related factor 2 (NRF2, also known as NFE2L2) activation are strongly associated with Ferroptosis resistance in NSCLC. Additionally, AIFM2 gene, which encodes Ferroptosis suppressor protein 1 (FSP1), was identified as the gene most significantly correlated with Ferroptosis resistance, followed by multiple NRF2 targets. We found that inhibition of NRF2 alone was not sufficient to reduce FSP1 protein levels and promote Ferroptosis, whereas FSP1 inhibition effectively sensitized KEAP1-mutant NSCLC cells to Ferroptosis. Furthermore, we found that combined inhibition of FSP1 and NRF2 induced Ferroptosis more intensely. Our findings imply that FSP1 is a crucial suppressor of Ferroptosis whose expression is partially dependent on NRF2 and that synergistically targeting both FSP1 and NRF2 may be a promising strategy for overcoming Ferroptosis resistance in Cancer.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-136057

iFSP1

99.96%, FSP1 Inhibitor

Ferroptosis

Cancer

Name
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