TXNDC12 inhibits lipid peroxidation and ferroptosis
Lanlan Tang,
Yan Yu,
Wenjun Deng,
Jiao Liu,
Yichun Wang,
Fanghua Ye,
Rui Kang,
Daolin Tang,
Qingnan He
Affiliations
Lanlan Tang
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Yan Yu
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Wenjun Deng
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Jiao Liu
DAMP Laboratory, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
Yichun Wang
Department of Critical Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510150, China
Fanghua Ye
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Rui Kang
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA
Daolin Tang
Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author
Qingnan He
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China; Corresponding author
Summary: Ferroptosis is a type of regulated cell death characterized by lipid peroxidation and subsequent damage to the plasma membrane. Here, we report a ferroptosis resistance mechanism involving the upregulation of TXNDC12, a thioredoxin domain-containing protein located in the endoplasmic reticulum. The inducible expression of TXNDC12 during ferroptosis in leukemia cells is inhibited by the knockdown of the transcription factor ATF4, rather than NFE2L2. Mechanistically, TXNDC12 acts to inhibit lipid peroxidation without affecting iron accumulation during ferroptosis. When TXNDC12 is overexpressed, it restores the sensitivity of ATF4-knockdown cells to ferroptosis. Moreover, TXNDC12 plays a GPX4-independent role in inhibiting lipid peroxidation. The absence of TXNDC12 enhances the tumor-suppressive effects of ferroptosis induction in both cell culture and animal models. Collectively, these findings demonstrate an endoplasmic reticulum-based anti-ferroptosis pathway in cancer cells with potential translational applications.
