1. Academic Validation
  2. CD38 inhibits ferroptosis to promote radiotherapy resistance in nasopharyngeal carcinoma by competitively binding to TRIM21 to stabilize SLC7A11 protein

CD38 inhibits ferroptosis to promote radiotherapy resistance in nasopharyngeal carcinoma by competitively binding to TRIM21 to stabilize SLC7A11 protein

  • Int J Biol Macromol. 2025 Jun;317(Pt 2):144742. doi: 10.1016/j.ijbiomac.2025.144742.
Wentao Li 1 Lin Liang 2 Siyi Liu 2 Feng Zeng 2 Jiaying Cao 2 Yan Lei 3 Xia Yuan 4 Qian He 5 Yanhong Zhou 6
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan 410013, China; Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China.
  • 2 Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China.
  • 3 Department of Blood Transfusion, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan 410013, China.
  • 4 Gastroenterology and Urology Department II, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan 410013, China.
  • 5 Department of Radiation Oncology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan 410013, China. Electronic address: heqian1162@hnca.org.cn.
  • 6 Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan 410078, China. Electronic address: zhouyanhong@csu.edu.cn.
Abstract

Radiotherapy is the treatment of choice for nasopharyngeal Cancer, but resistance to radiotherapy is the main obstacle. Previous studies have found that CD38 is involved in the occurrence and development of nasopharyngeal carcinoma and is closely related to the resistance of nasopharyngeal carcinoma cells to radiotherapy. In this study, targeted quantitative detection of energy metabolism and Co-IP combined with liquid chromatography-mass spectrometry suggested that CD38 may be closely related to Ferroptosis. It was further found that CD38 inhibited the levels of ferroptosis-related indicators in nasopharyngeal carcinoma cells, and CD38 promoted radiotherapy resistance by inhibiting Ferroptosis. Mechanistically, CD38, SLC7A11, and TRIM21 proteins interact with each Other, and CD38 inhibits TRIM21-mediated ubiquitinated degradation of the SLC7A11 protein in its K48-linked form by competitively binding to the E3 ubiquitin Ligase TRIM21. CD38 inhibits Ferroptosis in nasopharyngeal carcinoma cells by stabilizing SLC7A11 proteins to activate the SLC7A11/GSH/GPX4 Ferroptosis signaling axis, thereby promoting radiotherapy resistance. In summary, we demonstrated for the first time that CD38 stabilizes SLC7A11 proteins by competitively binding to TRIM21, and revealed a novel mechanism of the CD38/SLC7A11/GSH/GPX4 Ferroptosis signaling axis in radiotherapy resistance in nasopharyngeal carcinoma cells, highlighting the potential of CD38 as a radiosensitizing target for nasopharyngeal carcinoma.

Keywords

CD38; Ferroptosis; Nasopharyngeal carcinoma.

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