2. Academic Validation
  3. Selenomethionine as a dual-mechanism ferroptosis inhibitor: selenium-supply-driven GPX4 biosynthesis beyond transsulfuration and reductive-capacity-mediated ROS scavenging independent of GPX4 activity

Selenomethionine as a dual-mechanism ferroptosis inhibitor: selenium-supply-driven GPX4 biosynthesis beyond transsulfuration and reductive-capacity-mediated ROS scavenging independent of GPX4 activity

  • Cell Death Dis. 2026 Feb 14;17(1):224. doi: 10.1038/s41419-026-08466-x.
Chaoyi Xia # 1,  Xue Sun # 2,  Junyi Shao # 2,  Jingshu Min 2,  Chong Wei 2,  Feiyang Zhao 3,  Caiyun Fu 4,  Qiang Zhang 5
Affiliations

Affiliations

  • 1 Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, Zhejiang Provincial Key Laboratory of Drug Discovery and Development for Metabolic Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China. [email protected].
  • 2 Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, Zhejiang Provincial Key Laboratory of Drug Discovery and Development for Metabolic Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China.
  • 3 Postgraduate Training Base Alliance of Wenzhou Medical University (Wenzhou People's Hospital), Wenzhou, China.
  • 4 Zhejiang Provincial Engineering Research Center of New Technologies and Applications for Targeted Therapy of Major Diseases, Zhejiang Provincial Key Laboratory of Drug Discovery and Development for Metabolic Diseases, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, Zhejiang Province, China. [email protected].
  • 5 Department of Biophysics, and Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. [email protected].
  • # Contributed equally.
PMID: 41688429 DOI: 10.1038/s41419-026-08466-x
Abstract

Ferroptosis is an iron-dependent form of nonapoptotic cell death driven by lipid peroxidation. The selenium-dependent Glutathione Peroxidase 4 (GPX4) serves as the central regulator of Ferroptosis through enzymatic reduction of phospholipid hydroperoxides (PLOOH). While GPX4 remains the canonical Ferroptosis suppressor, whether alternative regulatory axes exist beyond this selenoprotein-mediated pathway remains unclear. In the present study, we identified selenomethionine as a novel resister of Ferroptosis induced by RSL3 through screening FDA drug library and natural product library. Mechanistically, selenomethionine serves as a selenium donor for GPX4 biosynthesis beyond the transsulfuration pathway. The anti-ferroptosis activity of selenomethionine persists even after CRISPR-mediated GPX4 knockout, revealing a GPX4-independent mechanism that relies on direct redox modulation via selenium-mediated Reactive Oxygen Species (ROS) scavenging. Significantly, selenomethionine administration effectively mitigated cisplatin-induced acute kidney injury in vivo by suppressing Ferroptosis. This work establishes selenomethionine as a unique dual-mechanism Ferroptosis suppressor that simultaneously modulates enzymatic antioxidant defense through GPX4 biosynthesis and non-enzymatic radical trapping via selenium-mediated redox cycling, providing new insights into therapeutic strategies for ferroptosis-related pathologies.

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