Selenoprotein thioredoxin reductase 1 promotes cancer cells ferroptosis by suppressing GPX4 expression

Ferroptosis is a type of regulated necrosis driven by iron-dependent lethal accumulation of lipid peroxides. Selenoprotein thioredoxin reductase (TrxR) plays crucial roles in cellular redox homeostasis. However, its role in ferroptosis remains unclear. Here, we report TrxR1 positively regulates ferroptosis. The selenocysteine of TrxR1 is required for its regulation of ferroptosis. Mechanistically, the CRL4A^CRBN E3 complex ubiquitinates KEAP1 at K84 and K312, driving KEAP1 degradation. Overexpression of TrxR1 increases KEAP1 stability by suppressing CRL4A^CRBN E3 complex mediated KEAP1 ubiquitination and degradation, enhances the interaction between NRF2 and KEAP1, promotes NRF2 ubiquitination and drives NRF2 degradation, which results in downregulation of GPX4 expression, thereby sensitizing cells to ferroptosis. Furthermore, high level of TrxR1 sensitizes cancer cells to ferroptosis in vivo. CRBN inhibitor thalidomide and IKE combination treatment results in markedly retarded tumor progression. Our study reveals a crucial pro-ferroptotic role for TrxR1 and nominates it as a potential biomarker for guiding future ferroptosis-inducing therapies in select cancers.