The long noncoding RNA SNHG12 defines KEAP1 stability and ferroptosis susceptibility by targeting E3 ligase TRIM25.

Ferroptosis is a novel type of programmed cell death caused by iron-dependent lipid peroxidation. Targeted induction of ferroptosis holds great promise for cancer treatment. SNHG, a newly recognized lncRNA family, has been reported to implicate in the proliferation, invasion, migration or drug resistance of cancer cells. Herein, we reported a SNHG member, SNHG12, is a novel ferroptosis regulatory lncRNA. Our data indicate that SNHG12 is upregulated during ferroptosis induction, with P53 potentially functioning as its transcription factor. In our experimental models, SNHG12 silence suppresses, while ectopic expression of SNHG12 expedites, Erastin- and RSL3-induced ferroptosis. Mechanistically, SNHG12 interact with the ubiquitin E3 ligase TRIM25, competitively interferes the TRIM25-KEAP1 interaction. The interaction of SNHG12-TEIM25 appears to preserve KEAP1 from TRIM25-mediated ubiquitination and proteasomal degradation. Consequently, SNHG12 restrain the antioxidant response of NRF2 to elevate the intracellular labile iron pool and accelerate GSH exhaustion in response to pro-ferroptotic insults, thereby modulating ferroptosis susceptibility in cancer cells. Collectively, our findings propose a novel regulatory circuit modulating ferroptosis, comprising SNHG12-TRIM25-KEAP1, and highlight the potential application of manipulating this regulatory axis in cancer treatment through ferroptosis.