NRF2-driven thiol metabolism creates a selective vulnerability to selenite

A four-hour selenite pulse selectively kills NRF2-hyperactive non-small cell lung cancer cells by disrupting mitochondrial function, including aconitase activity and respiration.

• Why it matters: NRF2 hyperactivation occurs in 20–30% of non-small cell lung cancers and is linked to therapy resistance, leaving a need for targeted vulnerabilities.
• What they did: The study tested NRF2-driven thiol export and extracellular reduction of selenite to selenide, then assessed mitochondrial effects and cell death pathways after selenite exposure and washout.
• The result: Selenite treatment abolished aconitase activity within hours and induced apoptosis-, ferroptosis-, pyroptosis-, necroptosis-, and disulfidptosis-independent death; in mice, a selenite-rich diet selectively suppressed NRF2-hyperactive tumor growth.

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