ArticleMolecular biology reports2026
The mechanism of deubiquitinase USP14 modifying HSP90AA1 to activate NRF2 signaling in lung cancer cell resistance to ferroptosis.
Article in Molecular biology reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Objective The deubiquitinating enzyme ubiquitin-specific protease 14 (USP14) has been implicated in LC; however, its specific mechanism in lung cancer (LC) remains inadequately clarified. This study investigated the mechanism of USP14 modifying heat shock protein 90 alpha family class A member 1 (HSP90AA1) to activate nuclear factor erythroid-2 related factor 2 (NRF2) signaling in ferroptosis resistance of LC cells. Methods LC cell lines A549/H1299 were transfected with small-interfering (si)-USP14, oe-USP14, si-HSP90AA1, or oe-NRF2, followed by treatment with the ferroptosis inducer Erastin, the NRF2 inhibitor ML385, or the proteasome inhibitor MG132. Cell viability, USP14, HSP90AA1, NRF2, ferroptosis/oxidative stress-related protein expression, and lipid peroxidation were measured. Co-immunoprecipitation was used to examine USP14-HSP90AA1 interaction and HSP90AA1 ubiquitination. Cycloheximide chase assays and immunofluorescence were performed to assess HSP90AA1 stability and NRF2 nuclear translocation, respectively. Results USP14 knockdown markedly reduced cell viability in Erastin-treated LC cells, decreased solute carrier family 7 member 11/glutathione peroxidase 4 expression, and increased malondialdehyde, Fe2+, and reactive oxygen species levels while reducing glutathione and enhancing lipid peroxidation. Conversely, USP14 overexpression enhanced ferroptosis resistance. USP14 increased HSP90AA1 stability through deubiquitination, whereas HSP90AA1 silencing partially reversed USP14-mediated ferroptosis resistance. HSP90AA1 overexpression promoted NRF2 nuclear translocation. NRF2 inhibition enhanced ferroptosis and partially reversed USP14-induced ferroptosis resistance, whereas NRF2 overexpression partially reversed the promotion of ferroptosis induced by USP14 knockdown. Conclusion USP14 stabilizes HSP90AA1 through deubiquitination, thereby activating the NRF2 signaling pathway and consequently enhancing ferroptosis resistance in LC cells.
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