SIRT6 restrains hyperactivated Nrf2 to enhance cisplatin response in lung cancer models

Persistent Nrf2 activation promotes tumor adaptation and chemoresistance, but mechanisms that restrain excessive Nrf2 signaling remain unclear. We investigated whether SIRT6 regulates Nrf2 in a state-dependent manner and influences cisplatin response using clinical database analyses, genetic and pharmacological interventions, A549 and HCC827 cells, and an A549 xenograft model. High NFE2L2 expression and a low-SIRT6/high-NFE2L2 pattern were associated with unfavorable outcomes. Nrf2 overexpression or tBHQ activation reduced cisplatin sensitivity, whereas SIRT6 overexpression, MDL-800 treatment, or Nrf2 inhibition enhanced cisplatin response. In xenografts, MDL-800 enhanced cisplatin-induced tumor suppression and partially reversed the protective effect of tBHQ. SIRT6 modestly increased basal ARE activity but suppressed transcription activated by Nrf2 overexpression, tBHQ, or CBP. This suppression persisted after proteasome or ubiquitination-pathway inhibition and was accompanied by reduced Nrf2 acetyl-lysine signal and nuclear accumulation. G60A retained inhibitory activity, whereas R65A showed markedly reduced inhibition; however, their context-dependent catalytic properties preclude assignment of a specific enzymatic mechanism and do not establish direct Nrf2 deacetylation. Mutational analysis functionally implicated the K599/K603/K604 cluster in SIRT6-sensitive regulation. Together, these findings identify a state-dependent SIRT6-Nrf2 relationship and suggest that SIRT6 restrains excessive Nrf2 activity through an acetylation-linked mechanism, thereby enhancing cisplatin response in lung cancer models.