The main findings can be summarized as follows: (1) Nrf2 was downregulated in the serum of SA‐sepsis patients, which was negatively correlated with severity of sepsis; (2) SA‐ALI was associated with oxidative stress injury and mitochondrial dysfunction, which were exacerbated by loss of Nrf2; (3) Nrf2 modulates PHB2 expression and intracellular distribution during SA‐ALI; and (4) Nrf2 overexpression increased PHB2 expression by directly binding to the PHB2 promoter and activating its transcription. Here, PHB2 is linked to Sepsis.