The CYP1A-HSF1 axis alleviates mitochondrial oxidative stress to limit HBO-induced lung endothelial barrier damage.

Although hyperbaric oxygen (HBO) therapy is an established medical intervention effective for various conditions, prolonged or excessive exposure can induce acute lung injury (ALI), the mechanisms of which remain poorly understood. In this study, we show that expression of CYP1A1 and CYP1A2, two isoforms of the cytochrome P450 (CYP) 1A subfamily, is significantly upregulated in mouse lung tissues and primary mouse lung microvascular endothelial cells (MLVECs) following HBO exposure. Global double knockout of CYP1A1 and CYP1A2 (referred to as CYP1A-deficient mice) exacerbated pulmonary endothelial dysfunction and ALI in response to HBO, whereas CYP1A inducer β-naphthoflavone (BNF) ameliorated these pathological changes. Mechanistically, activation of the heat shock factor 1 (HSF1) signaling pathway mediates the protective effects of CYP1A induction against HBO-induced mitochondrial oxidative stress, mitochondrial dysfunction, and endothelial cell apoptosis. Critically, HSF1 inhibition abolished BNF-induced HSF1 recruitment to the succinate dehydrogenase subunit C (SDHC) promoter, thereby suppressing SDHC transcription in HBO-exposed pulmonary endothelial cells. Furthermore, the HSF1-mediated protection is dependent on succinate dehydrogenase C (SDHC), thereby linking CYP1A upregulation to the preservation of pulmonary endothelial barrier integrity. CYP1A deficiency leads to reduced SDHC expression, resulting in enhanced mitochondrial oxidative stress, impaired mitochondrial function, and increased apoptosis in lung tissues under HBO conditions. Our findings reveal a previously unrecognized protective mechanism in which upregulation of CYP1A serves as an adaptive response against HBO-induced pulmonary endothelial injury by attenuating mitochondrial oxidative stress and restoring mitochondrial homeostasis via the HSF1/SDHC signaling axis.