Oxidative stress triggers ferroptosis, a form of cellular necrosis characterized by iron-dependent lipid peroxidation, and has been implicated in Mycobacterium tuberculosis (Mtb) pathogenesis. We investigated whether Bach1, a transcription factor that represses multiple antioxidant genes, regulates host resistance to Mtb. We found that BACH1 expression is associated clinically with active pulmonary tuberculosis. Bach1 deletion in Mtb-infected mice increased glutathione levels and Gpx4 expression that inhibit lipid peroxidation. Bach1^−/− macrophages exhibited increased resistance to Mtb-induced cell death, while Mtb-infected Bach1-deficient mice displayed reduced bacterial loads, pulmonary necrosis and lipid peroxidation concurrent with increased survival. Single-cell RNA-seq analysis of lungs from Mtb-infected Bach1^−/− mice revealed an enrichment of genes associated with ferroptosis suppression. Bach1 depletion in Mtb-infected B6.Sst1^S mice that display human-like necrotic lung pathology also markedly reduced necrosis and increased host resistance. These findings identify Bach1 as a key regulator of cellular and tissue necrosis and host resistance in Mtb infection.

氧化应激会引发铁死亡，这是一种以铁依赖性脂质过氧化为特征的细胞坏死形式，并且与结核分枝杆菌(Mtb) 的发病机制有关。我们研究了 Bach1（一种抑制多种抗氧化基因的转录因子）是否调节宿主对 Mtb 的抵抗力。我们发现 BACH1 表达在临床上与活动性肺结核相关。 Mtb 感染小鼠中 Bach1 缺失会增加谷胱甘肽水平和 Gpx4 表达，从而抑制脂质过氧化。 Bach1 ^-/−巨噬细胞表现出对 Mtb 诱导的细胞死亡的抵抗力增强，而感染 Mtb 的 Bach1 缺陷小鼠则表现出细菌负荷减少、肺坏死和脂质过氧化减少，同时存活率增加。对 Mtb 感染的Bach1 ^−/−小鼠肺部的单细胞 RNA 序列分析揭示了与铁死亡抑制相关的基因富集。在表现出类似人类坏死性肺病理学的 Mtb 感染 B6.Sst1 ^S小鼠中，Bach1 缺失也显着减少了坏死并增加了宿主抵抗力。这些发现表明 Bach1 是 Mtb 感染中细胞和组织坏死以及宿主抵抗力的关键调节因子。