Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5′-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5′-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO–PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.

氧气对于地球上的所有后生生物至关重要，并影响生理和病理条件下的各种生物过程。虽然已经确定了诱导急性缺氧反应的氧传感系统，包括缺氧诱导因子途径，但那些在长期缺氧下运行的系统仍有待阐明。在这里，我们展示了吡哆醇 5′-磷酸氧化酶 (PNPO) 可催化维生素 B6 的生物活化，可作为氧传感器并调节巨噬细胞中的溶酶体活性。长时间缺氧下PNPO活性降低，维生素B6的活性形式5′-磷酸吡哆醛（PLP）减少，并抑制溶酶体酸化，从而导致巨噬细胞中铁失调、TET2蛋白丢失和炎症反应延迟消退。在 PLP 依赖性代谢中，超硫化物合成在长时间缺氧中受到抑制，导致溶酶体抑制和随之而来的巨噬细胞促炎表型。 PNPO-PLP 轴创建了一个独特的氧传感层，可随着长时间缺氧而逐渐关闭 PLP 依赖性代谢。