This study reveals that NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. The hypoxic response is controlled by HIF-1, whose α subunit is stabilized under low oxygen conditions. NF-κB, a key regulator of innate immunity, is also involved in the hypoxic response. The study shows that NF-κB is a critical transcriptional activator of HIF-1α in macrophages responding to bacterial infection and in the liver and brain of hypoxic animals. IKKβ deficiency results in defective induction of HIF-1α target genes, including VEGF, and elevated astrogliosis in hypoxic mice. This indicates that IKKβ provides an important physiological link between the hypoxic response and innate immunity/inflammation. Hypoxia is characterized by reduced oxygen pressure in tissues and can occur in various pathophysiological conditions, including ischemia, cancer, and inflammation. During ischemia, HIF-1α activation leads to the induction of genes that restore blood supply and energy production, maintaining tissue integrity. HIF-1α is also involved in the expression of inflammatory cytokines, which are regulated by NF-κB. However, hypoxia can activate IKKβ by inhibiting PHDs that negatively modulate IKKβ activity. The study used IKKβ-deficient mice and primary macrophages to explore the relationship between IKKβ, NF-κB, and HIF-1α under in vivo conditions. The study found that IKKβ is required for the hypoxia-induced accumulation of HIF-1α in macrophages and for the induction of HIF-1 target genes such as VEGF and Glut-1. IKKβ deficiency also led to reduced HIF-1α mRNA expression. These findings suggest that IKKβ is essential for the hypoxic response in macrophages and in intact mice. The study also showed that IKKβ deficiency leads to increased astrogliosis in the brains of hypoxic mice, possibly due to defective production of VEGF, a cytokine with anti-inflammatory properties. The study highlights the importance of IKKβ in linking the hypoxic response and innate immunity. It suggests that IKKβ inhibitors may not be useful in treating neuroinflammatory disorders and that individuals treated with IKKβ or NF-κB inhibitors should avoid hypoxic conditions. The findings indicate a tight coupling between two ancient stress responses: innate immunity and the hypoxic response. NF-κB enhances glycolytic energy metabolism and angiogenic factor production, in addition to its role in proinflammatory cytokine expression. This expands the regulatory potential of NF-κB, leading to more effective host defense responses. The ability of NF-κB to promote HIF-1α activation during hypoxia also enhances its prosurvival function, as theThis study reveals that NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. The hypoxic response is controlled by HIF-1, whose α subunit is stabilized under low oxygen conditions. NF-κB, a key regulator of innate immunity, is also involved in the hypoxic response. The study shows that NF-κB is a critical transcriptional activator of HIF-1α in macrophages responding to bacterial infection and in the liver and brain of hypoxic animals. IKKβ deficiency results in defective induction of HIF-1α target genes, including VEGF, and elevated astrogliosis in hypoxic mice. This indicates that IKKβ provides an important physiological link between the hypoxic response and innate immunity/inflammation. Hypoxia is characterized by reduced oxygen pressure in tissues and can occur in various pathophysiological conditions, including ischemia, cancer, and inflammation. During ischemia, HIF-1α activation leads to the induction of genes that restore blood supply and energy production, maintaining tissue integrity. HIF-1α is also involved in the expression of inflammatory cytokines, which are regulated by NF-κB. However, hypoxia can activate IKKβ by inhibiting PHDs that negatively modulate IKKβ activity. The study used IKKβ-deficient mice and primary macrophages to explore the relationship between IKKβ, NF-κB, and HIF-1α under in vivo conditions. The study found that IKKβ is required for the hypoxia-induced accumulation of HIF-1α in macrophages and for the induction of HIF-1 target genes such as VEGF and Glut-1. IKKβ deficiency also led to reduced HIF-1α mRNA expression. These findings suggest that IKKβ is essential for the hypoxic response in macrophages and in intact mice. The study also showed that IKKβ deficiency leads to increased astrogliosis in the brains of hypoxic mice, possibly due to defective production of VEGF, a cytokine with anti-inflammatory properties. The study highlights the importance of IKKβ in linking the hypoxic response and innate immunity. It suggests that IKKβ inhibitors may not be useful in treating neuroinflammatory disorders and that individuals treated with IKKβ or NF-κB inhibitors should avoid hypoxic conditions. The findings indicate a tight coupling between two ancient stress responses: innate immunity and the hypoxic response. NF-κB enhances glycolytic energy metabolism and angiogenic factor production, in addition to its role in proinflammatory cytokine expression. This expands the regulatory potential of NF-κB, leading to more effective host defense responses. The ability of NF-κB to promote HIF-1α activation during hypoxia also enhances its prosurvival function, as the