Sympathetic Signaling Activation in Macrophages Alleviates LPS-induced ARDS through the HDC-H1R-SLC7A11 Axis

Acute respiratory distress syndrome (ARDS) is a life-threatening inflammatory lung disorder in which ferroptosis plays a critical role in promoting macrophage-mediated tissue injury. However, the upstream neuroimmune signals regulating ferroptosis remain unclear. Here, we demonstrate that norepinephrine (NE) significantly suppresses LPS-induced ferroptosis in alveolar macrophages (AMs) via β2-adrenergic receptor (β2-AR) signaling. NE reduced lipid peroxidation, preserved mitochondrial structure, and upregulated SLC7A11 and GPX4 expression both in vitro and in vivo. Transcriptomic analysis identified HDC as a key NE-responsive gene, which promotes histamine-mediated H1 receptor (H1R) activation and downstream STAT3 signaling, thereby enhancing SLC7A11 expression. Pharmacological inhibition of β2-AR, H1R, or STAT3, as well as HDC knockdown, abolished the anti-ferroptotic effects of NE. Importantly, salbutamol, a selective β2-AR agonist, recapitulated the protective effects of NE and mitigated LPS-induced lung injury. These findings identify a β2-AR–HDC–H1R–STAT3–SLC7A11 axis that mediates the neuroimmune regulation of ferroptosis in AMs, offering a potential therapeutic target for ARDS.