MITF programs macrophage iron homeostasis to drive gut-liver inflammatory axis in early life

Systemic chronic inflammation (SCI) is a key driver of non-communicable diseases. Early-life stressors disrupt intestinal homeostasis, promoting SCI, but the mechanisms are unclear. Using translational models, we identify dysregulated iron homeostasis as a pivotal disruptor of intestinal barrier integrity. Single-cell profiling reveals that neutrophils and macrophages mediate iron-dependent mucosal defense. Stress induces iron overload in gut epithelial cells and macrophages, a process governed by the transcription factor MITF. MITF-mediated iron dysregulation in macrophages is associated with neutrophil recruitment to the lamina propria, concomitant with elevated levels of the CXCL8, synchronizing with hepatic inflammatory and metabolic dysregulation via the gut-liver axis. Mechanistically, abnormal iron homeostasis couples with interferon signaling, and MITF modulates iron-related genes (FTH1, TFRC, and FRRS1). Therapeutic mitigation of iron dyshomeostasis preserves barrier function and attenuates systemic inflammation. Our findings identify MITF as a key regulator of gut-liver inflammatory cascades and nominate abnormal iron homeostasis as a target for early-life inflammatory disorders.