The Emerging Role of Transcription Factor Spi-C in Macrophage Biology and Inflammatory Pathogenesis

Spi-C is a member of the ETS (E26 transformation-specific) family of transcription factors, a group of proteins that regulate gene expression in animals by binding to specific DNA sequences. Spi-C has emerged as a central regulator of macrophage adaptation to iron exposure, inflammatory stress, and tissue injury. Studies show that Spi-C programs iron-recycling macrophages by promoting expression of key iron-handling genes, thereby supporting iron efflux, safe intracellular iron storage, and the development of red pulp macrophages critical for systemic iron recycling. Its expression is strongly induced by heme and iron, enabling macrophages to respond adaptively to increased heme turnover, whereas Spi-C deficiency leads to impaired iron recycling and pathological iron accumulation. Beyond iron homeostasis, Spi-C is increasingly recognized as a regulator of inflammatory disease, functioning as an anti-inflammatory and tissue-protective factor across multiple models, including lipopolysaccharide (LPS)–induced systemic inflammation and colitis, where Spi-C deficiency leads to enhanced cytokine production, increased tissue injury, and impaired repair. By integrating NF-κB-driven inflammatory cues with metabolic adaptation, Spi-C maintains macrophage homeostasis across tissues. This short review summarizes these known functions and provides a forward-looking perspective that Spi-C may also regulate macrophage susceptibility to ferroptosis, an iron-dependent form of cell death implicated in diverse inflammatory and degenerative conditions.