USP9X trims STAT1 to curb oncostatin M activity and intestinal inflammation

Macrophages are critical regulators of intestinal homeostasis. They sense their environment rapidly and adapt their function accordingly. In IBD, proinflammatory macrophages accumulate in the mucosa, sustain cytokine production, and drive repeated cycles of tissue damage. Oncostatin M (OSM) is a key cytokine involved in intestinal inflammation [ 1 , 2 ]. Produced primarily by myeloid cells and T cells in inflamed mucosal tissue, OSM signals through stromal and epithelial cells to perpetuate inflammation and resist resolution, and its mucosal expression predicts the failure of anti-TNF therapy [ 1 , 3 ]. Despite its clinical importance, what controls OSM production in the inflamed gut remains poorly understood. A new study by Zhang and colleagues, published in this issue, addresses that question [ 4 ]. The authors identify USP9X, a deubiquitinase, as a critical brake on macrophage OSM expression. USP9X removes K27-linked ubiquitin chains from STAT1 at lysine 544, limiting STAT1 nuclear entry and OSM transcription. The loss of this checkpoint in myeloid cells worsens experimental colitis, and neutralizing OSM rescues it. This work defines a USP9X–STAT1–OSM axis that connects ubiquitin editing to a cytokine with direct clinical relevance in IBD (Fig. 1 ). Fig. 1: USP9X–STAT1–OSM axis in intestinal macrophages. Full size image In USP9X-sufficient macrophages (left), USP9X removes K27-linked ubiquitin chains from STAT1 lysine 544, limiting STAT1 nuclear translocation and OSM transcription. In USP9X-deficient macrophages (right), K27-linked chains accumulate at K544, enhancing STAT1 nuclear import. STAT1 occupies the OSM promoter and drives OSM expression, promoting proinflammatory myeloid accumulation and colitis