Abstract

The islet immune microenvironment contributes critically to β cell dysfunction in type 2 diabetes (T2D), but its regulatory mechanisms remain unclear. We show that β cell dysfunction in T2D patients and diabetic mice correlates with elevated nucleolar stress and reduced expression of BAF60C, a switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling factor. β cell-specific BAF60C deletion aggravates high-fat diet (HFD)-induced hyperglycemia, nucleolar stress, and islet inflammation, whereas BAF60C overexpression displays protection. BAF60C suppresses islet inflammation by promoting REG3B expression and secretion, thereby modulating β cell-macrophage crosstalk. Mechanistically, BAF60C forms an RNA-protein complex with nucleophosmin (NPM1) and Reg3b mRNA to modulate Reg3b mRNA decay. Restoration of the BAF60C-REG3B axis through REG3B supplementation or exercise alleviates inflammation and improves glucose homeostasis in obese and T2D mice, revealing a non-canonical role for BAF60C in linking nucleolar stress to β cell failure.