毛蜕皮素可激活髓系 AMPK，恢复 Lgr5⁺干细胞的稳态，并促进溃疡性结肠炎患者黏膜修复。

Abstract

Dioscin promotes mucosal regeneration and prevents UC-associated dysplasia. • Dioscin activates myeloid AMPK to suppress inflammatory macrophages. • AMPKα1 is identified as a direct pharmacological target of Dioscin. • Dioscin restores macrophage–ISC crosstalk via IL-1β regulation. • Myeloid AMPK emerges as a therapeutic target for ulcerative colitis. Ulcerative colitis (UC) is a chronic relapsing inflammatory disease with limited efficacy in achieving durable mucosal healing and preventing dysplasia. Macrophage–intestinal stem cell (ISC) crosstalk plays a central role in epithelial regeneration and tumorigenic transition but remains therapeutically underexplored. Here, we show that Dioscin, a natural steroidal saponin from Dioscoreae Rhizoma, alleviates DSS-induced acute colitis and AOM/DSS-induced chronic colitis-associated dysplasia by reprogramming macrophage-dependent ISC homeostasis. Dioscin significantly reduced disease severity, suppressed inflammatory macrophage infiltration, and restored Lgr5⁺ ISC compartments, whereas macrophage depletion abolished these protective effects. In vitro, Dioscin inhibited M1 polarization of LPS/IFN-γ-stimulated macrophages, improved epithelial barrier integrity, and enhanced ISC proliferation in organoid systems via modulation of macrophage-conditioned signaling. Mechanistically, IL-1β was identified as a key macrophage-derived mediator linking inflammatory activation to ISC dysfunction. Importantly, Dioscin directly interacted with catalytic α1 subunit of AMP-activated protein kinase (AMPKα1), activated AMPK/Raptor signaling, and suppressed mTORC1-dependent inflammatory responses, while pharmacological inhibition with Compound C or myeloid-specific deletion of AMPKα1 ( Prkaa1 ᶠˡ/ᶠˡ, nLysM-Cre) abrogated its effects. Collectively, Dioscin ameliorates experimental colitis and dysplasia by activating myeloid AMPK signaling, inhibiting IL-1β-driven macrophage–ISC dysregulation, and restoring epithelial regeneration, highlighti