Blocking the m⁶Am methyltransferase PCIF1 in macrophages attenuates colitis progression by preventing neuronal damage

Macrophage–enteric neuron dialog is crucial for intestinal homeostasis, but its specific role and underlying mechanism in inflammatory bowel disease (IBD) pathogenesis remain elusive. Here, we demonstrate that colonic macrophage-mediated extracellular matrix (ECM) remodeling orchestrates enteric neuronal maturation and dictates colitis progression. The depletion of Pcif1, recognized as a unique methyltransferase for m⁶Am mRNA methylation, in macrophages attenuates colitis and protects enteric neurons from inflammation-driven degeneration. Specifically, Pcif1-deficient macrophages increase ECM accumulation, promoting their own extravasation into enteric neuronal plexuses and the maturation of enteric neurons, thereby curbing inflammation-driven neuronal injury and colitis progression. Mechanistically, Pcif1-mediated m⁶Am modification inhibits the translation of Znf219 mRNA and represses the Znf219-Egr1 axis, a master transcriptional module that governs ECM remodeling. Finally, pharmacological blockade of PCIF1 promotes macrophage-mediated ECM deposition and suppresses colitis and neuronal loss. Our findings reveal a novel mechanism whereby ECM remodeling in macrophages drives enteric neuronal maturation and illuminate the m⁶Am machinery as a promising therapeutic target for preventing neuronal loss in IBD patients.