Elevated SPARC Disrupts the Intestinal Barrier Integrity in Crohn's Disease by Interacting with OTUD4 and Activating the MYD88/NF‐κB Pathway

Abstract Disruption of the intestinal epithelial barrier results in increased permeability and is a key factor in the onset and progression of Crohn's disease (CD). The protein SPARC is primarily involved in cell interaction and migration, but its specific role in the intestinal epithelial barrier remains unclear. This study demonstrates that SPARC is significantly overexpressed in both CD patients and murine models of colitis. Furthermore, mice deficient in SPARC exhibits resistance to chemically induced colitis, a phenomenon associated with the modulation of barrier‐associated proteins. Mechanistically, it is elucidated that SPARC competitively binds to OTUD4 in conjunction with MYD88, facilitating the translocation of p65 from the cytoplasm to the nucleus and subsequent activation of the p65‐MLCK/MLC2 pathway, thereby compromising barrier integrity. Additionally, it is identified that the elevated expression of SPARC in CD is regulated via the METTL3‐YTHDF1 axis. These findings indicate that SPARC levels are elevated in patients with CD and in colitis‐induced mice, leading to intestinal barrier damage through direct interaction with OTUD4 and subsequent activation of the MYD88/p65/MLCK/MLC2 signaling pathway. Consequently, targeting SPARC or the OTUD4/MYD88/p65/MLCK/MLC2 axis may offer novel insights into the molecular mechanisms underlying CD and represent a potential therapeutic strategy.