Intestinal Epithelial METTL3 Deficiency Exacerbates Sepsis-Induced Barrier Injury via NF-κB/MLCK Pathway and the Protective Role of Curcumin

Sepsis, a life-threatening systemic response to infection, frequently causes multiple organ dysfunction, with intestinal barrier injury playing a critical role. While METTL3, a key RNA methyltransferase, is involved in many biological processes, its specific function in sepsis remains unknown.

We analyzed METTL3 expression in intestinal tissues from 30 sepsis patients (2020-2022) undergoing partial bowel resection. We then used mice with intestine-specific METTL3 deletion (METTL3^IEC-/-) and Wild-Type (WT) controls, subjecting them to Cecal Ligation and Puncture (CLP) to model sepsis. Intestinal inflammation, barrier function, and the NF-κB/MLCK pathway were assessed. We also evaluated the therapeutic effect of curcumin administered via gavage at different doses.

METTL3 expression was significantly reduced in necrotic/perforated tissues from sepsis patients. METTL3^IEC-/- mice exhibited worsened intestinal inflammation and barrier dysfunction after CLP compared to WT mice. This was associated with increased activity of the NF-κB/MLCK pathway. Crucially, curcumin treatment effectively reduced the expression of key pathway components (p65 and MLCK). This led to significant improvements: reduced intestinal injury, decreased inflammation, and enhanced barrier function.

METTL3 is essential for maintaining intestinal barrier integrity during sepsis. Its deficiency exacerbates damage via the NF-κB/MLCK pathway. Targeting this pathway, potentially with curcumin, represents a promising therapeutic strategy for sepsis-induced intestinal injury. These findings clarify METTL3's role and highlight curcumin's therapeutic potential.

METTL3 is essential for maintaining intestinal barrier integrity during sepsis. Its deficiency exacerbates damage, mediated through the NF-κB/MLCK pathway. Targeting this pathway, potentially with curcumin, represents a promising therapeutic strategy for sepsis-induced intestinal injury. These findings clarify METTL3's role and highlight curcumin's therapeutic potential.