Intestinal Epithelial METTL3 Deficiency Exacerbates Sepsis-InducedBarrier Injury via NF-κB/MLCK Pathway and the Protective Role ofCurcumin

Introduction: 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 Methods: 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 (METTL3IEC-/- ) 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. Results: METTL3 expression was significantly reduced in necrotic/perforated tissues from sepsis patients. METTL3IEC-/- mice exhibited worsened intestinal inflammation and barrier dysfunction after CLP compared to WT mice. This was associated with increased activity of the NFκB/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. Discussion: 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 poten Conclusion: 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 sepsisinduced intestinal injury. These findings clarify METTL3's role and highlight curcumin's therapeutic potential.