Palmitoylation reprograms the intestinal mucosal barrier microenvironment: potential mechanisms and promising therapeutic targets.

Homeostasis of the intestinal mucosal barrier microenvironment is contingent upon the coordinated interplay among mechanical, chemical, and immunological barriers. Recent studies have demonstrated that protein S-palmitoylation, a dynamic and reversible lipid modification, holistically reprograms the intestinal mucosal barrier microenvironment. This is achieved by modulating the membrane localization of tight junction proteins (Claudins and ZO proteins) and E-cadherin/catenin complexes, the secretion and anchoring of MUC2, as well as the membrane recruitment and signaling activation of receptors such as TLR4, NOD2, and NLRP3. Dysregulation of this modification not only drives barrier collapse and chronic inflammation in inflammatory bowel diseases (IBD), such as ulcerative colitis, but also exacerbates pathological progression by modulating the phenotypic remodeling of innate immune cells, including macrophages and neutrophils. Targeting the palmitoylation cycle-including ZDHHC acyltransferases, depalmitoylases (APTs and PPTs), or upstream metabolic enzymes like FASN-using either the broad-spectrum inhibitor 2-BP or selective inhibitors (ML348 and Palmostatin B), has shown promise in preclinical models restore barrier function and attenuate intestinal inflammation. However, it is important to emphasize that the therapeutic potential of these agents in IBD is currently supported primarily by in vitro and animal studies, and their clinical efficacy and safety remain to be established. This review systematically proposes a conceptual framework for the "reprogramming of the intestinal mucosal barrier microenvironment by S-palmitoylation." By integrating current evidence spanning from molecular modifications to barrier functions and from mechanistic insights to therapeutic strategies, we aim to provide novel molecular targets and a theoretical foundation for the development of mucosal healing therapies that are independent of traditional immunosuppression.