TIGAR regulates intestinal mucus barrier integrity by inhibiting lactylation of G6PD/6PGD in ulcerative colitis

Oxidative stress and metabolic dysregulation in goblet cells are pivotal in ulcerative colitis (UC) pathogenesis. TIGAR promotes the synthesis of NADPH and contributes to mitigate oxidative stress, but how it regulates NADPH production and affects UC remains unclear. Here we demonstrate that TIGAR inhibits lactylation of the key NADPH-synthesizing enzymes G6PD (at K432) and 6PGD (at K38), thereby preserving their enzymatic activities by promoting G6PD homodimer formation and 6PGD binding to NADP+. In male UC mice, persistently low TIGAR expression elevates lactate levels, promoting the lactylation of G6PD and 6PGD and impairing their function. This process suppresses NADPH synthesis, exacerbating goblet cell oxidative stress. The resulting decline in Trx1 reductase activity induces S-nitrosylation of the mucin-processing enzyme AGR2, thereby inhibiting mature MUC2 production and compromising the intestinal mucus barrier. Our findings elucidate a mechanistic pathway through which TIGAR maintains cellular redox homeostasis, presenting it as a potential therapeutic target for UC. This study reveals that reduced TIGAR expression in ulcerative colitis promotes G6PD/6PGD lactylation, inhibiting NADPH production, and promotes Trx1 and AGR2 S-nitrosylation, impairing mature MUC2 synthesis and damaging the intestinal mucus barrier.