Targeting hepcidin to restore oral iron efficacy after vertical sleeve gastrectomy.

Background: Metabolic bariatric surgery (MBS) such as Vertical Sleeve Gastrectomy (VSG) is the most effective intervention for obesity but commonly results in iron deficiency, inadequately managed by oral iron supplementation. This study aimed to investigate mechanisms underlying the inefficacy of oral iron supplementation post-VSG, evaluate clinical relevance through patient studies, and test the therapeutic potential of curcumin, a hepcidin inhibitor, to improve iron management. Methods: Diet-induced obese mice underwent VSG or sham surgery and received either regular-iron or iron-rich diets postoperatively, with or without curcumin supplementation. Systemic and tissue iron metrics, expressions of genes and proteins involved in iron metabolism were analyzed. Clinically, we evaluated circulating hepcidin levels in VSG patients developing iron deficiency vs. matched controls without deficiency at 6-months post-surgery. Results: In mouse models, VSG induced persistent iron deficiency that could not be corrected by oral iron supplementation. VSG increased intestinal dietary iron uptake capacity, yet oral iron triggered a disproportionate rise in hepatic hepcidin. The resulting hepcidin-mediated ferroportin loss traped absorbed iron within enterocytes, hepatocytes, and macrophages, producing persistent systemic iron deficiency despite supplementation. Moreover, curcumin, a hepcidin-suppressive intervention, restored ferroportin protein, mobilized sequestered iron, and rescued serum iron indices while leaving the VSG-induced intestinal iron absorption machinery intact. In patients 6 months after VSG receiving routine oral iron supplementation, those with iron deficiency exhibit higher hepcidin than matched non-deficient controls, and hepcidin levels were inversely correlated with circulating iron levels. Conclusions: These results reframe post-VSG iron deficiency as a disorder of iron mobilization and regulation, not merely reduced absorption. Clinically, they argue for therapeutic strategies that target the hepcidin-ferroportin axis to restore the efficacy of oral iron supplementation in correcting iron deficiency following MBS.