Fucoidan Modulates USP22/HIF-1α Against Ferroptosis in Diabetic Nephropathy

Ubiquitin-specific protease 22 (USP22), which was found to serve as a specific deubiquitinase of hypoxia-inducible factor-1α (HIF-1α), plays an important role in diabetic nephropathy (DN) pathological mechanisms, but currently available therapies remain insufficient to fully arrest its progression. Fucoidan (FO), a marine-derived fucose-rich sulfated polysaccharide, has been reported to treat acute renal damage and chronic renal failure by ameliorating ferroptosis. But whether FO could modulate USP22/HIF-1α in the pathogenesis of DN is unknown. Here, db/db mice were treated with the USP22 inhibitor S02 or FO for 13 weeks, and renal injury was subsequently characterized through biochemical, histological, and molecular analyses. S02 or FO administration markedly alleviated renal structural injury, improved fasting blood glucose and renal functional indices, and reduced oxidative stress, iron deposition, and the expression of profibrotic and proinflammatory mediators in diabetic kidneys. Mechanistically, protective effects were associated with suppression of USP22 by deubiquitinating HIF-1α, and amelioration of ferroptosis-related renal damage. Notably, inhibition of USP22 by FO recapitulated the renoprotective phenotype. Together, these findings suggest that FO mitigates DN by constraining USP22/HIF-1α-driven ferroptotic and oxidative injury, thereby supporting its potential as a natural therapeutic candidate for DN.