Shikonin attenuates diabetic Parkinsonian neuronal injury by facilitating p53/SLC25A28-mediated iron shuttling.

Diabetes significantly increases the risk of Parkinson's disease (PD), and mitochondrial dysfunction is considered a shared pathological mechanism between diabetes and PD. Although our previous research indicated that shikonin ameliorates hyperglycemia-driven PD progression through dual regulation of glycolysis (via inhibition of pyruvate kinase muscle isozyme 2) and mitochondrial function, its mitochondrial repair mechanism remains unclear. Here, we demonstrate that shikonin repairs neuronal damage induced by high glucose and 6-hydroxydopamine via a PKM2-independent, p53/Solute Carrier Family 25 Member 28 (SLC25A28)-dependent mitochondrial iron shuttle. Proteomic analysis revealed that shikonin activates the SLC25A28-cytochrome c axis, maintaining mitochondrial Fe2+ homeostasis. Molecular validation confirmed that shikonin directly binds to p53 (isothermal titration calorimetry KD = 6.3 μM), promotes mitochondrial translocation of p53, and subsequently activates SLC25A28. This process facilitates Fe2+-dependent assembly of the cytochrome c/cytochrome c oxidase subunit 4 complex, restoring oxidative phosphorylation. Our work uncovers the p53/SLC25A28 axis as a target for shikonin-mediated mitochondrial iron homeostasis, providing a therapeutic strategy for diabetes-associated PD.