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

  • Biochem Pharmacol. 2026 Apr:246:117731. doi: 10.1016/j.bcp.2026.117731.
Yanwei Wang  1 ,  Ziwei Han  2 ,  Shanshan Pan  2 ,  Minsong Guo  2 ,  Meihong Wu  3 ,  Xuesong Liu  2 ,  Yuan Zhou  4 ,  Jiahui Zhao  4 ,  Yong Chen  2 ,  Tengfei Xu  5
Affiliations
  • 1. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Department of Pharmacology, Medical College, Jiaxing University, Jiaxing 314001, China.
  • 2. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 3. Quzhou Hospital of Traditional Chinese Medicine, Quzhou 324000, China; Quzhou TCM Hospitalat the Junction of Four Provinces Affiliated to Zhejiang Chinese Medical University, Quzhou 324000, China.
  • 4. Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
  • 5. College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
PMID: 41571207 DOI: 10.1016/j.bcp.2026.117731
Abstract

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.

Keywords
Chemical proteomics; Iron homeostasis; P53; SLC25A28; Shikonin.
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