USP25
promotes ferroptosis in diabetic retinopathy by deubiquitinating p53 and suppressing the
GPX4
/
SLC7A11
axis
Yanjun Gao, Wenjing Zhao, Qiannan Chai, Cunxi Ye ABSTRACT
Objective
To explore the expression of the deubiquitinase (DUB) USP25 in diabetic retinopathy (DR) and its mechanistic role in regulating ferroptosis.
Methods
Bioinformatics was used to screen for DR‐related DUB candidate genes. USP25 expression was validated in a streptozotocin‐induced diabetic mouse model and high glucose (HG)‐treated ARPE‐19 cells. Loss‐ and gain‐of‐function approaches for USP25 were employed to assess retinal structural damage, tight junction proteins, cell viability, and TUNEL positivity. Ferroptosis‐related changes were evaluated by measuring iron content, Fe 2+ fluorescent signals, lipid peroxidation levels, and antioxidant enzyme activities. The molecular mechanism underlying USP25‐mediated ferroptosis was elucidated through bioinformatics prediction, co‐immunoprecipitation, and protein stability assays, followed by rescue experiments with p53 knockdown.
Results
USP25 was upregulated in the retinas of diabetic mice. USP25 knockdown ameliorated retinal structural damage and restored the expression of tight junction proteins (ZO‐1 and occludin) in DR mice. USP25 exacerbated HG‐induced cellular injury and ferroptosis by promoting iron accumulation, enhancing lipid peroxidation, suppressing the antioxidant defense system, and downregulating the ferroptosis suppressors GPX4 and SLC7A11. Mechanistically, USP25 stabilized p53 protein by reducing its ubiquitination. Rescue experiments further demonstrated that p53 knockdown significantly reversed ferroptosis‐related alterations in the context of USP25 overexpression, mitigating ferroptosis‐related damage in ARPE‐19 cells and retinal tissues of diabetic mice.
Conclusion
USP25 is aberrantly upregulated in DR and promotes ferroptosis by deubiquitinating and stabilizing p53, thereby exacerbating retinal damage. The USP25–p53–ferroptosis axis may represent a potential therapeutic target for DR intervention.