m6A demethylase ALKBH5 reduces ferroptosis in diabetic retinopathy through the m6A ‐ YTHDF1 ‐ ACSL4 axis

Apr 10, 2025Diabetic medicine : a journal of the British Diabetic Association

ALKBH5 enzyme lowers cell damage in diabetic eye disease by controlling m6A-related regulation of ACSL4

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Abstract

ALKBH5 is under-expressed in the retinal tissues of diabetic retinopathy (DR) mouse models.

YTHDF1 and ACSL4 were found to be up-regulated in the same retinal tissues.
Ectopic expression of ALKBH5 or knockdown of YTHDF1 reduced ferroptosis in both in vitro and in vivo models.
This reduction in ferroptosis was associated with lower levels of iron, malondialdehyde, and reactive oxygen species, and higher levels of glutathione.
ALKBH5 was shown to influence the stability of ACSL4 mRNA through m6A modification in a YTHDF1-dependent manner.
Overexpression of ALKBH5 or knockdown of YTHDF1 led to decreased ferroptosis and alleviated DR symptoms.

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AIM: Diabetic retinopathy (DR) represents the main ocular complication of diabetes. Targeting ferroptosis is a promising treatment of choice for various diabetic complications. N6-methyladenosine (m6A) demethylase alkylation repair homolog protein 5 (ALKBH5) functions as a pivotal regulator of ferroptosis, and we investigated its role and molecular mechanisms in ferroptosis in DR.

METHODS: A DR mouse model was developed by streptozotocin (STZ) intraperitoneal injection. High glucose (HG)-induced human retinal pigment epithelial cells (ARPE-19) were used as a DR model in vitro. ALKBH5, YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression levels were examined by RT-qPCR and Western blot. The biological functions of ALKBH5 in vitro and in vivo were investigated by gain-of-function and loss-of-function analyses. ALKBH5's downstream regulatory mechanisms were detected by bioinformatics analysis, RNA pull-down, MeRIP-qPCR and actinomycin D assay.

RESULTS: ALKBH5 was under-expressed while YTHDF1 and ACSL4 were up-regulated in the retinal tissues of STZ-induced DR mice and HG-stimulated ARPE-19 cells. Ectopically expressed ALKBH5 or YTHDF1 knockdown partially reversed the increased ferroptosis in vitro and in vivo, evidenced by decreased levels of Fe, malondialdehyde and reactive oxygen species yet increased glutathione level. ALKBH5 mediated m6A modification of ACSL4 mRNA and disrupted its stability in a YTHDF1-dependent manner. Importantly, in vivo data demonstrated that overexpression of ALKBH5 or YTHDF1 knockdown repressed ferroptosis and alleviated DR by down-regulating ACSL4. 2+

CONCLUSION: These findings suggest that ALKBH5 may delay DR progression by reducing ferroptosis through the m6A-YTHDF1-ACSL4 axis, offering therapeutic paradigms for the treatment of DR.

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m6A demethylase ALKBH5 reduces ferroptosis in diabetic retinopathy through the m6A ‐ YTHDF1 ‐ ACSL4 axis

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