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The function and mechanism of aldh3b1 in diabetic retinopathy

ABSTRACT: Sphingosine-1-phosphate (S1P), a crucial sphingolipid mediator, plays a pivotal role in the pathogenesis of diabetic retinopathy (DR) by influencing angiogenesis, inflammation, photoreceptor apoptosis, neurodegeneration, and fibrosis through interaction with its five specific receptors (S1PRs). These receptors have been recognized as promising targets for therapeutic intervention in various diseases and several S1PR-targeted drugs are already in clinical use or trials. Despite extensive research into the role of S1P, the impact of its primary metabolic product, 2-hexadecenal (2-HD), remains unexplored. Recent studies have suggested ALDH3B1 as an enzyme in the detoxification of 2-HD. In this study, we established a CRISPR-mediated aldh3b1 knockout zebrafish to examine the in vivo effects of 2-HD accumulation. The absence of aldh3b1 led to elevated 2-HD levels, causing abnormal retinal vasculature in larval and adult zebrafish. Using transcriptomic and metabolomic analyses, we discovered that 2-HD accumulation and aldh3b1 deficiency triggered iron dysregulation and subsequent ferroptosis in both larval and adult zebrafish. Further examination revealed that 2-HD modulates ferroptosis by directly interacting with S1PR5. This finding is supported by integrative analyses of single-cell RNA sequencing and RNA sequencing from human retinal DR samples , highlighting the therapeutic potential of targeting S1PR5. In summary, our findings not only elucidate a novel pathway involving 2-HD detoxification and its critical role in the retinal vasculature, but also propose targeting S1PR5 as an innovative therapeutic strategy in the treatment of DR.

ORGANISM(S): Danio rerio

PROVIDER: GSE264377 | GEO | 2026/03/01

REPOSITORIES: GEO

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Project description:Diabetic retinopathy (DR), a leading cause of irreversible vision loss in the working-age population, is an inflammatory, neuro-vascular complication of diabetes with poorly understood mechanism. N6-methyladenosine (m6A) modification plays crucial roles in biological and pathological events, while its role in DR remain elusive. Herein, we identified the pathological involvement of m6A demethylase FTO in DR. FTO expression was elevated in proliferative membranes of DR patients, endothelial cells (EC) under diabetic stress, and retinal vessels of diabetic murine models. FTO overexpression in EC promoted EC cycle progression and tip cell formation to facilitate angiogenesis in vitro, in mice and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetes-induced microvascular leakage, and mediated EC-microglia crosstalk to induce retinal inflammation and subsequent neurodegeneration in vivo and in vitro. Mechanistically, FTO regulated EC features depending on its demethylation activity via modulating CDK2 mRNA stability with YTHDF2 as the reader. Moreover, FTO up-regulation in EC under diabetic conditions was driven by lactic acid mediated histone lactylation. FB23-2, which inhibits FTO’s m6A demethylase activity, suppressed diabetes associated endothelial phenotypes in vitro and in vivo. Noteworthy, we developed a novel macrophage membrane coated and PLGA-Dil based nanoplatform encapsulating FB23-2 for systemic administration, and confirmed its targeting and therapeutic efficacy in mice. Collectively, our study demonstrated an FTO-mediated regulatory network that coordinates EC biology and retinal homeostasis in DR, providing a promising nanotherapeutic approach for DR treatment. Diabetic retinopathy (DR), a leading cause of irreversible vision loss in the working-age population, is an inflammatory, neuro-vascular complication of diabetes with poorly understood mechanism. N6-methyladenosine (m6A) modification plays crucial roles in biological and pathological events, while its role in DR remain elusive. Herein, we identified the pathological involvement of m6A demethylase FTO in DR. FTO expression was elevated in proliferative membranes of DR patients, endothelial cells (EC) under diabetic stress, and retinal vessels of diabetic murine models. FTO overexpression in EC promoted EC cycle progression and tip cell formation to facilitate angiogenesis in vitro, in mice and in zebrafish. FTO also regulated EC-pericyte crosstalk to trigger diabetes-induced microvascular leakage, and mediated EC-microglia crosstalk to induce retinal inflammation and subsequent neurodegeneration in vivo and in vitro. Mechanistically, FTO regulated EC features depending on its demethylation activity via modulating CDK2 mRNA stability with YTHDF2 as the reader. Moreover, FTO up-regulation in EC under diabetic conditions was driven by lactic acid mediated histone lactylation. FB23-2, which inhibits FTO’s m6A demethylase activity, suppressed diabetes associated endothelial phenotypes in vitro and in vivo. Noteworthy, we developed a novel macrophage membrane coated and PLGA-Dil based nanoplatform encapsulating FB23-2 for systemic administration, and confirmed its targeting and therapeutic efficacy in mice. Collectively, our study demonstrated an FTO-mediated regulatory network that coordinates EC biology and retinal homeostasis in DR, providing a promising nanotherapeutic approach for DR treatment.

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The function and mechanism of aldh3b1 in diabetic retinopathy

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