The function and mechanism of aldh3b1 in diabetic retinopathy

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.