Despite decades of investigation, Aldose Reductase (AR; AKR1B1) -an enzyme that plays a key role in the metabolism of glucose and other carbonyl compounds and whose hy-peractivity contributes to oxidative stress and vascular dysfunction- inhibitors have failed to translate into clinical application for Diabetic Retinopathy (DR). We argue that these failures might arise from non-selective inhibition, which does not consider AR’s dual roles in pathology but also in retinal health, as AR is also an important detoxifying enzyme for aldehydes produced during oxidative stress, and discuss the missing structural infor-mation, despite the over one hundred crystal structures of AR in complex with inhibitors. Our review bridges this gap by proposing how recent advances in structural biology, namely, fragment-based drug discovery and MicroED, provide novel ways of selectively modulating AR functions, offering advantages in the detection of weak, allosteric, or conformation-dependent binding events. Despite past challenges, we suggest that therapeutic targeting or finding new-generation inhibitors for AR will become more effective once we have a clearer understanding of AR’s requirements for selective inhi-bition of its pathological and physiological functions. By integrating fragment screening and structural biology, we outline a strategy to reinvigorate AR modulation as a viable retina-specific approach for managing DR first, although potentially relevant across multiple diabetic microvascular complications later.

Aldose Reductase (AR; AKR1B1) is an enzyme that plays a key role in the metabolism of glucose and other carbonyl compounds, and whose hyperactivity contributes to oxidative stress and vascular dysfunction. Despite decades of investigation into this enzyme, inhibitors have failed to translate into clinical application for Diabetic Retinopathy (DR). We argue that these failures might arise from non-selective inhibition, considering the dual roles of AR, which contribute not only to DR pathology but also support retinal health, as AR is an important detoxifying enzyme for aldehydes produced during oxidative stress. Here, we discuss missing structural information, despite more than one hundred crystal structures of AR in complex with inhibitors. Our review bridges this gap by discussing how recent advances in structural biology, e.g., fragment-based drug discovery and MicroED, provide novel ways to selectively modulate AR functions, offering advantages for the detection of weak, allosteric, or conformation-dependent binding events. Despite past challenges, we suggest that therapeutic targeting of AR to find new-generation inhibitors will become more effective once we have a clearer understanding of the requirements for selective inhibition of AR, blocking its pathological impact while preserving its physiological functions. By integrating fragment screening and structural biology, we outline a strategy to reinvigorate AR modulation as a viable retina-specific approach for managing DR, with potentially broader relevance toward multiple diabetic microvascular complications.