Hydroxysafflor Yellow A for Diabetic Retinopathy: A Critical Review of Retinal Neurovascular Mechanisms and Systemic-to-Ocular Pharmacokinetic Barriers.

Oxidative stress contributes to retinal neurovascular injury through inflammation, mitochondrial dysfunction, blood-retinal barrier (BRB) disruption, microcirculatory impairment, and regulated cell death. Hydroxysafflor yellow A (HSYA), a water-soluble quinochalcone C-glycoside derived from safflower (Carthamus tinctorius L.), modulates oxidative and inflammatory signaling, apoptosis, mitochondrial injury, endothelial barrier dysfunction, and neurovascular damage in experimental ischemic, inflammatory, and metabolic disorders. This review critically evaluates the direct ocular evidence for HSYA in diabetic retinopathy and examines the systemic-to-ocular pharmacokinetic and delivery barriers that constrain its ophthalmic translation. Current ocular evidence is limited and concentrated mainly in DR models, in which HSYA attenuates oxidative stress, inflammation, BRB disruption, and apoptosis, potentially through Nrf2/HO-1 signaling. Evidence in retinal photic injury is limited, whereas the proposed relevance of HSYA to retinal ischemia-reperfusion injury, glaucoma, and AMD remains largely hypothesis-generating. The principal translational challenge is whether HSYA can achieve pharmacologically relevant exposure in ocular target tissues. Future studies should integrate dose, plasma and ocular exposure, target engagement, retinal structure, local safety, and visual function in disease-specific models. Accordingly, evidence from non-DR models is discussed primarily to define mechanistic hypotheses and experimental priorities rather than to establish ophthalmic efficacy.