N-(4-Hydroxyphenethyl)-(4E)-decenamide derived from natural phytochemical of Anacyclus root ameliorates diabetic retinopathy by inhibiting angiogenesis via PARK7.

Anacyclus pyrethrum (L.) DC. is a herbaceous species of the Asteraceae family. This medicinal plant has been widely used in traditional medicine to treat diabetes and its associated complications. N-(4-Hydroxyphenethyl)-(4E)-decenamide (HPD) is a synthetic derivative of natural N-alkylamides extracted from its roots. To date, the therapeutic efficacy and molecular mechanisms of HPD against diabetic retinopathy (DR) have not been fully clarified. This study aimed to explore the therapeutic potential of HPD against DR and clarify its molecular mechanisms. HPD was chemically synthesized. Its anti-angiogenic efficacy was evaluated using both in vitro and in vivo assays. Proteomic analysis, combined with molecular docking and surface plasmon resonance (SPR), was employed to screen and validate the direct binding targets of HPD. Additionally, siRNA-mediated gene knockdown was performed to clarify the functional role of the identified target in DR pathology. In vitro and in vivo experiments demonstrated that HPD significantly inhibited pathological angiogenesis and restored retinal thickness in diabetic retinopathy (DR) model mice. Proteomics analysis, coupled with surface plasmon resonance (SPR) validation, revealed that HPD directly and exclusively bound to PARK7. Furthermore, knockdown of PARK7 exacerbated pathological angiogenesis, whereas intervention with HPD markedly reversed this phenotypic alteration. HPD directly targets PARK7 to attenuate diabetic retinopathy by suppressing pathological angiogenesis, preserving retinal structure, and maintaining blood-retinal barrier integrity.