Kinsenoside alleviates retinal pigment epithelium cell injury in age-related macular degeneration-like retinal injury through exosome-associated modulation of JNK/MAPK signaling.

BACKGROUND

Dry age-related macular degeneration (AMD) is driven largely by retinal pigment epithelium (RPE) cell injury. Kinsenoside (KN) exhibits protective activity on RPE cells, but the direct effect on dry AMD and underlying molecular mechanisms remain unclear.

OBJECTIVE

This study aimed to investigate the protective effects of KN against RPE cell injury and dysfunction in dry AMD and to elucidate its regulatory mechanisms.

METHODS

An A2E- and blue light-induced ARPE-19 cell injury model and a blue light-induced AMD-like retinal injury mouse model were established. RPE cytotoxicity, apoptosis, senescence, inflammation, and melanogenesis-associated marker expression were evaluated. MAPK signaling was analyzed by Western blotting, and mechanistic analyses were performed using a JNK inhibitor, molecular docking analysis, an in vitro JNK enzymatic activity assay, exosome characterization, and exosome functional assays.

RESULTS

KN treatment significantly attenuated cytotoxicity, apoptosis, cellular senescence, inflammatory responses, and melanogenesis-associated marker alterations in AMD-like ARPE-19 cells. In vivo, KN reduced drusen-like deposition, improved retinal structural integrity, and partially restored outer nuclear layer thickness while suppressing senescence and inflammation. Mechanistically, KN preferentially attenuated pathological JNK activation under the examined conditions and reduced JNK enzymatic activity in vitro. Pharmacological JNK inhibition phenocopied the protective effects of KN with no additive benefit, indicating pathway convergence. Exosome inhibition, transfer, and depletion experiments supported the contribution of exosome-associated signaling to KN-mediated cytoprotection.

CONCLUSION

These findings suggest that KN alleviates RPE cell injury under AMD-like stress, at least partly through exosome-associated modulation of JNK/MAPK signaling.