Co-activation and signal crosstalk between parthanatos and mitophagy in light-induced retinal injury.

Prolonged light exposure is an important environmental risk factor for retinal degeneration, yet the interaction between distinct cell death pathways during retinal photodamage remains unclear. Here, we demonstrate that light injury simultaneously activates PARP-1-dependent parthanatos and PINK1/Parkin-mediated mitophagy in photoreceptor cells. Light exposure markedly increased PARP-1 activity, poly(ADP-ribose) (PAR) accumulation, and mitophagy-related proteins, including PINK1, p-Parkin, and LC3B-II. Importantly, our results reveal a previously unrecognized crosstalk between parthanatos and mitophagy. PARP-1 inhibition not only attenuated parthanatos but also suppressed excessive mitophagy, indicating that PARP-1 acts as a key upstream regulator linking these two pathways. Conversely, inhibition of mitophagy alleviated light-induced retinal damage. Both in vitro and in vivo experiments further demonstrated that combined inhibition of PARP-1 and mitophagy produced a stronger neuroprotective effect than either intervention alone, preserving photoreceptor structure and retinal function. These findings identify PARP-1-mediated crosstalk between parthanatos and mitophagy as a critical mechanism underlying retinal light injury and provide a potential therapeutic strategy for photoreceptor degeneration.