A recent study demonstrated that imbalanced pro-apoptotic ISR signaling contributes to deoxysphingolipid-mediated toxicity in retinal disease and identified potential therapeutic strategies, such as pharmacologic enhancement of ATF6 activity or treatment with ATF6-regulated neurotrophic factor MANF, that attenuate the associated retinal degeneration (Rosarda et al., 2023). The gene discussed is MANF; the disease is retinal degeneration.