Intermittent fasting inhibits ferroptosis by modulating CD36 and its palmitoylation to alleviate diabetic dry eye

Abstract Background Excessive lipid accumulation in the lacrimal glands under diabetic conditions can lead to lacrimal gland dysfunction and reduced tear secretion, subsequently resulting in ocular surface inflammation, dry eye syndrome, and corneal vulnerability, ultimately compromising the patient’s quality of life. There are limited and easily implemented intervention strategies to reduce excessive lipid accumulation. While intermittent fasting (IF) has emerged as a promising metabolic intervention, its mechanistic underpinnings and therapeutic potential in diabetes-associated lacrimal gland disorders require systematic elucidation. Methods Diabetic mice were divided into three groups for an 8-week dietary intervention: ad libitum, meal feeding, and every-other-day feeding. After dietary intervention, we assessed the damage to lacrimal glands and ocular surface, and elucidated lipid accumulation, ferroptosis, and functional changes in the lacrimal glands. Transcriptomic analysis was used to examine gene expression. CD36 and its palmitoylation were examined around three groups. In addition, damage to the ocular surface and lacrimal glands was assessed in vivo, after the mice were injected with the ferroptosis inhibitor Fer-1 and CD36 shRNA. Results In this study, we found that compared with caloric restriction, IF more effectively reduced lipid accumulation in the lacrimal glands of diabetic db/db mice, decreased lipid peroxidation and ferroptosis, and improved function. IF downregulated CD36 expression and its palmitoylation, potentially mediated by ZDHHC20. CD36 shRNA and ferroptosis inhibition (Fer-1) comparably restored lacrimal secretory function, yet only CD36 knockdown concurrently resolved lipidostasis and ferroptosis. Conclusions This analysis identifies CD36 as a key regulator bridging lipotoxic stress and ferroptotic execution in diabetic lacrimal gland dysfunction. Importantly, our findings suggest that ferroptosis may serve as the critical effector mechanism converting metabolic overload to glandular dysfunction, suggesting potential therapeutic value in dual targeting of lipidostasis and cell death pathways. Significance Intermittent fasting, which appears more effective than that of caloric restriction, may be associated with reduced lipid absorption resulting from decreased CD36 expression and its palmitoylation on lacrimal gland cell membranes. These findings uncover a potential novel treatment strategy for diabetic dry eye. Graphical Abstract