Growth differentiation factor 15 impairs periodontal ligament stem cell proteostasis via integrated stress response to drive diabetic periodontitis.

INTRODUCTION: Periodontitis progresses more rapidly and severely in individuals with type 2 diabetes mellitus (T2DM), yet whether the integrated stress response (ISR) contributes to the progression of diabetic periodontitis has not been elucidated. OBJECTIVES: This study aims to clarify the impact and mechanisms of growth differentiation factor 15 (GDF15) in diabetic periodontitis. METHODS: We performed single-cell RNA sequencing on periodontal tissues and integrated the datasets with bidirectional Mendelian randomization to identify ISR-related alterations associated with impaired periodontal regeneration under diabetic conditions. Functional analyses were conducted in periodontal ligament stem cells (PDLSCs) subjected to diabetic-inflammatory conditions. Genetic deletion, antibody-based neutralization of GDF15, and ISR inhibition were used to evaluate therapeutic rescue effects in diabetic mice. RESULTS: We identify GDF15 as an important effector of ISR signaling in PDLSCs. T2DM induces sustained PERK-eIF2α activation accompanied by GDF15 induction, leading to translational repression, loss of proteostasis, and impaired osteogenic differentiation. Mechanistically, GDF15 silencing preserved BiP-PERK complex stability and attenuated downstream PERK-eIF2α activation under diabetic-inflammatory stress. Genetic ablation or pharmacologic neutralization of GDF15, as well as ISR inhibition, partially restores PDLSC proteostasis and bone-forming capacity, preserving periodontal tissue regenerative capacity in diabetic mice. CONCLUSION: These findings suggest that GDF15 contributes to ISR-mediated PDLSC dysfunction and impaired periodontal regeneration under diabetic conditions. Targeting pathological GDF15-ISR signaling may provide mechanistic insight for future strategies to improve periodontal regenerative outcomes in T2DM.