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.