PI3KCD gene expression and its role in diabetic intervertebral disc degeneration running title: PI3KCD gene crucial for diabetic IDH.

Diabetes mellitus (DM) affects 8% of the population and impacts various connective tissues. Obesity, type 2 diabetes mellitus (T2DM), and their metabolic effects are increasingly linked to intervertebral disc degeneration (IVDD). Diabetic patients develop disc degeneration at younger ages and with higher frequency than non-diabetics. To investigate the role of PI3KCD in high glucose-induced IVDD and explore potential therapeutic approaches. The study examined PI3KCD expression in nucleus pulposus (NP) cells under high glucose conditions and investigated its regulatory mechanism through the PI3K/AKT pathway. The effects of PI3KCD agonist 740Y-P were also evaluated. High glucose conditions significantly decreased PI3KCD expression in NP cells. PI3KCD knockdown accelerated high glucose-induced NP cell death. The study revealed PI3KCD regulates NP cells via the PI3K/AKT pathway, with high glucose potentially reducing PI3KCD expression through increased cellular oxidative stress. The PI3KCD agonist 740Y-P demonstrated potential in partially reversing diabetes-induced IVDD, presenting a promising therapeutic approach for diabetic IVDD treatment.