HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation.

Lipid accumulation in renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aims to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we show that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulates the phosphorylation of INSIG1 and INSIG2, which disrupts the interaction between INSIG proteins and SCAP, leading to SREBP activation. TEC-specific overexpression of HSPA8 restrains these changes. INSIG1/2 can be phosphorylated by protein kinase R (PKR), while HSPA8 recognizes PKR and recruits the E3 ubiquitin ligase to promote PKR ubiquitination and degradation. Under temporary hyperglycemic stimulation, SREBP1 transcriptionally activates HSPA8 expression. Conversely, persistent hyperglycemia reduces HSPA8 levels via promoting NF-κB-mediated transcriptional inhibition of HSPA8. Collectively, these findings indicate that the molecular chaperone HSPA8 serves as a negative feedback regulator of SREBPs, lipogenesis, and DKD development.