GSK3β drives early diabetic tubulopathy via TFEB‐mediated mitochondrial dysfunction

Abstract Growing evidence implicates diabetic tubulopathy (DT), driven by tubular atrophy and interstitial fibrosis, as a major determinant of renal insufficiency and disease outcome in diabetic kidney disease (DKD). This perspective underscores the need to elucidate tubular‐specific pathogenic mechanisms. An emerging perspective suggests that mitochondrial dysfunction is an early event in DKD, although the precise pathological mechanism remains unknown. Our previous work identified glycogen synthase kinase 3β (GSK3β) as a potential novel biomarker for DKD. Thus, we further revealed that GSK3β was hyperactivated in the renal tubule of DKD, which was positively correlated with early mitochondrial dysfunction. Conversely, therapeutic targeting of GSK3β with TDZD‐8 or genetic silencing attenuated early mitochondrial dysfunction and delayed DT. Mechanistically, the key downstream effector through which GSK3β accelerates DKD progression is the Transcription factor EB (TFEB) signaling pathway. Specifically, upon activation, GSK3β inhibits the nuclear translocation of TFEB, leading to dysregulated TFEB transcriptional function, which in turn mediates early mitochondrial damage in experimental models of DKD. This is manifested as alterations in mitochondrial morphology, dynamics, mitophagy, and reactive oxygen species production. Therefore, GSK3β overexpression accelerates early mitochondrial dysfunction in renal tubules during DKD by impairing TFEB nuclear translocation, providing a rationale for targeting the GSK3β/TFEB axis to preserve mitochondrial fitness in DT.