Ovatodiolide alleviates renal fibrosis through regulating metabolic reprogramming via targeting glucose-6-phosphate dehydrogenase.

Background: Ovatodiolide (Ova) is a bioactive compound from Anisomeles indica (l.) Kuntze, which has been traditionally utilized to tonify the kidney function. There is limited targeted therapies available for renal fibrosis (RF) in chronic kidney disease (CKD).

Purpose: This study aims to investigate the effect of Ova on RF and its underlying mechanism.

Methods: Unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction (UUO) were intragastrically administrated by solvent (vehicle group) or Ova at two concentations (25 and 50 mg kg day) as treatment groups and telmisartan (Tel) as a positive control group. Mass spectrometry (MS), HuProt proteome microarray, surface plasmon resonance (SPR) assays and molecular docking were utilized to explore the molecular mechanism by which Ova regulated metabolic reprogramming in renal tubular epithelial cells (RTECs). In vitro, RTECs were subjected to small interfering RNA (siRNA) and mutant plasmids to evaluate the role of glucose-6-phosphate dehydrogenase (G6PD) in metabolic reprogramming.

Results: Ova treatment markedly attenuated RF in UIRI and UUO mice by suppressing pentose phosphate pathway (PPP) overactivation. Ova bound specifically to G6PD's Lys403 site, promoted its acetylation and thereby inhibited dimer formation and enzymatic activity without affecting overall protein expression. Notably, Ova effectively inhibited but did not completely abolish G6PD activity, thereby preserving basal PPP levels crucial for cellular survival and physiological functions.

Conclusion: For the first time, we identify Ova as a potential therapeutic agent for RF through selective modulation of G6PD. These findings advance the development of metabolism-targeted therapies for RF, offering scientific and translational value.