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Abstract: FR-PO1039

Aldehyde Dehydrogenase 2 Interacts with PHB2 to Alleviate Renal Fibrosis and Ferroptosis in a Mitochondria-Dependent Manner

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms


  • Li, Jiaying, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Xu, Jiatong, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Shi, Xiaoxiao, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China
  • Chen, Limeng, Peking Union Medical College Hospital, Dongcheng-qu, Beijing, China

We recently proved the protective role of acetaldehyde dehydrogenase 2 (ALDH2) in acute kidney injury (AKI). In this study, we aimed to investigate the impact of ALDH2 on renal fibrosis in regulating ferroptosis in a mitochondria-dependent manner.


Renal fibrosis model was established by unilateral ureteral obstruction (UUO) in C57BLmice, followed by injection of Alda-1 (an ALDH2 agonist) on the first postoperative day and continued for 14 days until mice were sacrificed. We assessed renal fibrosis, ferroptosis, and mitochondrial function in vivo and in vitro using RSL-3 (a ferroptosis-inducing agent) in human renal proximal tubular epithelial (HK-2) cells, with or without Alda-1 (20μm). Furthermore, we identified the potential targets of ALDH2 in regulating ferroptosis and mitochondrial dysfunction by mass spectrometry screening and co-immunoprecipitation assays, then explored the role of ALDH2 on different cell types by single-cell RNA sequencing.


ALDH2 protein was reduced by 64% in UUO mice accompanied by renal interstitial fibrosis. ALDH2 agonist Alda-1 alleviated renal interstitial fibrosis, as confirmed by Masson staining and the decreased expression of α-SMA and collagen 1. Ferroptosis was initiated during UUO-induced renal fibrosis, while Alda-1 inhibited ferroptosis, indicated by reduced malonaldehyde (MDA) (1.60±0.10 versus 0.66±0.08 nmol/mg, P<0.001) and elevated GSH/GSSH ratio (1.42±0.32 versus 6.80±0.84, P<0.05). In addition, decreased mitochondrial-related proteins (PGC-1α and ATP5a1) were observed in UUO mice but reversed by Alda-1 treatment. In HK-2 cells, ALDH2 improved RSL-3-induced ferroptosis, fibrosis, and mitochondrial dysfunction. Mechanistically, mass spectrometry screening and co-immunoprecipitation assays revealed the interaction of ALDH2 with prohibitin 2 (PHB2), a crucial mitophagy receptor and ferroptosis inhibition target. Immunofluorescence staining revealed the co-localization of ALDH2 and PHB2, and Alda-1 facilitated PHB2 recruitment into mitochondria from the cytoplasm.


ALDH2 might be a promising therapeutic target in alleviating renal fibrosis and ferroptosis by interacting with PHB2 to facilitate their mitochondrial translocation.