REDD1 deficiency alleviates podocyte PANoptosis and restores autophagy in diabetic kidney disease

  • Mol Med. 2026 May 21;32(1):112. doi: 10.1186/s10020-026-01510-8.
Mengyu Liu  1 ,  Chen Yuan  1 ,  Yue Li  1 ,  Shan Song  1  2 ,  Lin Mu  2  3 ,  Yawei Bian  1 ,  Xinran Li  1 ,  Xiaoxue Yu  1 ,  Guiying Li  4 ,  Yonghong Shi  5  6
Affiliations
  • 1. Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China.
  • 2. Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China.
  • 3. Department of Nephrology, Second Hospital of Hebei Medical University, Shijiazhuang, 050051, China.
  • 4. Department of Nephrology, Affiliated Hospital of Hebei University of Engineering, Handan, 056000, China.
  • 5. Department of Pathology, Hebei Medical University, Shijiazhuang, 050017, China. [email protected].
  • 6. Hebei Key Laboratory of Kidney Disease, Shijiazhuang, 050017, China. [email protected].
PMID: 42168844 DOI: 10.1186/s10020-026-01510-8
Abstract

Background: Podocyte loss and death are pathological hallmarks of diabetic kidney disease (DKD), and PANoptosis (Apoptosis, Pyroptosis, and Necroptosis) in podocytes is crucial to DKD progression. Regulated in development and DNA damage response 1 (REDD1) is a multifaceted regulator involved in metabolism, oxidative stress, Autophagy, and cell fate. In this study, we aimed to investigate the effects and underlying mechanisms of REDD1 on podocyte PANoptosis and Autophagy in DKD.

Methods: REDD1 knockout (KO) mice were induced to diabetes by intraperitoneal injections of streptozotocin (STZ). We assessed renal function, albuminuria, kidney pathology, and podocyte injury in diabetic mice. In vitro, mouse podocyte cells (MPCs) were transfected with REDD1 shRNA plasmid, stratifin (SFN) expression plasmid, SFN siRNA, and treated with TFEB activator 1 or GSK-872 and cultured in high glucose (HG) medium. Gene and protein expression was assessed by real-time quantitative PCR, western blotting, immunofluorescence, and immunohistochemistry. Apoptosis, Cytoskeleton change, mitochondrial morphology and membrane potential were evaluated in podocytes.

Results: REDD1 KO improved renal function and reduced mesangial expansion, podocyte loss, and markers related to PANoptosis in podocytes in diabetic mice. In vitro, REDD1 knockdown suppressed HG-induced PANoptosis, cytoskeletal disorganization, mitochondrial damage, and mitochondrial membrane potential reduction in podocytes. In addition, REDD1 deletion restored Autophagy and transcription factor EB (TFEB) expression in diabetic kidneys. Meanwhile, REDD1 knockdown alleviated Autophagy dysfunction and promoted TFEB nuclear translocation in podocytes exposed to HG. Moreover, REDD1 KO inhibited podocyte SFN expression in diabetic mice. SFN knockdown or receptor interacting protein kinase 3 (RIPK3) inhibitor GSK-872 alleviated HG-induced PANoptosis and Autophagy dysfunction in podocytes. Besides, overexpression of SFN reversed the effect of REDD1 knockdown on PANoptosis and Autophagy in HG-treated podocytes.

Conclusions: REDD1 deficiency protects against podocyte injury through inhibiting PANoptosis and restoring Autophagy in DKD. REDD1 is a potential therapeutic target to slow the progression of DKD.

Keywords
Autophagy; Diabetic kidney disease; PANoptosis; Podocyte; REDD1; Stratifin.
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