ZDHHC8-mediated S-palmitoylation of RAD21 causes mitochondrial dysfunction in diabetic nephropathy via inhibiting ACSM3 transcription

  • Cell Death Differ. 2026 Jul 15. doi: 10.1038/s41418-026-01816-4.
Wei Chen  #  1  2 ,  Yinyin Chen  #  3 ,  Shaobin Duan  1  2 ,  Hao Li  1  2 ,  Yang Gao  1  2 ,  Weiying Zhang  1  2 ,  Guoyong Liu  4 ,  Jiayi Wang  5 ,  Xiaofei Peng  6 ,  Liyu He  7  8
Affiliations
  • 1. Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, Changsha, PR China.
  • 2. National Clinical Research Center for Metabolic Diseases, Changsha, PR China.
  • 3. Department of Nephrology, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha, PR China.
  • 4. Department of Nephrology, The First Affiliated Hospital of Changde Vocational Technical College, Changde, PR China.
  • 5. Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, PR China.
  • 6. Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha, PR China.
  • 7. Department of Nephrology, The Second Xiangya Hospital, Central South University, Key Lab of Kidney Disease and Blood Purification in Hunan, Changsha, PR China. [email protected].
  • 8. National Clinical Research Center for Metabolic Diseases, Changsha, PR China. [email protected].
  • # Contributed equally.
PMID: 42457923 DOI: 10.1038/s41418-026-01816-4
Abstract

Tubulointerstitial injury exerts a key role in diabetic nephropathy (DN) development; however, its potential mechanism is still unclear. We explored the role and molecular mechanisms of RAD21 cohesin complex component (RAD21) in mitochondrial dysfunction during tubulointerstitial injury of DN. We found that RAD21 was down-regulated, but its S-palmitoylation level was up-regulated in DN. RAD21 overexpression attenuated renal tubulointerstitial injury, fibrosis and mitochondrial dysfunction in DN. In addition, zinc finger DHHC-type palmitoyltransferase8 (ZDHHC8) served as a key acetyltransferase that catalyzed RAD21 S-palmitoylation at C78 site, which led to heat shock protein member 8 (HSPA8)-mediated lysosomal degradation of RAD21. Down-regulation of RAD21 repressed the transcription and expression of ACSM3. ACSM3 deficiency abrogated the beneficial effect of RAD21 overexpression on mitochondrial dysfunction during tubulointerstitial injury in DN. In conclusion, ZDHHC8-mediated S-palmitoylation of RAD21 favored its lysosomal degradation with assistance of HSPA8, which repressed ACSM3 transcription to cause mitochondrial dysfunction, thereby accelerating DN progression.

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