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Triptolide impedes high glucose-induced cell function in HK2 cells through PRKN-mediated ubiquitination of ACSL1

Jiangsong Jia1, Wen-Ming Zhao1, Xin Wang1

  • 1Department of Pharmacy, Henan Provincial People's Hospital; People's Hospital of Zhengzhou University; People's Hospital of Henan University, Zhengzhou, Henan, 450003, China.

The Journal of Endocrinology
|November 26, 2025
PubMed

Insights

Triptolide (TP) protects against diabetic nephropathy by upregulating parkin (PRKN), which degrades acyl-CoA synthetase long-chain family member 1 (ACSL1), mitigating renal tubular injury and ferroptosis.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Diabetic nephropathy (DN) is a major complication of diabetes, leading to renal tubular injury.
  • Understanding the molecular mechanisms underlying DN is crucial for developing effective treatments.
  • Triptolide (TP) is a bioactive compound with potential therapeutic applications in DN.

Purpose of the Study:

  • To investigate the protective role of Triptolide (TP) in renal tubular injury during diabetic nephropathy (DN).
  • To elucidate the underlying mechanism involving acyl-CoA synthetase long-chain family member 1 (ACSL1) and parkin (PRKN).
  • To explore TP's effect on ferroptosis and the NRF2/SLC7A11/GPX4 pathway in DN.

Main Methods:

  • DN models were established in HK2 cells (high glucose) and mice (high-fat diet/streptozocin).
  • Cell viability, proliferation, apoptosis, and inflammation were assessed using CCK-8, EdU, flow cytometry, and ELISA.
  • Ferroptosis, protein levels, mRNA expression, protein interaction, and ubiquitination were analyzed using specific kits, qPCR, western blotting, and co-immunoprecipitation.

Main Results:

  • Triptolide (TP) mitigated high glucose-induced apoptosis, inflammation, and ferroptosis in HK2 cells.
  • TP's protective effects were mediated by upregulating parkin (PRKN), which promotes the ubiquitination and degradation of acyl-CoA synthetase long-chain family member 1 (ACSL1).
  • TP activated the anti-ferroptosis NRF2/SLC7A11/GPX4 pathway and ameliorated kidney injury in DN mice.

Conclusions:

  • Triptolide (TP) protects renal tubular cells from high glucose-induced injury by upregulating PRKN, leading to ACSL1 degradation.
  • TP ameliorates diabetic nephropathy (DN) by inhibiting ferroptosis via the NRF2/SLC7A11/GPX4 pathway.
  • TP demonstrates therapeutic potential for treating diabetic nephropathy (DN).
Keywords:
Acyl-CoA synthetase long-chain family member 1Diabetic nephropathyFerroptosisParkinTriptolide

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