Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Andrographolide as a Multi-Target Therapeutic Agent in Diabetic Nephropathy: Insights into STAT3/PI3K/Akt Pathway Modulation

  • Yuan Yin (School of Chemistry and Chemical Engineering, North University of China) ;
  • Jing He (Department of Endocrinology, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University) ;
  • Yu Fang (Department of Pharmacy, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University) ;
  • Min Wei (Department of Pharmacy, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University) ;
  • Wang Zhang (Department of Endocrinology, The Third People’s Hospital of Hefei, Hefei Third Clinical College of Anhui Medical University)
  • Received : 2024.11.04
  • Accepted : 2025.01.12
  • Published : 2025.05.01
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Abstract

Diabetic nephropathy (DN) remains a leading cause of end-stage renal disease (ESRD), driven by chronic inflammation, oxidative stress, and apoptosis. Current therapies targeting glycemic and blood pressure control fail to address the underlying molecular mechanisms of DN. This study investigates the therapeutic potential of andrographolide (AD), a diterpenoid lactone from Andrographis paniculata, in mitigating DN by modulating key molecular pathways. Through integrative network pharmacology, molecular docking, and in vivo/in vitro experiments, 107 overlapping DN-related targets were identified, with STAT3, PI3K, and AKT1 emerging as core nodes. Molecular docking revealed high binding affinities between AD and these targets, supporting its modulatory potential. In vivo, AD significantly improved renal function in streptozotocin-induced DN rats, reducing proteinuria, glomerular hypertrophy, and renal fibrosis. AD also attenuated oxidative stress, decreased pro-inflammatory cytokine levels, and enhanced antioxidant enzyme activities, demonstrating systemic anti-inflammatory and antioxidative effects. In vitro studies further confirmed that AD alleviates podocyte oxidative stress and apoptosis under high glucose conditions by suppressing the RAGE-NF-κB and STAT3/PI3K/Akt pathways. Histological analyses revealed substantial improvements in renal architecture, including reductions in fibrosis and mesangial expansion. These results underscore AD's multi-target mechanism, directly addressing DN's core pathological drivers, including inflammation, oxidative stress, and apoptosis. As a natural compound with notable safety and efficacy, AD holds promise as an adjunct or standalone therapeutic agent for DN. This study establishes a robust preclinical foundation for AD, warranting further exploration in clinical trials and its potential application in other diabetic complications.

Keywords

Acknowledgement

We gratefully acknowledge the Department of Pathology at Anhui University of Chinese Medicine and the Department of Endocrinology at The Third People's Hospital of Hefei for their technical support and expertise. We also thank Anhui Medical University for providing essential facilities and infrastructure for this research. This research was supported by the Health research project of Anhui Province (No. AHWJ2023BAa20017) and the Health Research Project of Anhui Province (Grant No. AHWJ2023BAc20042).

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