2. Academic Validation
  3. Integrated metabolomics and proteomics analysis elucidated the therapeutic effect of Huangkui Capsule on tacrolimus-induced chronic nephrotoxicity in rats

Integrated metabolomics and proteomics analysis elucidated the therapeutic effect of Huangkui Capsule on tacrolimus-induced chronic nephrotoxicity in rats

  • J Ethnopharmacol. 2026 Apr 6:360:121196. doi: 10.1016/j.jep.2026.121196.
Tao Pang 1,  Tingting Tang 1,  Yejian Wang 2,  Jingjing Li 3,  Liyuan Yang 4,  Yuqiong He 1,  Hong Yang 1,  Jun Han 5,  Xia Tao 6,  Wansheng Chen 7,  Feng Zhang 8
Affiliations

Affiliations

  • 1 Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
  • 2 Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Department of Pharmacy, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
  • 3 Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 4 Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China; The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 5 Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China.
  • 6 Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China. Electronic address: [email protected].
  • 7 Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China; The SATCM Key Laboratory for New Resources & Quality Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. Electronic address: [email protected].
  • 8 Department of Pharmacy, Changzheng Hospital, Naval Medical University, Shanghai, 200003, China; College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China. Electronic address: [email protected].
PMID: 41534748 DOI: 10.1016/j.jep.2026.121196
Abstract

Ethnopharmacological relevance: Huangkui capsule (HK) has demonstrated significant efficacy in managing chronic kidney disease. Previous studies have shown that HK can alleviate kidney damage; however, the therapeutic effects of HK on tacrolimus-induced chronic nephrotoxicity (TCN) and the underlying molecular mechanisms remain unclear.

Aim of the study: To evaluate the effectiveness of HK in alleviating TCN and to explore its underlying mechanisms of action.

Materials and methods: The therapeutic efficacy of HK was evaluated on the TCN rat model using biochemical indices and histopathological examinations. Integrated kidney metabolomic and proteomic profiling were analyzed to reveal the TCN related distinct dysregulated pathways and potential targets, and provide mechanistic insights into the relationship between targets and active components from HK. Molecular docking and Western blot analyses were further used for the validation.

Results: TCN rats showed increased proteinuria and a deterioration of kidney function, accompanied by increased inflammation and oxidative stress, whereas HK improved kidney damage in a dose-dependent manner. Integrated metabolomics and proteomics analyses showed that HK inhibited TCN by the restoration of glutathione metabolism and upregulation of Gclc, Gclm, Slc7a11, Slc3a2, and Gpx4, and revealed a specific regulatory mechanism of Ferroptosis by the constructed "protein-pathway-metabolite" network analysis. Mechanistically, tacrolimus intervention increased intracellular Fe2+ levels, suppressed system xCT activity by downregulation of Slc7a11 and Slc3a2, and reduced Gpx4 levels, thereby increasing susceptibility to Ferroptosis. Tamarixetin and quercetin-7-O-β-glucuronide from HK could reverse these effects, restoring expression levels of Slc7a11, Slc3a2, and Gpx4, exhibiting effects comparable to Fer-1.

Conclusions: HK attenuated TCN through suppression of Ferroptosis, as demonstrated by integrated metabolomic and proteomic analyses. This protective effect was mediated by its bioactive components, specifically quercetin, tamarixetin, and quercetin-7-O-β-glucuronide, which enhanced GSH synthesis and inhibited lipid peroxidation via upregulation of Slc7a11/Slc3a2 system.

Keywords

Huangkui capsule; Metabolomics; Molecular mechanism; Proteomics; Tacrolimus-induced chronic nephrotoxicity.

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