2. Academic Validation
  3. Genistein ameliorates lupus nephritis via enhancing ERβ-mediated inhibition of STAT3-driven inflammation

Genistein ameliorates lupus nephritis via enhancing ERβ-mediated inhibition of STAT3-driven inflammation

  • Phytomedicine. 2026 Apr:153:157917. doi: 10.1016/j.phymed.2026.157917.
Jieli Pan 1,  Jinjun Ji 2,  Xingpan Xin 3,  Yihong Gan 4,  Zixin Huang 5,  Jing Chen 2,  Ying Li 2,  Jie Bao 2,  Yujun Tang 3,  Chengping Wen 6,  Li Xu 7
Affiliations

Affiliations

  • 1 College of Basic Medical, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310051, China; Medical Research Centre, Academy of Chinese Medical Science, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310051, China.
  • 2 College of Basic Medical, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310051, China.
  • 3 College of Basic Medical, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310051, China; Jinghua academy of Zhejiang Chinese Medicine University, Jinghua, 321015, PR China.
  • 4 Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China.
  • 5 College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
  • 6 College of Basic Medical, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310051, China; Jinghua academy of Zhejiang Chinese Medicine University, Jinghua, 321015, PR China; Department of Rheumatology, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310005, China. Electronic address: [email protected].
  • 7 College of Basic Medical, Zhejiang Chinese Medical University, 548 Binwen Road, Hangzhou 310051, China; Jinghua academy of Zhejiang Chinese Medicine University, Jinghua, 321015, PR China. Electronic address: [email protected].
PMID: 41653614 DOI: 10.1016/j.phymed.2026.157917
Abstract

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease with marked female predominance. Lupus nephritis (LN), one of its most severe manifestations, is strongly associated with aberrant activation of signal transducer and activator of transcription 3 (STAT3). Estrogen receptor β (ERβ) has been reported to exert immunoregulatory effects, but its role in restraining STAT3 signaling in LN remains unclear.

Purpose: This study aimed to investigate whether genistein, a phytoestrogen with selective affinity for ERβ, can modulate the ERβ-STAT3 axis to attenuate lupus nephritis.

Methods: The therapeutic effects of genistein were evaluated in MRL/lpr and pristane-induced lupus mouse models and in LPS-stimulated macrophages. Macrophage polarization, oxidative stress, mitochondrial function, and ERβ-STAT3 signaling were assessed using flow cytometry, biochemical assays, immunoblotting, and bioinformatic analyses.

Results: Genistein significantly ameliorated renal injury, reduced proteinuria, and decreased serum autoantibody and IL-6 levels in lupus models. Mechanistically, genistein suppressed M1 macrophage polarization by activating ERβ and inhibiting STAT3 and NF-κB signaling. Genistein also attenuated oxidative stress by preserving mitochondrial membrane potential, reducing Reactive Oxygen Species production, and restoring antioxidant capacity. Pharmacological blockade of ERβ markedly attenuated the anti-inflammatory effects of genistein, confirming ERβ-dependent regulation of STAT3 signaling.

Conclusion: This study identifies ERβ as a negative regulator of STAT3-driven inflammation and demonstrates that genistein therapeutically engages this axis to suppress macrophage-mediated renal injury, offering a promising therapeutic strategy for lupus nephritis.

Keywords

ERβ, Genistein, Macrophage polarization, SLE; Lupus Nephritis, STAT3.

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