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

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.