Genistein in autoimmune diseases: from experimental evidence to emerging clinical data

Autoimmune diseases are chronic inflammatory disorders characterized by loss of immune tolerance, activation of autoreactive immune cells, and progressive tissue injury. Despite advances in immunosuppressive and biologic therapies, treatment responses remain heterogeneous and long-term therapy is frequently associated with adverse effects and economic burden. These limitations have stimulated increasing interest in complementary immunomodulatory strategies, including naturally occurring bioactive compounds. Genistein, a soy-derived isoflavone belonging to the phytoestrogen family, has emerged as a promising candidate due to its pleiotropic anti-inflammatory, antioxidant, and immunoregulatory properties. At the molecular level, genistein functions as a tyrosine kinase inhibitor and modulates several signaling pathways implicated in immune regulation, including NF-κB, MAPK, and estrogen receptor-dependent pathways. Through these mechanisms, genistein influences cytokine production, lymphocyte activation, T-cell differentiation, and cellular redox homeostasis. A body of preclinical evidence supports the immunomodulatory potential of genistein in multiple autoimmune disease models, including systemic lupus erythematosus, rheumatoid arthritis, experimental autoimmune encephalomyelitis, type 1 diabetes, Sjögren's syndrome, autoimmune thyroid disease, and autoimmune blistering skin disorders. In these models, genistein administration has been associated with attenuation of inflammatory responses, reduced disease severity, and modulation of autoimmune pathways. Although precision medicine represents a major contemporary direction in autoimmune disease therapeutics, many patients continue to experience suboptimal clinical responses. In this context, multi-target compounds such as genistein may represent a potential adjunctive therapeutic approach. Clinical evidence remains limited; however, preliminary studies suggest potential immunomodulatory effects in humans. This mini review summarizes mechanistic, preclinical, and emerging clinical evidence regarding the role of genistein in autoimmune diseases.