Fibroblast growth factor 21 ameliorates psoriasiform inflammation and epidermal hyperplasia through the regulation of NF-κB and autophagy pathways

Background: Psoriasis is a chronic immune-mediated skin condition characterized by excessive epidermal growth and persistent inflammation. Although current therapies improve disease outcomes, limitations in long-term efficacy and safety remain. Fibroblast Growth Factor 21 (FGF21), involved in metabolic regulation, has been reported to display anti-inflammatory activity and support tissue homeostasis; however, its role in psoriasis is not fully understood.

Methods: A psoriasis-like mouse model established by imiquimod (IMQ) application was used to assess the in vivo activity of FGF21. Histopathological examination, cytokine analysis, immunohistochemistry, and western blotting were conducted to assess epidermal alterations and signaling pathways. In vitro, lipopolysaccharide-stimulated HaCaT keratinocytes were used to examine the impact of FGF21 on cell proliferation, Apoptosis, and inflammatory mediator expression, while primary normal human epidermal keratinocytes (NHEKs) were incorporated for validation. Furthermore, pathway alterations were evaluated, and pharmacological inhibition with chloroquine (CQ) was used to assess Autophagy dependence.

Results: FGF21 administration attenuated psoriasis-like skin lesions, reduced systemic inflammatory cytokine levels in IMQ-treated mice, and exhibited preliminary tolerability based on body weight and histology. In keratinocytes, FGF21 partially restored proliferation-apoptosis balance and suppressed inflammation, associated with reduced NF-κB activation. FGF21 also modulated autophagy-related proteins alongside PI3K/Akt inhibition, with increased SIRT1 expression and decreased STAT3 activation. Crucially, CQ perturbation revealed that the anti-inflammatory and anti-proliferative benefits of FGF21 depended on Autophagy restoration.

Conclusions: FGF21 modulates key inflammatory and autophagy-related signaling pathways in psoriasis-like mice model and may represent a promising therapeutic candidate in psoriasis and Other autoimmune inflammatory disorders.