Neferine ameliorates psoriasis through inducing oxidative stress-mediated keratinocyte apoptosis and suppressing inflammatory response via the Keap1-Nrf2 pathway.

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by keratinocytes (KCs) hyperproliferation and persistent inflammation. Current biologics are limited by high relapse rates and long-term safety concerns, prompting the search for multi-target natural small molecules. A murine psoriasis model was induced by 6-day continuous topical imiquimod (IMQ) application; cellular models were established by stimulating keratinocyte lines with tumor necrosis factor-alpha (TNF-α)/interleukin-17A (IL-17A). Network pharmacology and molecular docking were employed to predict targets, and small interfering RNA targeting Nrf2(siNrf2) was used for mechanistic validation. Neferine administration significantly attenuated epidermal hyperplasia, splenomegaly and cutaneous inflammation in vivo. In KCs, Neferine dose-dependently suppressed inflammatory cytokines and pathway proteins, elevated oxidative stress levels, decreased mitochondrial membrane potential (ΔΨm) and promoted apoptosis. Neferine bound Keap1, reduced its level, enhanced Nrf2 nuclear translocation and up-regulated HO-1/NQO1. siNrf2 abolished Nef-mediated inhibition of NF-κB/ERK phosphorylation, cytokine down-regulation and ΔΨm loss. Neferine ameliorates psoriasis by inducing oxidative stress-driven apoptosis in hyper-proliferative keratinocytes and by activating Keap1-Nrf2-mediated anti-inflammatory signaling to block the IL-23/IL-17 axis, offering a promising small-molecule strategy for psoriasis management.