Optimization of Ascidian-Derived Herdmanine D: Targeting Gouty Arthritis via the PPAR-γ/NF-κB/NLRP3 Pathway

Gouty arthritis, driven by monosodium
urate (MSU) crystal deposition
and dysregulated inflammation, remains a therapeutic challenge due
to the limitations of current treatments. Here, we investigate Herdmanine
D (HDD), a marine-derived alkaloid from the ascidian Herdmania momus. It was optimized via structure–activity
relationship (SAR) studies and computational modeling to enhance its
binding to peroxisome proliferator-activated receptor γ (PPAR-γ),
which regulates the PPAR-γ/NF-κB signaling pathway in
gout pathogenesis. The optimized HDD derivative 9a demonstrated potent PPAR-γ binding affinity and pharmacokinetic
properties, effectively suppressing NF-κB-driven pro-inflammatory
cytokines in vitro. In murine MSU-induced gouty arthritis
models, 9a alleviated synovial inflammation and tissue
damage. Mechanistically, 9a activated PPAR-γ to
inhibit NF-κB and attenuate NLRP3 inflammasome assembly. This
work highlights HDD as a unique marine scaffold for next-generation
antigout therapeutics, merging marine natural product safety with
rational design to address unmet clinical needs.