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 (<b>HDD</b>), a marine-derived alkaloid from the ascidian <i>Herdmania momus</i>. 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 <b>HDD</b> derivative <b>9a</b> demonstrated potent PPAR-γ binding affinity and pharmacokinetic properties, effectively suppressing NF-κB-driven pro-inflammatory cytokines <i>in vitro</i>. In murine MSU-induced gouty arthritis models, <b>9a</b> alleviated synovial inflammation and tissue damage. Mechanistically, <b>9a</b> activated PPAR-γ to inhibit NF-κB and attenuate NLRP3 inflammasome assembly. This work highlights <b>HDD</b> as a unique marine scaffold for next-generation antigout therapeutics, merging marine natural product safety with rational design to address unmet clinical needs.