Hydrogen Sulfide-Regulated NF-κB Signaling via Persulfidation: A Review.

Hydrogen sulfide (H2S) is an important endogenous gaseous signaling molecule that regulates diverse physiological and pathological processes through protein persulfidation. As a central regulator of inflammation and immune responses, NF-κB signaling is precisely controlled by post-translational modifications, and its dysregulation contributes to various inflammatory diseases. Recent studies reveal that H2S-mediated persulfidation is a key mechanism for fine-tuning NF-κB activity by targeting critical components, including p65, IKKβ, IκBα, and upstream regulators. Through site-specific S-sulfhydration, H2S modulates IKK activation, IκBα degradation, and p65 nuclear translocation, thereby limiting excessive NF-κB activation and inflammatory cytokine production. This review provides an integrated view of how endogenous H2S production and persulfidation-dependent signaling regulate inflammatory responses. Rather than simply summarizing individual pathways, we focus on the molecular mechanisms underlying H2S-mediated regulation of NF-κB-associated networks, including TLR4/NF-κB, PI3K/Akt/NF-κB, and MAPK/NF-κB pathways, and highlight its roles in oxidative stress, apoptosis, pyroptosis, and tissue repair. We further discuss current challenges in identifying persulfidation sites, understanding endogenous H2S regulation, and improving detection technologies. By proposing H2S as a precision modulator of inflammatory signaling, this review provides new insights into H2S biology and highlights future opportunities for developing targeted H2S-based therapeutic strategies.