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.