A zinc-glycyrrhizic acid hydrogel alleviates atopic dermatitis by targeting the TLR4/NLRP12-driven PANoptosis axis

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by epidermal barrier dysfunction and immune dysregulation. Increasing evidence suggests that dysregulated programmed cell death in keratinocytes and immune cells contributes critically to AD pathogenesis; however, the integrated mechanisms underlying these processes remain poorly understood. Here, we report the construction of a zinc-glycyrrhizic acid supramolecular hydrogel (ZnGA) via metal-ligand coordination and investigate its therapeutic potential and mechanism in AD. ZnGA exhibits excellent injectability, self-healing ability, and biocompatibility, enabling controlled release of Zn²⁺ and exerting anti-inflammatory activity. In a murine AD model and corresponding in vitro systems, ZnGA significantly alleviates skin inflammation, epidermal hyperplasia, and immune infiltration. Transcriptomic analysis reveals that ZnGA markedly suppresses inflammation-associated programmed cell death pathways, particularly those converging on PANoptosis. Mechanistic studies demonstrate that AD is accompanied by coordinated activation of apoptosis, pyroptosis, and necroptosis in keratinocytes and macrophages. ZnGA simultaneously inhibits these death modalities, thereby exerting a broad-spectrum anti-PANoptotic effect, while exerting an immune protective effect. Further investigation identifies the TLR4/NLRP12 signaling axis as a critical upstream regulator of PANoptosis in AD. ZnGA negatively regulates TLR4 and NLRP12 expression, effectively blocking downstream activation of PANoptosome-associated apoptotic, pyroptotic, and necroptotic pathways. Collectively, this study identifies PANoptosis as a key pathogenic mechanism in AD and presents ZnGA as a novel supramolecular therapeutic that alleviates AD by targeting the TLR4-NLRP12-PANoptosis axis. These findings provide new mechanistic insight and a promising materials-based strategy for the treatment of inflammatory skin diseases.