Keloids are dermal fibroproliferative disorders characterized by abnormal deposition of extracellular matrix and persistent inflammatory activation. Dysregulated innate immune signaling has been implicated in chronic fibrotic remodeling. However, it remains unknown whether pharmacological targeting of STING–TBK1 signaling can modulate coordinated inflammatory programmed cell death and fibrosis in keloids. In the present study, we investigated the functional and pharmacological relevance of STING–TBK1 signaling and its association with PANoptosis-like cell death in keloid fibrosis. An integrated transcriptomic analysis was conducted on several GEO datasets. Functional experiments were performed in patient-matched samples, primary human keloid fibroblasts, and a human keloid xenograft model. STING–TBK1 signaling was modulated by genetic silencing or pharmacological interventions, including amlexanox and triamcinolone acetonide. STING–TBK1 signaling was upregulated in keloid fibroblasts and tissues, and was positively associated with fibrosis markers. Keloid fibroblasts exhibited enhanced apoptosis, pyroptosis and necroptosis activation, consistent with a PANoptosis-like phenotype. STING silencing reduced TBK1–IRF3 activation and was accompanied by decreased expression of PANoptosis-related and profibrotic markers in vitro. Notably, pharmacological inhibition with amlexanox was associated with reduced STING–TBK1 signaling, PANoptosis-related markers, fibroblast proliferation and migration, and collagen deposition in vitro and in vivo. Triamcinolone acetonide treatment showed partially overlapping suppressive changes, although its effects should be interpreted with caution because of the pleiotropic actions of glucocorticoids. These findings suggest that STING–TBK1 signaling is associated with PANoptosis-like features and fibrotic remodeling in keloids and may represent a potential therapeutic target for antifibrotic immunomodulation. • STING–TBK1 signaling is upregulated in keloid fibroblasts and tissues. • Keloid fibroblasts exhibit PANoptosis-like inflammatory cell death features. • STING silencing is associated with reduced PCD- and fibrosis-related markers. • Amlexanox attenuates STING–TBK1 signaling and PANoptosis-like features. • Pharmacological modulation is associated with reduced keloid growth in vivo.
Wang et al. (Sun,) studied this question.