Fitoterapia · 2026
Xiao Zhen Fang mitigates cutaneous toxicity by inhibiting PANoptosis: Insights from untargeted metabolomics and transcriptomics.
СтатьяНазвание и аннотация: Перевод в очереди
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Wang Xin-Tian, Cheng Cheng, Li Ya-Qin, Chen Wen-Jing, Luo Ling, Yang Xin-Yu, Li Jian-Yue, Chen Yan, Liu Yu-Ping, Xing Hai-Yan
Аннотация
BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors and other targeted therapies frequently cause cutaneous toxicities, impairing patient quality of life and treatment adherence. This study investigated the molecular mechanisms underlying the protective effects of Xiao Zhen Fang (XZF), a traditional Chinese medicine formula, against EGFR inhibitor-induced dermatotoxicity.
METHODS: An erlotinib-induced mouse model of cutaneous toxicity was established. Transcriptomic and serum metabolomic profiles were collected and integrated to identify differentially expressed genes (DEGs), metabolites, and pathways. Protein-protein interaction (PPI) networks, machine learning algorithms, and enrichment analyses were applied, with selected biomarkers validated by Western blotting. To explore the role of PANoptosis, in vivo experiments with the caspase inhibitor Z-VAD-FMK were conducted, and skin barrier-related proteins were examined.
RESULTS: XZF reduced the incidence of rash, alleviated erythema and swelling, improved body weight, and decreased epidermal thickness in the cutaneous toxicity model. Multi-omics analysis revealed significant alterations in inflammatory and lipid metabolism pathways. Key preventive and therapeutic biomarkers, including cytokine signaling and stem cell-related genes, were identified. PANoptosis-related proteins such as Caspase-1, Gasdermin D, IL-1β,RIPK1,ZBP1,ASC and MLKL were markedly upregulated in the model but suppressed by XZF pretreatment. Furthermore, XZF modulated expression of TGM3, STAT6, P65, P53, KRT1, and KRT14 to restore skin barrier function. Co-treatment with Z-VAD-FMK weakened these regulatory effects, confirming PANoptosis as a critical mechanism.
CONCLUSION: XZF alleviates EGFR inhibitor-induced cutaneous toxicity by modulating inflammatory signaling pathways, lipid metabolism, stem cell regulatory mechanisms, and PANoptosis. This integrative multi-omics study systematically elucidates the therapeutic potential of XZF and highlights PANoptosis as a novel target for the prevention and treatment of drug-induced skin toxicity.
METHODS: An erlotinib-induced mouse model of cutaneous toxicity was established. Transcriptomic and serum metabolomic profiles were collected and integrated to identify differentially expressed genes (DEGs), metabolites, and pathways. Protein-protein interaction (PPI) networks, machine learning algorithms, and enrichment analyses were applied, with selected biomarkers validated by Western blotting. To explore the role of PANoptosis, in vivo experiments with the caspase inhibitor Z-VAD-FMK were conducted, and skin barrier-related proteins were examined.
RESULTS: XZF reduced the incidence of rash, alleviated erythema and swelling, improved body weight, and decreased epidermal thickness in the cutaneous toxicity model. Multi-omics analysis revealed significant alterations in inflammatory and lipid metabolism pathways. Key preventive and therapeutic biomarkers, including cytokine signaling and stem cell-related genes, were identified. PANoptosis-related proteins such as Caspase-1, Gasdermin D, IL-1β,RIPK1,ZBP1,ASC and MLKL were markedly upregulated in the model but suppressed by XZF pretreatment. Furthermore, XZF modulated expression of TGM3, STAT6, P65, P53, KRT1, and KRT14 to restore skin barrier function. Co-treatment with Z-VAD-FMK weakened these regulatory effects, confirming PANoptosis as a critical mechanism.
CONCLUSION: XZF alleviates EGFR inhibitor-induced cutaneous toxicity by modulating inflammatory signaling pathways, lipid metabolism, stem cell regulatory mechanisms, and PANoptosis. This integrative multi-omics study systematically elucidates the therapeutic potential of XZF and highlights PANoptosis as a novel target for the prevention and treatment of drug-induced skin toxicity.