Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Single-cell profiling uncovers kaempferol-mediated immunoregulation in the protection against experimental autoimmune hepatitis.
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Shi Qingmiao, He Yuting, Shen Shen, Lou Na, Fu Leiya, Lv Chi, Xue Chen, Li Li, Lu Juan, Gu Xinyu
Аннотация
BACKGROUND: Autoimmune hepatitis (AIH) is triggered by an aberrant immune response directed against hepatocyte autoantigens, ultimately leading to liver inflammation and hepatocellular damage. Kaempferol (KAE), a natural flavonoid, exhibits potent anti-inflammatory and hepatoprotective properties. However, the precise immunoregulatory mechanisms of KAE in alleviating AIH are still undefined.
OBJECTIVES: This study utilized comprehensive single-cell analysis to investigate the therapeutic efficacy and underlying immunoregulatory mechanisms of KAE in alleviating ConA-induced experimental AIH.
METHODS: Murine AIH models were established by concanavalin A (ConA) injection. The serum cytokine levels were measured using antibody microarray. Cytometry by time-of-flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) were employed to thoroughly examine the high-dimensional immune landscape at single-cell resolution. Multiple immunofluorescence assays were carried out to achieve in situ co-localization of the key markers.
RESULTS: KAE treatment significantly mitigated ConA-induced experimental AIH and reshaped the hepatic immune microenvironment. Comprehensive single-cell analysis revealed that KAE maintained hepatocyte homeostasis. Additionally, KAE promoted the expansion of M2 macrophages and upregulated Acod1, a key enzyme for itaconate synthesis, suggesting an anti-inflammatory effect of macrophages following KAE treatment. Furthermore, KAE significantly depleted pathogenic CD8+ resident memory T cells (Trm) and CD8+ central memory T cells (Tcm), probably through upregulation of Klf2 in CD8+ Tcm cells to inhibit lymphocyte tissue residency and induction of apoptosis in both pathogenic CD8+ Tcm and CD8+ Trm subsets.
CONCLUSION: This study demonstrated protective efficacy of KAE against AIH, providing novel insights for immunomodulatory therapy.
OBJECTIVES: This study utilized comprehensive single-cell analysis to investigate the therapeutic efficacy and underlying immunoregulatory mechanisms of KAE in alleviating ConA-induced experimental AIH.
METHODS: Murine AIH models were established by concanavalin A (ConA) injection. The serum cytokine levels were measured using antibody microarray. Cytometry by time-of-flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) were employed to thoroughly examine the high-dimensional immune landscape at single-cell resolution. Multiple immunofluorescence assays were carried out to achieve in situ co-localization of the key markers.
RESULTS: KAE treatment significantly mitigated ConA-induced experimental AIH and reshaped the hepatic immune microenvironment. Comprehensive single-cell analysis revealed that KAE maintained hepatocyte homeostasis. Additionally, KAE promoted the expansion of M2 macrophages and upregulated Acod1, a key enzyme for itaconate synthesis, suggesting an anti-inflammatory effect of macrophages following KAE treatment. Furthermore, KAE significantly depleted pathogenic CD8+ resident memory T cells (Trm) and CD8+ central memory T cells (Tcm), probably through upregulation of Klf2 in CD8+ Tcm cells to inhibit lymphocyte tissue residency and induction of apoptosis in both pathogenic CD8+ Tcm and CD8+ Trm subsets.
CONCLUSION: This study demonstrated protective efficacy of KAE against AIH, providing novel insights for immunomodulatory therapy.