Frontiers in immunology · 2026
Sunitinib induces macrophage dysfunction and impaired tissue regeneration through suppression of PPARγ.
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Zhang Zhouchen, Qiao Qiao, Li Jiannan, Li Qingxiang, Yang Yuanning, Zhou Ying, Huang Hongyuan, Chen Dongyan, Wang Yifei, Guo Yuxing
Аннотация
BACKGROUND: Sunitinib is a widely used multi-target tyrosine kinase inhibitor associated with side effects that may impair tissue repair and regeneration, potentially contributing to the onset of medication-related osteonecrosis of the jaw. Macrophages play a central role in tissue homeostasis and regeneration, and their dysfunction may be a key factor in this pathological process.
METHODS: In this study, a zebrafish tail fin injury regeneration model was used to investigate the effects of sunitinib on macrophage function and tissue regeneration. Transcriptomic analysis, immunofluorescence staining, RT-qPCR, and Seahorse mitochondrial stress assays were performed to elucidate the underlying mechanisms.
RESULTS: Sunitinib treatment significantly impaired macrophage migration and tissue regeneration in a concentration-dependent manner. Transcriptomic analysis revealed that sunitinib markedly suppressed the PPARγ signaling pathway, reparative gene programs, and mitochondrial metabolism. The density of PPARγ+ macrophages at the wound site was significantly reduced following sunitinib exposure. Treatment with rosiglitazone, a PPARγ agonist, effectively rescued the regeneration defects induced by sunitinib, restored macrophage infiltration, and recovered oxidative phosphorylation. Notably, these rescuing effects were abolished upon macrophage depletion.
DISCUSSION: Our results demonstrate that sunitinib impairs tissue regeneration by suppressing PPARγ signaling and oxidative phosphorylation in macrophages. Targeting the PPARγ pathway represents a promising therapeutic strategy to reverse sunitinib-associated deficits in tissue repair.
METHODS: In this study, a zebrafish tail fin injury regeneration model was used to investigate the effects of sunitinib on macrophage function and tissue regeneration. Transcriptomic analysis, immunofluorescence staining, RT-qPCR, and Seahorse mitochondrial stress assays were performed to elucidate the underlying mechanisms.
RESULTS: Sunitinib treatment significantly impaired macrophage migration and tissue regeneration in a concentration-dependent manner. Transcriptomic analysis revealed that sunitinib markedly suppressed the PPARγ signaling pathway, reparative gene programs, and mitochondrial metabolism. The density of PPARγ+ macrophages at the wound site was significantly reduced following sunitinib exposure. Treatment with rosiglitazone, a PPARγ agonist, effectively rescued the regeneration defects induced by sunitinib, restored macrophage infiltration, and recovered oxidative phosphorylation. Notably, these rescuing effects were abolished upon macrophage depletion.
DISCUSSION: Our results demonstrate that sunitinib impairs tissue regeneration by suppressing PPARγ signaling and oxidative phosphorylation in macrophages. Targeting the PPARγ pathway represents a promising therapeutic strategy to reverse sunitinib-associated deficits in tissue repair.