Sunitinib induces macrophage dysfunction and impaired tissue regeneration through suppression of PPARγ

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.

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.

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.

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.