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

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.