Sunitinib induces senolysis associated with modulation of platelet-derived growth factor receptor beta.

Receptor tyrosine kinases are critical regulators of cell survival, mediating responses to environmental changes and maintaining biological responsiveness. However, despite growing interest in developing senolytics that target survival factors in senescent cells as a promising strategy to overcome age-related diseases, the therapeutic potential of RTKs in senescence remains largely unexplored. In this study, we aimed to identify senolytic compounds that modulate RTK signaling and ameliorate age-related phenotypes by selectively inducing senescent cell death. Using a drug screening approach, we identified sunitinib, a multi-targeted RTK inhibitor that effectively suppresses PDGFR activation and induces apoptosis specifically in senescent HDFs (sHDFs) by activating caspase-9, -3, and -7. Moreover, in a mouse model of bleomycin-induced lung fibrosis in which senescent cells accumulate in the tissue, sunitinib reduced senescent cells and suppressed SASP expression. These findings, together with the observed increase in PDGFRβ phosphorylation in aged cells, led us to hypothesize that modulating PDGFRβ activity could induce senolysis. Indeed, knockdown of PDGFRβ expression sensitized senescent cells to cell death, with minimal effects on non-senescent HDFs (nsHDFs). At the mechanistic level, PDGFRβ and its downstream pathways, including the JAK2-STAT3 pathway, contributed to the senolytic response to sunitinib. Notably, sunitinib-induced JAK1 phosphorylation contributed to resistance to sunitinib in nsHDFs. Our findings suggest that sunitinib is a promising senolytic agent and that targeting PDGFRβ may represent a previously unknown approach to senolytics. Therefore, our study may provide a potential therapeutic strategy for age-related diseases associated with chronic inflammation.