Peficitinib ameliorates doxorubicin-induced cardiotoxicity by suppressing cellular senescence and enhances its antitumor activity

Irreversible cardiotoxicity limits the clinical applications of doxorubicin (DOX). Cardiotoxicity can be detected early using clinical assessment; however, effective preventive measures are still lacking. Peficitinib (ASP015K), a JAK (Janus kinase) inhibitor, is a potent anti-inflammatory agent in autoimmune diseases. Nevertheless, little research has been conducted on anti-ageing and anti-tumour therapies. In this study, we investigated whether ASP015K could attenuate DOX-induced cardiotoxicity through its anti-ageing effects and whether it would affect the tumour treatment effect of DOX by establishing senescence, acute heart injury, and xenograft models. We observed that ASP015K could antagonise the senescence induced by various factors, including hydrogen peroxide and DOX. In addition, ASP015K treatment significantly alleviated cardiac function damage, histopathological deterioration, myocardial fibrosis, and oxidative damage in acute injury mouse models. ASP015K enhanced the sensitivity of tumour cells to DOX therapy and significantly slowed down the tumour growth rate and tumour volume in the xenograft mouse model. Therefore, ASP015K is expected to be developed as a potential cardioprotective agent to prevent or reduce the cardiotoxic side effects of anthracyclines in chemotherapy.