Inhibition of SIRT1/HSF1 pathway contributes to doxorubicin-induced nephrotoxicity in ovarian tumor-bearing mice.

Doxorubicin (DOX) is a common drug used in chemotherapy to treat for advanced ovarian cancer, but it can cause organ damage, particularly to the kidneys. This study aimed to investigate whether the SIRT1/HSF1 pathway is associated with DOX-induced nephrotoxicity. Bioinformatics analysis was performed using single-cell RNA sequencing (scRNA-seq) data from DOX-treated kidneys to investigate the potential mechanism of DOX-induced renal damage. To explore the role of HSF1 in DOX-induced nephrotoxicity, the lentivirus HSF1 (Lv-HSF1) was injected after tumor implantation, followed by DOX administration. DOX prevented ovarian tumor growth but caused renal injury in mice, as evidenced by elevated UACR, increased blood BUN levels, and abnormalities in kidney structure and fibrosis. Bioinformatic analysis revealed fewer podocytes in the kidneys of DOX-exposed mice than in those of control mice, which was further confirmed by examining renal tissue and murine podocyte cells. Gene set enrichment analysis revealed significant enrichment of HSF1-dependent transactivation and HSF1 activation pathways specifically within podocytes obtained from DOX-treated mice, which was also validated in renal tissue samples. Furthermore, HSF1A attenuated DOX-induced podocyte injury in vitro. Lv-HSF1-targeted podocytes mitigate DOX-induced podocyte injury in vivo. Notably, SIRT1 expression was significantly downregulated in both kidney tissues and podocytes subjected to DOX treatment. The observed damage to podocytes induced by DOX may be attributed to an increase in HSF1 acetylation facilitated through the downregulation of SIRT1, a process that can be counteracted by the administration of the SIRT1 agonist RSV. Collectively, these findings demonstrated that suppression of the SIRT1/HSF1 signaling pathway contributes to DOX-mediated nephrotoxicity in mice bearing ovarian tumors.