Molecular signaling pathways in doxorubicin-induced nephrotoxicity and potential therapeutic agents

Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is extensively utilized in the clinical management of both solid and hematological malignancies. Nevertheless, the clinical application of this treatment is significantly limited by adverse reactions and toxicity that may arise during or after administration. Its cytotoxic effects are multifaceted, with cardiotoxicity being the most prevalent side effect. Furthermore, it has the potential to adversely affect other organs, including the brain, kidneys, liver, and so on. Notably, it has been reported that DOX may cause renal failure in patients and there is currently no effective treatment for DOX-induced kidney damage, which has raised a high concern about DOX-induced nephrotoxicity (DIN). Although the precise molecular mechanisms underlying DIN remain incompletely elucidated, prior research has indicated that reactive oxygen species (ROS) are pivotal in this process, triggering a cascade of detrimental pathways including apoptosis, inflammation, dysregulated autophagic flux, and fibrosis. In light of these mechanisms, decades of research have uncovered several DIN-associated signaling pathways and found multiple potential therapeutic agents targeting them. Thus, this review intends to delineate the DIN associated signaling pathways, including AMPK, JAKs/STATs, TRPC6/RhoA/ROCK1, YAP/TEAD, SIRTs, Wnt/β-catenin, TGF-β/Smad, MAPK, Nrf2/ARE, NF-κB, and PI3K/AKT, and to summarize their potential regulatory agents, which provide a reference for the development of novel medicines against DIN.