Mechanisms and the Role of p38 MAPK Signaling in Doxorubicin-Induced Cardiotoxicity: A Review

Doxorubicin (DOX) is a widely used anticancer agent, but its use carries the risk of cardiotoxicity. The underlying mechanisms of DOX-induced cardiac injury involve multiple interconnected processes, including oxidative stress, inflammatory activation, apoptosis, dysregulation of metal ion homeostasis, mitochondrial dysfunction, and impaired autophagy. The p38 mitogen-activated protein kinase (p38 MAPK) pathway functions as a stress-response central hub that integrates these signals and orchestrates downstream cellular outcomes via phosphorylation-dependent signaling cascades. This review summarizes current evidence on the molecular mechanisms of DOX-induced cardiotoxicity (DIC), with a focus on the pivotal role of the p38 MAPK pathway. We further discuss natural compounds that mitigate DIC via modulation of p38 MAPK signaling and examine emerging evidence on sex-specific cardioprotective effects mediated by distinct p38 MAPK isoforms. In addition, we briefly discuss the role of DOX nanoformulations in reducing cardiotoxicity, offering new insights into the mitigation of DIC.