Cardioprotective effects of paeonol: modulation of mitochondrial dynamics and mechanistic insights with focus on doxorubicin-induced cardiotoxicity

Doxorubicin (DOX) is an effective chemotherapeutic drug used to treat various malignancies like breast cancer and lymphomas, but its usage is limited owing to its harmful effects on the heart, causing cardiotoxicity. This heart damage is largely owing to mitochondrial dysfunction, including disrupted mitochondrial dynamics, oxidative stress, and cell death. Current strategies for managing DOX-induced cardiotoxicity have limited success, highlighting the need for novel therapeutic agents. In this context, paeonol, a natural phenolic compound from traditional Chinese medicine is a promising candidate with cardioprotective potential for its antioxidant, anti-inflammatory and mitochondria-protective properties during cancer therapy. It can improve mitochondrial health by restoring energy production and reducing harmful reactive oxygen species in various heart injury scenarios. Importantly, paeonol activates a specific pathway protein kinase C epsilon and signal transducer and activator of transcription 3 that increases levels of the mitochondrial fusion protein (Mfn2), helping to repair mitochondrial damage caused by DOX. This review explores how targeting mitochondrial fusion, especially through Mfn2, offers a new approach to prevent DOX-induced heart injury. Despite positive preclinical studies, further clinical studies are needed to validate the safety and efficacy of paeonol.