Heartbreakers and healers: RNA rebels in cardio-oncology

Abstract

Cancer therapies save lives but often "break hearts" by damaging the cardiovascular system. As survival improves, therapy-induced cardiotoxicity has become a defining challenge of modern oncology. Recent discoveries reveal that long non-coding RNAs (lncRNAs), once dismissed as genomic noise, are the "RNA rebels" orchestrating cellular responses to cancer treatments. These molecules act as both heartbreakers and healers, amplifying or counteracting oxidative stress, mitochondrial dysfunction, apoptosis, and vascular injury. In anthracycline, radiation, and VEGF-targeted therapies, lncRNAs govern key processes that dictate whether cells succumb to damage or mount protective repair responses. Pro-injury lncRNAs exacerbate senescence and inflammation, while protective ones preserve mitochondrial homeostasis and limit cell death. Beyond mechanistic insight, these molecules hold clinical promise as biomarkers and therapeutic targets, guiding RNA-based strategies to predict, prevent, and treat cardiotoxicity. Understanding how they blur the line between protection and harm may redefine how we safeguard the heart in the era of precision cardio oncology.

Keywords: Cancer Therapy; Cardiotoxicity; LncRNAs.

Fig. 1.

Mechanisms of cardiovascular injury induced by cancer therapies. Anthracyclines such as doxorubicin cause mitochondrial damage, ROS accumulation, and eNOS uncoupling, leading to endothelial apoptosis, senescence, and inflammation. Radiation therapy induces DNA damage and mitochondrial injury through ROS, triggering endothelial barrier dysfunction, telomere shortening, and chronic inflammation. VEGF/tyrosine kinase inhibitors (VEGFis/TKIs) impair VEGF signaling, reduce angiogenesis, and increase vascular tone, contributing to vascular rarefaction and hypertension. These therapies converge on endothelial dysfunction and microvascular rarefaction, key contributors to cancer therapy-induced cardiotoxicity.

Fig. 2.

Biogenesis, classification, and molecular mechanisms of long non-coding RNAs. Long non-coding RNAs are transcribed by RNA polymerase II and can be classified based on genomic location as antisense, intergenic, or intronic. In the nucleus, lncRNAs regulate gene expression by recruiting chromatin modifiers and transcription factors, modulating splicing, or contributing to subnuclear architecture. In the cytoplasm, lncRNAs can act as sponges for microRNAs. These diverse mechanisms allow lncRNAs to influence transcriptional and post-transcriptional networks relevant to vascular and cardiac responses to cancer therapy.

Fig. 3.

Mechanisms of lncRNAs in Anthracycline-Induced Cardiotoxicity. LncRNAs modulate key molecular pathways that influence cardiomyocyte and endothelial cell fate following doxorubicin (DOX) exposure. Protective lncRNAs, MALAT1, HOXB-AS3, CMDL-1, and NORAD, mitigate DOX-induced mitochondrial injury and oxidative stress by enhancing autophagy, preserving mitochondrial integrity, and reducing apoptosis. In contrast, LincRNA-p21 exacerbates cardiotoxicity by amplifying reactive oxygen species (ROS) generation and activating p53-dependent DNA damage and senescence pathways.

Fig. 4.

Mechanisms of lncRNAs in Radiation Therapy–Induced Cardiotoxicity. Ionizing radiation induces oxidative stress and endothelial DNA damage through lncRNA-mediated signaling pathways. PVT1 acts as a competing endogenous RNA (ceRNA) for miR-9-5p, leading to MAPK activation, elevated reactive oxygen species (ROS), and apoptosis. DINO and Trp53cor1 (lincRNA-p21, orange) are p53-responsive lncRNAs that amplify DNA damage responses, promoting cell-cycle arrest, apoptosis, and senescence.

Fig. 5.

LncRNAs Modulating Endothelial Responses to VEGF and VEGF Inhibition. VEGF and VEGF inhibitor (VEGFi) treatments modulate angiogenic signaling through context-dependent long non-coding RNAs (lncRNAs) that regulate vascular stability and endothelial sprouting. MEG3 enhances endothelial proliferation and migration during VEGF stimulation, promoting angiogenesis. H19 sponges miR-199a-5p to upregulate VEGFA expression, thereby supporting angiogenesis and endothelial survival. Conversely, MALAT1 is induced by VEGF but suppresses sprouting angiogenesis via p53-dependent senescence pathways.