Heartbreakers and healers: RNA rebels in cardio-oncology.

1.
Introduction
Cardiovascular diseases (CVDs) and cancer are leading causes of global death, accounting for an estimated 17.9 million and 10 million deaths annually, respectively, according to the World Health Organization (WHO) [1]. Although these diseases differ in pathology, they are increasingly seen as interconnected, leading to the emerging field of cardio-oncology [2]. As oncology advances improve survival rates, a concerning trend has appeared: many cancer treatments, while life-saving, can harm the heart and blood vessels. Cardio-oncology examines shared risk factors, molecular mechanisms, and the long-term cardiovascular complications of cancer therapies to enhance patient outcomes and survival [2,3].
Therapies including anthracyclines, radiotherapy, and targeted molecular agents have significantly improved cancer survival rates, yet they are also associated with cardiomyopathy, arrhythmias, and vascular dysfunction [4]. These toxicities are mechanistically linked to oxidative stress, inflammation, mitochondrial damage, and apoptosis. Oxidative stress occurs when the production of reactive oxygen species (ROS) exceeds the capacity of antioxidant systems, resulting in oxidative damage to DNA, proteins, and lipids—all of which contribute to cardiomyocyte injury and endothelial dysfunction [5]. This stress leads to activation of inflammatory pathways, contributing to endothelial activation and recruitment of immune cells, which further exacerbates vascular injury [6]. Mitochondria are vulnerable to chemotherapeutic damage, impaired mitochondrial integrity, and respiration. In response, they diminish ATP production, leading to the release of pro-apoptotic factors and initiation of intrinsic apoptosis in cardiomyocytes [7]. Notably, processes such as mitochondrial fusion and fission, vital for maintaining mitochondrial integrity, are disrupted by cancer therapies such as doxorubicin, ultimately contributing to cell death [8]. Together, these dysregulated pathways drive cumulative cardiovascular injury and are central to the pathogenesis of cancer therapy-induced cardiotoxicity.
As cancer survivorship continues to increase in the coming decade, the burden of long-term cardiovascular complications is becoming a major concern, affecting both quality of life and overall prognosis. CVDs in cancer survivors include a spectrum of disorders such as coronary artery disease, cardiomyopathy, peripheral arterial disease, and vascular dysfunction [9,10]. Moreover, the presence of CVD may not only reduce long-term survival but also heighten susceptibility to further cardiotoxic effects from treatment.
Recent research suggests that the intersection of oncology and cardiovascular pathology may be regulated, in part, by non-coding elements of the genome. Among these, long non-coding RNAs (lncRNAs) have gained attention for their roles in both cardiovascular and oncogenic processes. LncRNAs are increasingly recognized as critical regulators of gene expression, cellular stress responses, and apoptosis [11, 12]. Their dysregulation by cancer therapies in cardiac and vascular tissues positions them as important mediators of treatment-induced cardiotoxicity.
In this review, we examine how lncRNAs orchestrate the cardiovascular effects of cancer therapies, focusing on anthracyclines, radiation, and VEGF-targeting inhibitors. We first outline the molecular mechanisms that drive therapy-induced cardiotoxicity, then explore how lncRNAs reshape these pathways across key cardiovascular cell types, particularly cardiomyocytes and endothelial cells. These molecules, once considered genomic noise, have emerged as RNA rebels, simultaneously acting as heartbreakers and healers by tipping the balance between cellular injury and repair. By decoding their dual roles in oxidative stress, mitochondrial dysfunction, and vascular remodeling, we aim to illuminate how lncRNA regulation governs the onset and progression of cardiotoxicity. Understanding these molecular insurgents may ultimately guide the development of RNA-based therapies that protect the heart without diminishing anticancer efficacy, redefining the future of cardio-oncology.

2.
Cardiotoxicity: mechanisms of cardiovascular damage induced by cancer therapy
As cancer therapies continue to improve survival outcomes, increasing attention has turned to their unintended effects on the cardiovascular system. Cardiotoxicity has become a major clinical concern, as patients now live long enough to experience long-term cardiovascular complications from treatment. Across large population-based cohort studies, cancer survivors consistently exhibit higher rates of heart failure, arrhythmias, myocardial infarction, and cardiovascular death compared with the general population. For instance, a nationwide Japanese registry reported a 2.8-fold higher risk of cardiovascular mortality among cancer survivors [13], while other large cohorts from Canada, Denmark, and the United States have confirmed elevated risks of heart failure and overall cardiovascular mortality in survivors versus matched controls [9,13,14]. Similarly, a recent meta-analysis of over nine million survivors found a 47 % higher overall risk of cardiovascular disease compared with non-cancer controls [15]. Collectively, these findings establish cardiotoxicity as one of the leading non-cancer causes of morbidity and mortality in cancer survivors, underscoring the need for better mechanistic understanding and preventive strategies.
The National Cancer Institute has defined cancer treatment-related cardiotoxicity as “damage to the heart and/or the cardiovascular system that can occur during or after cancer treatment” [16]. A wide range of cancer therapies, including chemotherapy, radiation, and other targeted agents, are known to adversely affect both the heart and vascular system. One historically accepted framework classifies chemotherapeutic cardiotoxicity into two types based on reversibility and pathophysiology. Type I cardiotoxicity is typically caused by agents such as anthracyclines and results in irreversible cardiomyocyte damage through cell death pathways like apoptosis or necrosis [17]. Type II cardiotoxicity is typically associated with agents such as trastuzumab, a monoclonal antibody targeting HER2, and involves reversible myocardial dysfunction without cell death [17]. However, contemporary cardio-oncology guidelines emphasize that cardiotoxic effects encompass more than these two types [18]. Beyond myocardial injury, cancer treatments can provoke vascular toxicity, manifesting as hypertension, vasospasm, thromboembolism, or accelerated atherosclerosis, leading to acute coronary syndromes [18]. They may also elicit arrhythmogenic toxicity, including QTc interval prolongation and atrial fibrillation, or immune-mediated inflammatory injury, such as myocarditis associated with immune checkpoint inhibitors [19,20]. Recognizing this expanded spectrum of cardiotoxicity is critical for understanding diverse mechanisms and for guiding clinical decisions, risk stratification, surveillance, and long-term management strategies in cardio-oncology.
At the cellular level, these clinical manifestations originate from molecular damage within the cardiovascular system. Cardiomyocytes are densely packed with mitochondria but possess limited regenerative capacity, rendering them highly susceptible to apoptosis, oxidative stress, and mitochondrial dysfunction induced by chemotherapeutic agents [21,22]. Endothelial cells, which form the vascular lining, are directly exposed to circulating drugs and radiation, making them particularly vulnerable to oxidative stress, DNA damage, and inflammatory activation [23–25]. The interplay between cardiomyocyte injury and endothelial dysfunction forms a common mechanistic axis underlying both acute and chronic cardiovascular complications in cancer survivors.
2.1.
Anthracyclines
Anthracyclines are among the most widely prescribed and extensively studied chemotherapeutic agents due to their efficacy across a range of malignancies, including childhood cancers [9,26]. Despite their clinical utility, anthracyclines are well known for their cardiotoxic potential, with a clear dose-dependent relationship observed in both pediatric and adult populations [9,27]. Anthracyclines exert their anticancer activity primarily by inhibiting topoisomerase II and intercalating into DNA, thereby disrupting cellular replication and inducing apoptosis [26]. However, these exact mechanisms of action contribute to their off-target toxicity in cardiac tissue.
Clinically, anthracycline-related cardiotoxicity is classified into three categories: acute, early-onset, and late-onset chronic cardiomyopathy [28,29]. Acute toxicity arises within days to weeks after administration, whereas early-onset chronic cardiotoxicity develops within the first year and represents the most frequent and clinically relevant form. Late-onset cardiotoxicity can appear years or even decades after therapy completion [28]. Among anthracyclines, doxorubicin (DOX) is the most extensively studied and has been recognized as cardiotoxic since the late 1970s [27,28,30]. Other commonly used agents in this class include epirubicin (EPI) and idarubicin (IDA).
Mechanistically, anthracycline cardiotoxicity is driven by mitochondrial dysfunction, oxidative stress, and DNA damage [26,31]. DOX preferentially accumulates in mitochondria-rich cardiac tissue through its strong affinity for cardiolipin, a phospholipid of the inner mitochondrial membrane. Within mitochondria, DOX undergoes redox cycling at complex I (NADH dehydrogenase), generating reactive oxygen species (ROS) that impair mitochondrial DNA and membrane integrity. This cascade leads to the release of cytochrome c, apoptosis, and ultimately, the death of cardiomyocytes [26,31]. In addition, inhibition of topoisomerase IIβ in cardiomyocytes and iron-mediated ROS generation have been implicated as complementary pathways contributing to DOX-induced cardiac injury [32,33].
Beyond direct myocardial damage, DOX also affects the vascular endothelium, the first tissue barrier encountered by circulating drugs. Endothelial cells are highly susceptible to DOX-induced oxidative stress and eNOS uncoupling, resulting in decreased nitric oxide bioavailability and increased superoxide formation [34–36]. These redox alterations contribute to DNA damage, apoptosis, and the suppression of angiogenic potential, resulting in vascular loss and a reduction in capillary density in the heart, accompanied by inflammation that synergizes with damage to cardiomyocytes and accelerates cardiac dysfunction [34–37].

2.2.
Radiation therapy
Radiation therapy (RT) remains a cornerstone in cancer management, but despite technological advances that have reduced incidental cardiac exposure, cardiovascular toxicity continues to pose a major clinical concern [38,39]. Both acute and chronic cardiovascular complications have been observed following thoracic or mediastinal irradiation, including coronary artery disease (CAD), myocardial fibrosis, valvular dysfunction, and heart failure [40,41]. The risk and severity of these effects depend on total dose, fractionation, and cardiac volume exposed.
Clinically, radiation-induced heart disease (RIHD) may manifest months to decades after treatment, reflecting the progressive nature of radiation-induced vascular and myocardial injury. Early effects involve transient endothelial inflammation and microvascular dysfunction, while late complications include vascular rarefaction, fibrotic remodeling, and impaired myocardial perfusion [38].
Among normal tissues, the cardiovascular system is particularly vulnerable to radiation-induced injury, especially the vascular endothelium, which, after radiation exposure, exhibits increased permeability, capillary dilation, and inflammatory cell infiltration, as well as eventual structural changes, including thickening of the basement membrane [5,6]. Mechanistically, ionizing radiation generates ROS that trigger oxidative stress, DNA double-strand breaks, and activation of the ATM/ATR–p53–p21 signaling cascade, leading to apoptosis and senescence [5,6,42,43]. Senescent endothelial cells lose replicative capacity and adopt a proinflammatory phenotype marked by upregulation of adhesion molecules (VCAM-1, ICAM-1), secretion of cytokines, and endothelial-to-mesenchymal transition, which promote chronic vascular inflammation and fibrosis [44]. Radiation also impairs nitric oxide signaling, disrupts tight junction proteins (e.g., VE-cadherin), and reduces capillary density, collectively leading to microvascular rarefaction and reduced myocardial perfusion [45,46]. Over time, persistent microvascular injury amplifies oxidative stress, ischemia, and fibrotic signaling within the myocardium, establishing a synergistic cascade that drives both acute and chronic cardiovascular toxicity.

2.3.
TKI/VEGF
Tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) pathway have transformed cancer therapy across multiple malignancies, but their use is often limited by cardiovascular toxicity. TKIs act by blocking phosphorylation cascades that mediate cell proliferation, differentiation, and survival, including those involved in maintaining endothelial integrity, promoting angiogenesis, and regulating vascular tone [47,48]. VEGF inhibitors (VEGFis), which include both monoclonal antibodies against VEGF and small-molecule VEGFR TKIs, block angiogenic signaling, thereby starving tumors of blood supply and slowing disease progression [49].
Multiple cohort studies have shown that VEGF-TKIs are associated with new-onset or worsening hypertension, heart failure, and arterial thrombotic events, correlating with drug potency and off-target kinase inhibition [50–53]. Mechanistically, VEGFR inhibition reduces NO production, increases vascular resistance, and impairs endothelial cell viability, collectively leading to hypertension, elevated vascular tone, and diminished cardiac adaptability [54,55]. VEGF inhibition also reduces capillary density in cardiac tissue, compromising the heart’s ability to respond to physiological stress [56]. These cardiovascular risks can limit treatment duration and negatively affect long-term outcomes. Accordingly, early detection, risk stratification, and proactive management of VEGFi-induced cardiotoxicity are essential to balance oncologic efficacy with cardiovascular safety.

2.4.
Converging mechanisms of cardiotoxicity across cancer therapies
Collectively, cardiotoxicity from modern cancer therapies is multifactorial, arising from diverse but overlapping mechanisms that converge on oxidative stress, mitochondrial dysfunction, topoisomerase IIβ inhibition, endothelial injury, and inflammation [56–58]. Anthracyclines, for example, induce dose-dependent, irreversible myocardial injury via ROS generation and mitochondrial DNA damage, contributing to both acute and late-onset cardiomyopathy [27,28]. Radiation therapy, despite advances in delivery, continues to pose a risk for long-term cardiovascular complications, through vascular injury, fibrosis, and endothelial senescence, particularly affecting the coronary arteries and myocardium [6,59]. In parallel, VEGF-targeting therapies disrupt angiogenic signaling and endothelial homeostasis, reducing nitric oxide bioavailability and capillary density while promoting hypertension, ischemia, and impaired cardiac adaptation to stress (Fig. 1) [53,55]. Together, these agents underscore how different anticancer modalities converge on endothelial dysfunction and microvascular rarefaction, central pathways in therapy-induced cardiotoxicity.
Beyond therapy-specific mechanisms, patient-level factors substantially influence both the likelihood and severity of cardiotoxicity as well as treatment decisions. Meta-analyses have identified radiation exposure, preexisting hypertension, and advanced age as key risk modifiers that significantly increase the incidence of anthracycline-related cardiovascular events [9,60]. These clinical variables not only determine the individual susceptibility to cardiac injury but also guide oncologists in selecting therapeutic regimens and considering the use of cardioprotective agents in high-risk patients.
Despite growing awareness and updated cardio-oncology guidelines, effective cardioprotective strategies remain limited. Pharmacologic interventions such as dexrazoxane for anthracycline-induced toxicity and neurohormonal blockers (e.g., ACE inhibitors, beta-blockers) in high-risk patients have shown benefit in selected populations but are not universally applied or effective [9,61]. Non-invasive tools, such as echocardiography with strain imaging and circulating biomarkers like troponins and natriuretic peptides, have improved early detection of subclinical cardiac dysfunction and enabled timely intervention [57]. However, a major frontier in cardio-oncology lies in identifying molecular and epigenetic regulators of cardiotoxicity. Among these, LncRNAs, which modulate gene networks controlling apoptosis, mitochondrial dynamics, and inflammatory signaling, hold promise not only as early biomarkers of cardiac injury but also as novel therapeutic targets [62].

3.
Non-coding RNAs
Recent advances in high-throughput sequencing and bioinformatics have fundamentally transformed our understanding of genome architecture, revealing that approximately 98 % of the mammalian genome does not encode proteins [3,63]. Once regarded as “junk DNA”, these non-coding regions are now known to transcribe a diverse array of ncRNAs that play essential roles in regulating gene expression at both the transcriptional and post-transcriptional levels [2,64,65]. Among the most extensively studied are microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), each of which contributes to a broad spectrum of cellular functions and disease mechanisms [65,66]. Other ncRNA species, including tRNAs, rRNAs, piRNAs, and snRNAs, fall outside the scope of this review.
miRNAs are short ncRNAs, typically 20–23 nucleotides in length, that post-transcriptionally regulate gene expression by binding to complementary sequences in the 3’ untranslated region (3’ UTR) of mRNAs, thereby repressing translation or promoting degradation [65]. In contrast, lncRNAs are transcripts longer than 500 nucleotides that lack protein-coding potential [11]. The human genome is estimated to contain between 20,000 and 100,000 lncRNA genes, yet only 1000–2000 have been functionally characterized to date [67]. Compared to mRNAs, lncRNAs show lower evolutionary conservation, fewer exons, and greater splicing diversity [12,63]. Structurally, many lncRNAs resemble mRNAs: they are transcribed by RNA polymerase II and often possess a 5′ cap and a 3′ poly-A tail [11,68]. This group encompasses various transcript types, including intergenic (lincRNAs), antisense, and intronic transcripts derived from protein-coding genes [12,63]. Interestingly, some lncRNAs also contain small open reading frames (sORFs) that encode micropeptides, short peptides that regulate mitochondrial function, metabolism, and cell cycle progression [69]. LncRNAs can regulate gene expression through diverse mechanisms, including chromatin remodeling, transcriptional interference, and by acting as molecular sponges for miRNAs (Fig. 2) [67]. Importantly, lncRNAs can function in cis, regulating the expression of neighboring genes, or in trans, influencing distant loci through interactions with transcription factors, chromatin modifiers, or RNA-binding proteins [70].

4.
LncRNAs in cancer therapy-induced cardiotoxicity
LncRNAs have emerged as essential regulators of cardiovascular function, integrating transcriptional and post-transcriptional networks that govern cardiac remodeling, angiogenesis, and inflammatory signaling [71–74]. Their dysregulation under therapeutic stress provides a molecular link between cancer treatment and cardiovascular injury.
Several endothelial-enriched lncRNAs, including MALAT1 and MEG3, are critical modulators of angiogenic and stress-response pathways. MALAT1 is induced by hypoxia and enhances endothelial proliferation and sprouting angiogenesis, whereas MEG3 increases with endothelial aging and suppresses pro-angiogenic signaling, thereby impairing vascular repair [73,75,76]. Through these context-dependent effects, endothelial lncRNAs shape the balance between vascular adaptation and dysfunction during therapy.
In cardiomyocytes, which possess limited regenerative capacity, lncRNAs regulate susceptibility to oxidative stress, mitochondrial dysfunction, and apoptosis, key mediators of anthracycline and radiation-induced injury [15,21,77]. By modulating these stress-response networks, lncRNAs influence cell survival, contractile function, and metabolic stability, thereby determining the extent of cardiac damage. Understanding how lncRNAs govern endothelial and myocardial responses to therapy reveals the molecular basis of cardiotoxicity and their promise as biomarkers and therapeutic targets.
4.1.
Anthracyclines
Multiple lncRNAs modulate DOX-induced cardiac injury, functioning either as protective regulators or mediators of damage [65]. Among them, MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) is highly expressed in endothelial cells and cardiomyocytes under conditions of hypoxia and oxidative stres [78]. Originally identified in lung cancer, MALAT1 regulates apoptosis, proliferation, and autophagy [78–80]. Recent work has demonstrated its protective role in anthracycline cardiotoxicity. For example, Xia et al. (2020) showed that hypoxia-preconditioned exosomes from mesenchymal stem cells deliver MALAT1 to cardiomyocytes. In DOX-induced cardiotoxicity, MALAT1, delivered via hypoxia-preconditioned mesenchymal stem cell exosomes, functions as a competing endogenous RNA (ceRNA) that binds miR-92a-2p, as confirmed by luciferase reporter and RNA pull-down assays, thereby derepressing ATG4A, restoring autophagic activity, and reducing cellular senescence (Fig. 3) [81]. MALAT1 overexpression alleviates mitochondrial injury and improves metabolic function, highlighting its cardioprotective potential, though validation in vivo remains necessary [81]. Future studies should incorporate in vivo models, as current evidence is derived primarily from in vitro assays. Additionally, examining the MALAT1–miR-92a-3p–ATG4A axis in endothelial and other cardiac cell types will clarify whether this mechanism exerts broader cardioprotective effects across the cardiovascular system.
HOXB-AS3 is similarly upregulated in DOX-treated rat cardiomyocytes (H9c2) [82,83]. Silencing HOXB-AS3 with short hairpin RNA (shRNA) results in increased apoptosis and decreased viability, likely via loss of miR-875-3p sponging and consequent downregulation of protein kinase A (PKA) (Fig. 3) [82,83]. While these findings suggest a cardioprotective role for HOXB-AS3, questions remain about its mechanism of action, primarily since HOXB-AS3 is described as mainly a nuclear lncRNA. Yet, it was reported to act in the cytoplasm without direct evidence of interaction between the lncRNA and miR-875-3p [82,83].
The mitochondrial dynamic-related lncRNA CMDL-1 is significantly downregulated after DOX exposure in both in vitro H9c2 cardiomyocytes and in vivo rat models [84]. CMDL-1 interacts with the fission regulator Drp1, modulating its phosphorylation at serine 637 to restrain excessive mitochondrial fragmentation. Overexpression of CMDL-1 restores Drp1 phosphorylation, limits apoptosis, and mitigates DOX-induced mitochondrial dysfunction, suggesting a role in preserving cardiomyocyte integrity (Fig. 3) [84].
The conserved lncRNA NORAD (Non-coding RNA activated by DNA damage) provides further mitochondrial protection. In human AC16 cardiomyocytes, DOX induces NORAD expression, which sequesters PUMILIO RNA-binding proteins to prevent repression of mitochondrial fission factor (MFF) [85]. This action maintains mitochondrial quality control by balancing fission and mitophagy, thereby reducing ROS accumulation and apoptosis (Fig. 3) [85]. NORAD overexpression decreases the expression of key pro-apoptotic pathways, such as Caspase-3, Bax, and Apaf-1, while upregulating the anti-apoptotic Bcl-2 [85], thereby reinforcing NORAD’s cardioprotective role.
Conversely, lincRNA-p21, a lncRNA known for regulating cellular aging and heart disease, is markedly elevated in vitro in DOX-treated murine HL-1 cardiomyocytes [86]. Elevated lincRNA-p21 promotes ROS generation, telomere shortening, and p53-dependent cell-cycle arrest, whereas its silencing reverses these effects, underscoring its pro-senescent and deleterious influence (Fig. 3) [86]. While this study provides strong evidence that lincRNA-p21 facilitates DOX-induced senescence, its limitations include reliance on a single in vitro model, the absence of primary or human cardiac cells, and the lack of in vivo confirmation.
Taken together, these findings underscore the diverse and cell-specific roles of lncRNAs in anthracycline cardiotoxicity. By modulating apoptosis, oxidative stress, autophagy, and mitochondrial dynamics, lncRNAs represent promising diagnostic biomarkers and therapeutic targets (Fig. 3). Yet, most data derive from cardiomyocyte studies; elucidating their functions in endothelial and other cardiac cell types will be essential for developing comprehensive RNA-based cardioprotective strategies.

4.2.
Radiation therapy
Radiation-induced cardiotoxicity alters the expression of multiple lncRNAs, many of which exhibit dose-dependent upregulation in response to ionizing radiation. Among these, plasmacytoma variant translocation 1 (PVT1) plays a pivotal role in mediating endothelial and cellular injury. While PVT1 promotes tumor resistance to chemotherapy through regulation of apoptosis, autophagy, and DNA damage repair [63,65,87], its role in non-tumor tissue appears detrimental. In human umbilical vein endothelial cells (HUVECs) exposed to X-ray radiation, PVT1 expression increases with escalating doses, and its knockdown attenuates radiation-induced apoptosis and reduces ROS accumulation (Fig. 4) [88]. Mechanistically, PVT1 acts as a competing endogenous RNA (ceRNA), sponging miR-9-5p, which typically represses pro-apoptotic and oxidative stress–related genes. However, this interaction was only demonstrated in vitro, and direct binding between PVT1 and miR-9-5p was not experimentally validated. Thus, while radiation-induced PVT1 upregulation may exacerbate endothelial injury through putative MAPK-dependent oxidative signaling, further in vivo confirmation is required to substantiate this proposed ceRNA mechanism [88].
Transcriptomic studies in irradiated mouse hearts reveal widespread lncRNA remodeling consistent with a p53-dependent stress response [40,41]. Whole-body irradiation significantly upregulates lncRNAs such as PVT1, TUG1 (Taurine Upregulated Gene 1), DINO (Damage-Induced Noncoding RNA), Trp53cor1 (lincRNA-p21), and Abhd11os, suggesting a conserved role in the cardiac radiation injury response [40,41]. Of these, DINO is directly induced by p53 following DNA double-strand breaks and stabilizes p53 protein levels, thereby sustaining the activation of downstream targets, including p21, Bax, and Puma. Through this amplification loop, DINO promotes cell cycle arrest and apoptosis, linking radiation-induced lncRNA signaling to cardiomyocyte loss and tissue injury (Fig. 4) [40,41,89]. This function is particularly relevant given that p53 activation is a hallmark of ionizing radiation-induced double-strand DNA breaks [40,41,89,90].
Together, these findings establish that radiation-induced lncRNAs are not only biomarkers of cardiac injury but also mechanistic drivers of DNA damage signaling and apoptotic responses that underlie radiation cardiotoxicity (Fig. 4). However, current studies remain limited by their reliance on isolated cell models, predominantly HUVECs, which fail to capture the in vivo interplay between endothelial, fibroblast, and cardiomyocyte compartments. Future research integrating multicellular and in vivo models will be crucial in defining how lncRNAs orchestrate cross-cellular signaling in radiation-injured hearts and in evaluating their potential as therapeutic targets for mitigating cardiovascular toxicity (Table 1).

4.3.
Tyrosine kinase inhibitors (TKI)/vascular endothelial growth factors inhibitors (VEGF)
VEGF-TKIs disrupt signaling pathways essential for vascular homeostasis, leading to hypertension, microvascular rarefaction, and endothelial dysfunction [91,92]. Recent studies suggest that lncRNAs modulate endothelial sensitivity to VEGF signaling and may influence vascular injury in this context.
MEG3 plays a key role in regulating endothelial cell proliferation, migration, and angiogenesis [93,94]. In HUVECs, MEG3 knockdown markedly inhibits VEGF-induced tube formation and migration, demonstrating its necessity for a normal angiogenic response (Fig. 5) [94]. Mechanistically, MEG3 silencing disrupts VEGF-mediated activation of ERK1/2 and Akt, key pathways that drive endothelial growth and survival, and reduces stromal cell–derived factor-1 expression [94–96]. Conversely, MEG3 overexpression in breast cancer cells suppresses angiogenesis-related genes and impairs endothelial tube formation, highlighting its context-dependent regulation of vascular function [97]. In vivo, MEG3 knockdown in a corneal neovascularization model reduced pathologic angiogenesis and inflammation, supporting its role in vascular remodeling [94]. However, whether VEGF signaling directly regulates MEG3 expression remains unclear, and current evidence is limited to in vitro and ocular models, rather than the cardiac endothelium.
The lncRNA H19, an imprinted and evolutionarily conserved transcript, functions as molecular hub linking lncRNA–microRNA networks to VEGF-dependent angiogenesis. In mesenchymal stem cells (MSCs), H19 functions as a ceRNA for miR-199a-5p, preventing repression of VEGFA and enhancing VEGFR2-mediated MAPK/ERK signaling [98]. The direct interaction between H19 and miR-199a-5p was experimentally validated by dual-luciferase reporter assays, confirming their physical binding and regulatory relationship. Co-culture experiments with MSCs and endothelial cells demonstrate that H19 overexpression increases VEGFA secretion and tube formation, while H19 silencing elevates miR-199a-5p levels, reduces VEGFA expression, and impairs angiogenesis (Fig. 5) [98,99]. These results suggest that H19 sustains VEGF-dependent vascular responses and may influence endothelial recovery during VEGFi therapy.
The multifunctional MALAT1, known for its cardioprotective effects against DOX toxicity, also modulates angiogenesis via VEGF signaling pathways. In endothelial cells, MALAT1 knockdown enhances sprouting and tube formation, whereas MALAT1 deficiency in Matrigel plug assays increases neovascularization [75,100]. These findings indicate an anti-angiogenic role under physiological conditions. Although direct VEGFA regulation by MALAT1 has not been confirmed, its depletion alters VEGF responses, suggesting it influences endothelial sensitivity to VEGF signaling [75]. Under hypoxia, MALAT1 may act as a negative feedback regulator, preventing excessive angiogenesis and maintaining vascular stability (Fig. 5). These findings suggest an anti-angiogenic role for MALAT1 in endothelial cells, contrasting with its protective, pro-survival role in cardiomyocytes. Notably, MALAT1 displays cell--type–specific effects—protective in cardiomyocytes yet suppressive in endothelium—underscoring the complexity of targeting this lncRNA therapeutically (Table 1).
In summary, MEG3, H19, and MALAT1 illustrate the context-dependent regulation of VEGF signaling by lncRNAs. By shaping angiogenic capacity and hypoxic adaptation, these lncRNAs converge on pathways that drive hypertension, microvascular rarefaction, and endothelial apoptosis —hallmarks of VEGFi-induced cardiotoxicity (Fig. 5). Their dualistic roles complicate therapeutic targeting but also highlight opportunities for RNA-based interventions aimed at preserving vascular integrity during VEGF-targeted cancer therapy.

5.
Clinical potential of lncRNAs in cancer therapy-induced cardiotoxicity
Rapid advances in lncRNA biology are reshaping our understanding of cardiovascular complications arising from cancer therapies. These molecules influence core cellular processes disrupted by chemotherapy and targeted treatments, including oxidative stress, apoptosis, endothelial dysfunction, and angiogenesis, positioning them as both biomarkers and therapeutic targets in cardio-oncology.
While most current cancer therapies act on proteins, RNA-based approaches are gaining momentum as tools to modulate gene networks more precisely [67]. Therapeutic modalities such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), miRNA mimics, antimiRs, and CRISPR-Cas9-based editing are being explored for lncRNA modulation [101]. Among these, ASOs are the most advanced for targeting nuclear lncRNAs due to their ability to bind complementary RNA sequences and suppress expression [11]. Similarly, siRNA-based approaches effectively silence cytoplasmic lncRNAs by engaging RNA-induced silencing complexes, offering precise inhibition of lncRNAs involved in oncogenic or cardiotoxic pathways [102].
Despite strong preclinical interest, no current in vivo studies directly test whether modulating lncRNAs can mitigate radiation- or VEGFi-induced cardiotoxicity. Nevertheless, emerging data suggest that lncRNAs could be leveraged to enhance regenerative and reparative therapies. Several lncRNAs regulate stem cell differentiation and function, potentially improving the efficacy of mesenchymal stem cell (MSC)–based interventions. For instance, MSC-derived exosomes enriched in lncRNAs and miRNAs have demonstrated cardioprotective effects in preclinical models by promoting angiogenesis, reducing endothelial dysfunction, and attenuating cardiac remodeling [78,103,104]. LncRNAs that inhibit cardiomyocyte apoptosis or enhance vascular repair may be harnessed to protect against treatment-induced cardiotoxicity without compromising antitumor efficacy.
Clinically, the most immediate application of lncRNAs lies in biomarker development. Their cell- and tissue-specific expression and remarkable stability in circulation make them promising noninvasive indicators of cardiovascular injury [105,106]. Circulating lncRNAs have already demonstrated diagnostic utility in oncology and are now being investigated as early predictors of cancer therapy–induced cardiotoxicit [107]. Notably, plasma MALAT1 and NEAT1 levels correlate with the severity of radiation-associated cardiac and pericardial injury, suggesting their potential to detect cardiotoxicity before conventional biomarkers such as troponins or natriuretic peptides become elevated [108].

6.
Conclusion, challenges, and future directions
Far from being passive genomic bystanders, RNA rebels actively regulate key cellular processes disrupted by cancer therapies. Despite their potential, several significant challenges hinder the clinical translation of lncRNA-based approaches.
First, current knowledge is derived mainly from in vitro or animal studies centered on cardiomyocytes or whole-heart tissue, which fail to capture the complexity of the cardiovascular microenvironment. Endothelial cells, central to the development of therapy-induced cardiotoxicity, remain underexplored. While chemotherapeutic agents clearly disrupt endothelial function, this effect may be modulated by lncRNAs [3]. The absence of dedicated endothelial models for assessing lncRNA dynamics under stress remains a major limitation. Future research using endothelial organoids, ex vivo vascular systems, microfluidic platforms, or lineage-specific in vivo models will provide more physiologically relevant insight and help bridge the gap between experimental findings and clinical cardiotoxicity [109,110].
Second, although tens of thousands of lncRNAs are transcribed, only a small subset has been functionally characterized in the cardiovascular system. Many potential regulators of therapy-induced cardiotoxicity remain unvalidated. Their diverse mechanisms—including protein binding, chromatin remodeling, transcriptional control, and RNA sponging—combined with cell-type specificity, nuclear localization, and poor sequence conservation, make them challenging therapeutic targets. These same features also complicate delivery strategies and increase the risk of off-target effects [101,111].
Third, while RNA-based therapeutics offer promising avenues to modulate lncRNA activity, most remain at the preclinical stage. Antisense oligonucleotides and siRNAs require improved stability, delivery, and tissue specificity to effectively target cardiac or vascular compartments [112–114]. Approaches such as lipid nanoparticles, viral vectors, and exosome-based delivery are under investigation, but their safety and efficacy in human cardio-oncology have yet to be established. Key priorities include developing endothelial-specific models, performing in vivo validation, and refining RNA design to minimize off-target effects.
Finally, lncRNAs hold significant potential as diagnostic biomarkers. Their stability in circulation, tissue specificity, and detectability in plasma make them attractive for noninvasive monitoring of cardiovascular injury. However, few studies have correlated circulating lncRNAs with established biomarkers, such as troponin or BNP, which limits their clinical adoption [105–107]. Expanding large-scale validation and integrating multi-omics approaches will be crucial to establishing predictive value.
In summary, research on lncRNAs in cancer therapy-induced cardiotoxicity remains at an early stage but is rapidly advancing. Progress will depend on integrative efforts linking RNA therapeutics, vascular biology, and precision oncology. As these scientific and technical barriers are addressed, lncRNAs may reshape cardio-oncology by enabling new strategies to detect, prevent, and mitigate cardiovascular injury in cancer survivors.