Mitochondria are the primary site of oxygen consumption in cells, and the mitochondrial respiratory chain is the main source of ROS (Varga et al., 2015). Radiotherapy disrupts the mitochondrial respiratory chain, leading to reduced ATP production, increased ROS generation, decreased antioxidant capacity, and induction of apoptosis (Vona et al., 2019). NADPH oxidases (NOXs) are the primary enzymatic sources of ROS in the cardiovascular system (Lassègue and Griendling, 2010). NOX2 and NOX4 are the most abundant NOXs in the heart and are primarily expressed in the cardiomyocytes and endothelial cells. These enzymes catalyze the transfer of electrons from NADPH to molecular oxygen, leading to the generation of oxygen free radicals (Seddon et al., 2007). Radiotherapy accelerates ROS levels by activating NADPH oxidase and cyclooxygenase (Azzam et al., 2012). Radiation increases ROS generation and accumulation by altering the upstream sources of ROS and disrupting the balance of endogenous antioxidant defense mechanisms, including glutathione, ascorbic acid, and catalase (Najafi et al., 2017). ROS are highly reactive and damage cellular lipids, proteins, and nucleic acids (Gajowik and Dobrzyńska, 2014). Cardiac muscle cells are rich in mitochondria, with 35%–40% more mitochondria compared to other cells, making them susceptible to damage (Xie et al., 2024).

ROS activate I-κB kinase, which mediates I-κB phosphorylation, thereby marking it for ubiquitination and proteasomal degradation. This leads to the release of NF-κB, which then translocates to the nucleus, binds to the promoter regions of target genes, and induces the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-8 (Morgan and Liu, 2011). Cyclooxygenase (COX-2) and arachidonate-5-lipoxygenase (5-LPO) are NF-κB target genes and are both sources of ROS generation. During arachidonic acid metabolism, both 5-LPO and COX-2 produce prostaglandin H2 (PGH2) and generate ROS. Intracellular ROS also directly activates NF-κB (Morgan and Liu, 2011). A positive feedback loop exists between NF-κB and ROS. ROS activates NF-κB, which in turn increases the production of ROS by increasing the expression of COX-2 and 5-LPO (Rashidi et al., 2017). NF-κB enhances adhesion capacity of the leukocytes by inducing the expression of adhesion molecules. Infiltrating neutrophils exacerbate endothelial cell damage by secreting various pro-inflammatory cytokines. Infiltrating monocytes differentiate into activated macrophages and oxidize low-density lipoproteins (LDLs) via ROS. Subsequently, they transform into foam cells, a process closely associated with the development of atherosclerosis (Ping et al., 2020). NF-κB-induced inflammation is linked with radiation-induced myocardial injury. Increased expression of intercellular adhesion molecules (ICAMs) and vascular cell adhesion molecules (VCAMs) enhances adhesion of the leukocytes to the endothelial cells and thrombi. Subsequently, occlusion of the vascular lumen by microthrombi and vascular stenosis causes filling defects and focal ischemia, leading to myocardial cell death and fibrosis (Slezak et al., 2017).

Insulin-like growth factor-1 (IGF-1) is the primary mediator of signals from the growth hormone to the body’s tissues (Kenchegowda et al., 2018). IGF-1 also regulates vascular tone by modulating the IRS/PI3K/Akt anti-inflammatory/antioxidant stress pathway and the PI3K-independent pro-inflammatory and oxidative stress pathway involving Grb/Shc/MAPK (King et al., 2016). IRS/PI3K/Akt pathway activation leads to phosphorylation of the endothelial nitric oxide synthase (eNOS) at Ser1179 and the production of nitric oxide (NO). During early stages of radiotherapy, ROS phosphorylates serine 1,177 on eNOS in the human venous endothelial cells, leading to increased NO production (Sakata et al., 2015). ROS react with NO to generate reactive nitrogen species (RNS), thereby reducing the bioavailability of NO. ROS also induce synthesis of vasoconstrictive substances such as prostaglandins and impair vasomotor responses, leading to vascular stenosis (Baselet et al., 2019). IGF-1 stimulates endothelin-1 (ET-1) expression by activating the Shc/Grb/MAPK pathway through IGF-R, IR, or hybrid receptors (Sugamura and Keaney, 2011). ET-1, a potent vasoconstrictive peptide secreted by the endothelial cells, antagonizes the vasodilatory effects of NO, and exhibits pro-oxidative and pro-inflammatory properties (Marquezine and Wajchenberg, 2007). Circulating IGF-1 levels are elevated in minipigs after radiation; moreover, elevated IGF-1 levels post-radiation are positively associated with adverse cardiac events (Kenchegowda et al., 2018). PI3K/Akt pathway inhibition and concurrent activation of the MAPK pathway re-directs IGF-1 signaling towards oxidative and pro-inflammatory responses (Kenchegowda et al., 2018). IGF-1 resistance is associated with vasoconstriction, reduced blood flow, hypoperfusion, and increased oxidative stress, which together form a vicious cycle. It is noteworthy that the tilt of IGF-1 signaling towards the MAPK branch not only directly causes oxidative stress and vascular dysfunction but also can synergize with the TGF-β1 signaling pathway, collectively promoting cardiac fibroblast activation and abnormal extracellular matrix deposition, ultimately exacerbating myocardial fibrosis.

Transforming growth factor-β (TGF-β) plays a pivotal role in radiation-induced fibrosis. TGF-β triggers fibrosis through both classical and non-classical signaling pathways. The classical pathway involves activation of target genes such as type I collagen, type III collagen, CTGF, and α-actin by TGF-β via Smad transcription factors (Mollova et al., 2015). TGF-β also promotes via Smad-independent pathways, such as Rho/ROCK pathway (Ge et al., 2017). In animal models of RIHD, reduced cardiac function and myocardial fibrosis are observed within 2–6 months after radiation exposure (Dreyfuss et al., 2021). Radiotherapy-induced ROS is a direct activator of TGF-β1, which upregulates collagen synthesis in a dose-dependent manner (Yarnold and Brotons, 2010). ROS and TGF-β1 form a positive feedforward loop that amplifies fibrotic signals (Ahamed and Laurence, 2017). Recent research reveals that the crosstalk between ROS and TGF-β1 extends beyond direct activation. ROS can induce histone modifications (e.g., H3K27ac) (Randhawa et al., 2023) and DNA demethylation at the TGF-β1 promoter region through epigenetic mechanisms (Oba et al., 2018), thereby maintaining sustained high expression of its pro-fibrotic genes. This epigenetic “reprogramming” may be a crucial molecular memory mechanism underlying the progression of RIHD years or even decades after radiotherapy, also offering new theoretical perspectives for developing epigenetically targeted drugs.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and are primarily used to lower cholesterol levels. They also demonstrate pleiotropic effects and cardioprotective benefits in preclinical studies (Ziegler et al., 2017; Monceau et al., 2010; Lenarczyk et al., 2015; Kura et al., 2016). In patients who underwent breast-conserving surgery and adjuvant whole-breast radiotherapy (n = 1,481), statin therapy significantly reduces the risk of major adverse cardiac events (MACE) [adjusted HR = 0.34 (95% CI, 0.25–0.44)]. Rosuvastatin and pravastatin demonstrate the highest risk reduction and a dose-response relationship (Huang et al., 2024). Statins also reduce the expression of TGF-β1, Smad3/P-Smad3, ROCK I, and p-Akt in a dose-dependent manner in the Sprague-Dawley rats and alleviate radiation-induced cardiac fibrosis (Zhang et al., 2015). In mouse models, statins exert antioxidant and anti-inflammatory effects and reduce doxorubicin-induced cardiac toxicity by decreasing nitrotyrosine levels, increasing the levels of SOD2, and inhibiting the mitochondrial apoptotic pathway (Riad et al., 2009). Overall, statins protect against RIHD and fibrosis by decreasing lipid levels, inflammation, and oxidative stress.

The renin-angiotensin-aldosterone system (RAAS) plays a significant role in cardiac remodeling. ACEIs inhibit ROS production, reduce myocardial damage due to oxidative stress and inflammation, and increase NO production via the bradykinin system, thereby protecting blood vessels (Bertrand, 2004). In rats, treatment with lisinopril after radiotherapy improves left ventricular diastolic function and posterior wall thickness, and increases maximal mitochondrial respiration and reserve capacity (Ortiz de Choudens et al., 2022). Captopril significantly improves respiratory rate and cardiopulmonary density/structure in rats undergoing thoracic radiotherapy. Furthermore, captopril reduces radiation-induced pleural and pericardial effusions and cardiac fibrosis, thereby improving left ventricular end-diastolic pressure (van de et al., 2015). However, only few clinical studies have investigated the cardiovascular protective effects of ACEIs in RIHD. Therefore, further research studies are needed to confirm whether ACEIs can effectively protect against RIHD.

Oxidative stress and inflammatory responses play critical roles in the development and progression of RIHD. Therefore, antioxidants represent a potential therapeutic approach for alleviating RIHD. Several Chinese herbal extracts and natural compounds alleviate radiation-induced cardiac oxidative and myocardial fibrosis (van de et al., 2015).

Sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, extracted from a traditional Chinese medicinal (TCM) herb Salvia miltiorrhiza (Danshen), exhibits several pharmacological effects (Gu et al., 2016; Chen et al., 2017; Xuan et al., 2017). In primary cardiomyocytes (PCMs) from Sprague-Dawley (SD) rats exposed to radiation, STS exerts significant cardiac protective, anti-inflammatory, and antioxidant effects by reducing cTnT leakage, p38/p-p38, and caspase-3 expression levels, and enhances Bcl-2/BAX levels (Ma et al., 2024).

Astragaloside IV (AST), a pharmacologically active component isolated from the Chinese herb Astragalus membranaceus (Ren et al., 2023), reduces ROS production in cardiac fibroblasts (CFs) from irradiated rats. AST also decreases the expression levels of Col-1, TGF-β1, and p-Smad2/3 expression and suppresses X-ray-induced downregulation of TIMP1 and Smad7, thereby attenuating radiation-induced fibrotic damage (Gu et al., 2014).

Zingerone, a natural polyphenol (Ahmad et al., 2015) possesses antioxidant (Rajan et al., 2013), anti-inflammatory (Kim et al., 2010), anticancer (Vinothkumar et al., 2014), and antibacterial activities (Kumar et al., 2013). In rats, zingerone pretreatment significantly reduces radiation- or cisplatin-induced cardiac histological abnormalities and cardiac toxicity markers, and increases plasma cardiac troponin T and B-type natriuretic peptide levels. It also significantly decreases oxidative stress by reducing malondialdehyde levels and increases glutathione levels as well as catalase activity; moreover, zingerone reduces inflammation markers in rats (Soliman et al., 2018).

In preclinical studies, pentoxifylline (PTXF; a phosphodiesterase inhibitor) (Samlaska and Winfield, 1994) is effective in decreasing radiation-induced fibrosis, either alone or in combination with α-tocopherol (vitamin E) (Chiao and Lee, 2005). A randomized clinical trial confirmed the efficacy of combined PTXF therapy for radiation-related side effects (Delanian et al., 2003). Dose-dependent cardioprotective effects of PTXF are associated with NF-κB inhibition and downregulation of pro-inflammatory cytokines (TNF-α and IL-6) (Zhang et al., 2005; Ji et al., 2004). PTXF also demonstrates antioxidant properties similar to vitamin E (Delanian et al., 2003) and inhibits TGFβ1 mRNA expression (Liu et al., 2009).

Hesperidin (hesperetin-7-rutinoside) is a bioflavonoid found in plant extracts (e.g., tea and olive oil) and citrus fruits (Tejada et al., 2018; Kilic et al., 2019). Diosmin (HDC), a hesperidin derivative and natural flavonoid (Srinivasan and Pari, 2012) significantly reduces collagen deposition, lipid peroxidation, and malondialdehyde (MDA) levels and enhances SOD activity in rats undergoing radiotherapy, thereby demonstrating anti-inflammatory and antioxidant effects (Koosha and Sheikhzadeh, 2022). The oral administration of 100 mg/kg hesperidin for 7 days in rats scheduled to receive a single 18 Gy dose of γ-ray chest irradiation reduced myocardial oxidative damage, inflammatory response, and fibrosis (Rezaeyan et al., 2016).

Apart from statins, ACEIs, and various antioxidants, several other drugs have shown significant potential in preventing and treating RIHD. Recently, aldosterone receptor antagonists have gained increasing attention in treating myocardial hypertrophy and heart failure. The cardioprotective effects of spironolactone are related with the epidermal growth factor receptor (EGFR) (Yavas et al., 2011). In doxorubicin-treated rats, spironolactone (SP) inhibits cardiac toxicity by decreasing TGF-β1 and phosphorylated-Smad3 levels (Liu et al., 2016). Spironolactone also effectively suppresses cardiac fibrosis induced by trastuzumab and radiotherapy in rats (Yavas et al., 2017). Metformin is one of the most effective drugs for treating type 2 diabetes (Bailey and Day, 1989; Inzucchi et al., 2015). Metformin inhibits radiation-induced senescence phenotypes in the human aortic endothelial cells (HAECs) and mice. Metformin increases the expression of DNA repair-related genes (e.g., BARD1 and RAD51) in the senescent and radiation-damaged cells. Therefore, metformin prevents radiation-induced cardiac toxicity by promoting DNA damage repair (Park et al., 2022). N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP) is a ubiquitous endogenous peptide and an important mediator of the beneficial effects of the ACE inhibitors. Ac-SDKP is the precursor of thymosin-β4 and plays a significant role in tissue healing and cell differentiation (Lenfant et al., 1991; Smart et al., 2007). Ac-SDKP suppresses macrophage-dependent inflammatory and fibrotic pathways by migrating to the perinuclear cytoplasm of rat macrophages and inhibiting the release of the carbohydrate-binding surface protein Mac-2 and reducing TGF-β1, collagen I, and collagen III levels in the irradiated cardiac fibroblasts, thereby counteracting radiation-induced toxicity (Sharma et al., 2018).