In DIC, iron overload arises not simply from enhanced iron uptake but from a disease-specific disruption of the entire “uptake–storage–export” regulatory axis. Unlike other pathological contexts, DOX interferes with the central regulatory protein Park7/DJ-1 by promoting its ubiquitination and proteasomal degradation, which, in turn, destabilizes iron–sulfur clusters that are essential for cellular iron sensing and metabolic control [12]. This disruption not only compromises mitochondrial function but also aberrantly activates iron regulatory protein 1, leading to inappropriate upregulation of transferrin receptor 1 and initiating iron metabolic imbalance in DIC. DOX further exploits the autophagic degradation machinery by stabilizing nuclear receptor coactivator 4 (NCOA4), inducing excessive ferritinophagy. This process accelerates lysosomal degradation of ferritin, the principal intracellular iron storage complex, resulting in a substantial release of labile iron ions [13]. Such forced iron mobilization distinguishes the “active” iron overload observed in DIC from iron accumulation caused by simple iron excess. Similarly, DOX suppresses the activity of ferroportin, the sole known cellular iron exporter. Pharmacological activation of the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, which restores ferroportin expression, confers significant cardioprotection [14], further underscoring the pathogenic contribution of impaired iron efflux in DIC.

Under conditions of DOX-induced iron overload and oxidative stress, the cardiomyocyte antioxidant defense system undergoes progressive, multi-tiered functional failure, with endogenous compensatory responses generally insufficient to maintain redox homeostasis. In DIC, impairment of the GPX4 axis occurs through a dual mechanism. DOX directly inhibits the cystine transporter solute carrier family 7 member 11 (SLC7A11), resulting in depletion of substrates required for reduced glutathione (GSH) synthesis [15]. Similarly, DOX suppresses nuclear translocation and transcriptional activity of the master antioxidant regulator Nrf2 through epigenetic mechanisms, including protein arginine methyltransferase 4-mediated modifications, reducing GPX4 expression [16]. This simultaneous loss of both enzymatic substrate and catalytic capacity creates a pronounced vulnerability within the antioxidant defense network.

The GSH-independent ferroptosis suppressor protein 1 (FSP1)–mediated ubiquinone–ubiquinol antioxidant system is also disrupted in DIC myocardium, as reflected by decreased FSP1 protein levels and enhanced ubiquitin-dependent degradation [17]. Upstream regulatory pathways are similarly perturbed by DOX, including competitive inhibition of Nrf2 by the transcriptional repressor BTB and CNC homology 1 (Bach1) [18] and derepression of the pro-death c-Jun N-terminal kinase signaling pathway following the loss of GSH S-transferase P1 activity [19]. Although cardiomyocytes can inducibly generate endogenous protective mediators, such as prostaglandin E2, to activate limited cytoprotective signaling [20], these adaptive responses are insufficient to restore global antioxidant capacity during sustained DOX exposure.

The therapeutic efficacy of targeting these antioxidant pathways depends heavily on the specific metabolic context imposed by DOX. For example, activation of transcription factor EB to enhance autophagy under DOX stress, as observed with alternate-day fasting, paradoxically aggravated cardiotoxicity [21], underscoring that additional metabolic perturbations in an already destabilized system may be detrimental rather than protective.

DOX actively remodels lipid metabolism to generate a membrane environment enriched in oxidation-prone substrates while simultaneously enhancing the efficiency of lipid peroxidation reactions. In the setting of DIC, both the expression and activity of acyl-CoA synthetase long-chain family member 4 are significantly upregulated, leading to a substantial increase in long-chain polyunsaturated fatty acids, particularly arachidonic and adrenic acids, within membrane phospholipids [22,23]. These fatty acids serve as preferential substrates for lipid peroxidation. DOX specifically induces 15-lipoxygenase-1 expression in experimental models [24], an enzyme that directly catalyzes the peroxidation of polyunsaturated fatty acids in membrane phospholipids. The resulting lipid peroxides not only compromise membrane integrity but also activate pro-inflammatory signaling pathways, such as the mitogen-activated protein kinase cascade, establishing a self-reinforcing cycle of cellular injury.

A study suggests that under the metabolic stress associated with DIC, methionine metabolism may be aberrantly rerouted, with its downstream product, S-adenosylmethionine, unexpectedly driving pro-ferroptotic metabolic fluxes [25]. Further complexity arises from the context-dependent roles of molecules that are typically cytoprotective at low levels. For example, heme oxygenase-1, when excessively expressed in DIC, may shift from a protective factor to a promoter of ferroptosis by catalyzing extensive heme degradation and releasing large amounts of free iron [26].

Both the initiation and progression of ferroptosis in DIC are orchestrated by a highly integrated network that links multiple regulated cell-death modalities with systemic stress responses. The mitochondrion serves as a central hub and signal amplifier within this network, coupling diverse death pathways. DOX-driven mitochondrial iron accumulation, excessive reactive oxygen species generation, and lipid peroxidation directly impair mitochondrial structure and function. Mitochondrial DNA released from damaged organelles can subsequently activate cytosolic pattern-recognition receptors, such as the absent in melanoma 2 inflammasome, promoting assembly of the PANoptosome complex. This complex can trigger pyroptosis, apoptosis, and necroptosis concurrently, explaining the pronounced synergy of multi-modal cell death observed in DIC [27].

The endoplasmic reticulum, a key sensor of cellular stress, responds to disrupted homeostasis by activating the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2α (eIF2α)/activating transcription factor 4 (ATF4)–mediated integrated stress response. Recent evidence indicates that, in the context of DIC, the protein estrogen-responsive B-box protein amplifies this pathway by facilitating ubiquitination of glucose-regulated protein 78, ultimately enhancing Nrf2 signaling and upregulating its downstream targets SLC7A11 and GPX4. This process constitutes an intrinsic endoplasmic reticulum stress–derived protective axis against ferroptosis [28].

These intracellular events unfold within a complex multicellular cardiac microenvironment. Damage-associated signals released from ferroptotic cardiomyocytes can activate resident immune cells, including B lymphocytes, which subsequently secrete pro-inflammatory mediators and autoantibodies [29]. This establishes a self-perpetuating cycle of inflammation and cell death, highlighting DIC as a systemic pathological process in which cardiomyocyte-intrinsic death mechanisms and immune responses are tightly interconnected. Thus, effective therapeutic strategies must concurrently target both cellular and immunological dimensions of disease progression.

This tier prioritizes preemptive intervention and offers the greatest clinical and economic value by preventing cardiac injury before its onset. Ongoing controversies surrounding dexrazoxane, particularly concerns related to myelosuppression and potential compromise of antitumor efficacy, highlight the pressing need for alternative prophylactic strategies. As a result, two major directions have emerged: advanced cardiac-targeted drug delivery systems that reduce myocardial exposure through pharmaceutical engineering, and biomarker-guided precision prophylaxis. The latter approach applies baseline risk stratification, such as elevated inflammatory markers including peptidoglycan recognition protein 1 (PGLYRP1) [32], to identify patients at high risk who may benefit from early intervention. Promising adjuvant agents, exemplified by a novel synthetic derivative of bifendate (F-α-DDB) [34], which did not exacerbate epirubicin-induced cardiotoxicity in preclinical studies, reflect efforts to achieve cardioprotection without diminishing chemotherapeutic effectiveness.

This tier represents the central therapeutic response, directly targeting the molecular effectors responsible for cardiotoxic injury. Its structure aligns with the core ferroptosis cascade, encompassing dysregulated iron metabolism, failure of antioxidant defenses, and lethal lipid peroxidation. Similarly, therapeutic agents are designed to interrupt this process at key control points, ranging from iron chelators and iron efflux enhancers (e.g., asiatic acid [14]) to antioxidants that directly reinforce GPX4 activity (e.g., selenomethionine [37]). This tier also incorporates emerging regulatory nodes, such as the estrogen-responsive B-box protein [28], which suppresses ferroptosis by activating the integrated stress response, as well as multi-target compounds like a histone methyltransferase inhibitor (BRD4770) [31] that concurrently inhibit ferroptosis and apoptosis. Such agents may offer advantages in counteracting the interconnected PANoptotic death network.

Once cardiotoxic injury has occurred, therapeutic priorities shift from limiting cell death to enhancing endogenous repair mechanisms, systemic resilience, and long-term functional recovery. This tier capitalizes on intrinsic homeostatic capacity and includes pharmacological activation of endogenous protective pathways, such as the prostaglandin E2 (PGE₂)/EP1 signaling axis [20], as well as multi-component systemic modulators, including traditional herbal formulations like qishen granules [44], which exert effects through pleiotropic regulatory networks. Foundational non-pharmacological strategies play a critical role. Structured exercise programs [46], for example, represent a highly accessible and effective intervention that improves mitochondrial function, attenuates ferroptosis, and serves as a cornerstone of comprehensive cardiac rehabilitation.

Effective management of DIC requires a dynamic, coordinated implementation of a multi-tiered strategy. This process begins with pre-treatment risk stratification based on genetic profiles and baseline biomarkers, which should inform subsequent preemptive interventions focused on source control, such as cardiac-targeted drug delivery systems or prophylactic agents in high-risk patients. This preventive foundation must be integrated with close monitoring throughout chemotherapy, using sensitive modalities including global longitudinal strain and emerging mechanism-specific biomarkers, such as circulating neutrophil extracellular trap DNA [35], to identify subclinical cardiac injury at the earliest stage. Early detection should prompt timely initiation of mechanism-directed therapies that directly inhibit core pathological processes, particularly ferroptosis. Throughout treatment and into survivorship, this strategy should be reinforced by adjunctive systemic modulation and structured rehabilitation, including exercise and selected natural compounds, to enhance endogenous repair capacity, preserve functional reserve, and improve long-term cardiac outcomes. Translating this comprehensive framework into routine clinical practice remains a major challenge, requiring sustained advances in translational research, rigorous validation of personalized monitoring strategies, and careful optimization to ensure cardioprotection without compromising antitumor efficacy.

Accurate monitoring begins with rigorous pre-treatment risk stratification. Current clinical practice largely adheres to international guidelines that classify risk based on conventional parameters, such as cumulative DOX dose (≥250 mg/m² considered high risk) and patient age [52]. However, these factors alone do not adequately account for the significant interindividual variability in cardiotoxic risk observed under comparable treatment exposures.

Genetic susceptibility constitutes a critical complementary dimension of risk assessment. Pharmacogenomic studies have demonstrated that specific genetic polymorphisms influence DOX metabolism, cellular transport, and cardiomyocyte repair capacity. Variants in genes such as retinoic acid receptor gamma and solute carrier family 28 member 3 have been clearly linked to increased susceptibility to anthracycline-induced cardiotoxicity [53]. Polymorphisms in cytochrome P450 enzymes and ATP-binding cassette subfamily B member 1 modulate drug pharmacokinetics, altering myocardial exposure to toxic metabolites [54]. Incorporating genetic risk profiling before treatment initiation can therefore more precisely identify patients who require intensified surveillance and early intervention, beyond what traditional clinical factors can achieve.

Baseline circulating biomarkers further enhance predictive accuracy. Growing clinical evidence indicates that serum biomarker profiles obtained before chemotherapy can reliably predict subsequent cardiotoxic risk. For instance, a prospective study in breast cancer patients demonstrated that, even before the first chemotherapy cycle, individuals who later developed cardiotoxicity showed significantly elevated mRNA and protein levels of four biomarkers, PGLYRP1, cathelicidin antimicrobial peptide (CAMP), matrix metallopeptidase 9 (MMP9), and carcinoembryonic antigen-related cell adhesion molecule 8 (CEACAM8), in peripheral blood compared with those who remained unaffected [32]. Similarly, a retrospective analysis revealed that baseline serum concentrations of sphingosine-1-phosphate and dihydrosphingosine-1-phosphate, as well as plasma levels of specific ceramides measured before anthracycline-based therapy, were significantly associated with adverse cardiac outcomes following treatment [33]. These results suggest that pre-existing or chemotherapy-unmasked subclinical inflammatory and metabolic states serve as important biological indicators of cardiac vulnerability.

The treatment phase represents a critical window for detecting and intervening in reversible subclinical myocardial injury, particularly ALVD, necessitating monitoring tools with greater sensitivity than LVEF. Circulating biomarker panels offer promising opportunities for early detection. Conventional markers of myocardial injury, such as high-sensitivity cardiac troponin and N-terminal pro–B-type natriuretic peptide, while highly specific, show limited sensitivity (approximately 8%–32%) for identifying ALVD [50] and therefore primarily reflect established injury rather than early dysfunction. Biomarkers that directly capture ferroptosis-related pathology provide a novel dimension for early surveillance. For example, reductions in serum GSH and elevations in malondialdehyde directly indicate a collapse of intracellular antioxidant defenses and ongoing lipid peroxidation [42]. Furthermore, alterations in proteins associated with regulatory pathways, such as the angiotensin II type 1 receptor and the fat mass and obesity-associated protein/p21 axis, reflect upstream signaling disturbances linked to cardiotoxicity [30,55]. Longitudinal monitoring of these mechanistic biomarkers may enable earlier identification of cardiotoxic initiation and progression than traditional indicators.

Cardiac imaging modalities are advancing toward greater sensitivity and quantitative precision. Echocardiographic global longitudinal strain (GLS) is well established as a more sensitive marker of subclinical myocardial dysfunction than LVEF, with early GLS impairment strongly associated with the subsequent development of overt cardiac dysfunction [56]. Cardiac magnetic resonance imaging, further enhances early detection through techniques such as longitudinal relaxation time mapping, extracellular volume quantification, and transverse relaxation time mapping, which non-invasively assess myocardial fibrosis and edema and can reveal histopathological changes concurrent with or even preceding GLS abnormalities. Moreover, emerging molecular imaging probes have enabled in vivo, ferroptosis-specific imaging in animal models, detecting myocardial injury signals 24–48 hours earlier than conventional modalities [57]. Although currently confined to preclinical research, these approaches highlight the potential for ultra-early and mechanism-specific diagnosis in the future.

The integration of intelligent technologies and digital health platforms is further transforming the paradigms of cardiac monitoring. Deep learning–based artificial intelligence models can synthesize multi-modal data, including echocardiographic parameters (e.g., tissue Doppler imaging), longitudinal clinical variables, and biomarker profiles, to generate comprehensive risk assessments. Such models have demonstrated high accuracy in predicting medium-term (e.g., 24-month) risk of cancer therapy–related cardiac dysfunction and can identify subtle patterns that may elude human interpretation [58]. Similarly, wearable devices enabling continuous remote monitoring of heart rate, rhythm, and patient-reported outcomes, such as exercise intolerance and dyspnea, can capture early compensatory changes or emerging symptoms between clinic visits. When integrated into clinical decision support systems, these data streams can automatically trigger alerts, shifting cardiac surveillance from intermittent, clinic-based evaluations to continuous, dynamic, whole-course management [59].

The final stage of monitoring focuses on objectively evaluating therapeutic effectiveness while proactively addressing the persistently elevated cardiovascular risk associated with DOX exposure. When cardioprotective interventions, such as ferroptosis inhibitors, are initiated in response to monitoring findings, objective and highly sensitive metrics are required to assess treatment efficacy. Biomarkers closely linked to the underlying injury mechanisms, including the GSH-to-malondialdehyde ratio or the magnitude of improvement in GLS, can serve as early and responsive indicators of therapeutic benefit, informing timely treatment adjustment and optimization [60].

DOX-induced cardiotoxicity is characterized by delayed onset, with clinical manifestations potentially emerging years or even decades after completion of chemotherapy. Therefore, long-term cancer survivors should be incorporated into structured cardiovascular surveillance programs that include regular evaluation of cardiac function, such as GLS and LVEF, alongside rigorous management of conventional cardiovascular risk factors. This longitudinal care should be closely integrated with patient-reported outcomes and remote monitoring technologies, establishing an active, continuous system for early detection and prevention of symptomatic heart failure and premature atherosclerotic cardiovascular disease [59].