Search Results (535)

Perioperative stress induces profound molecular and cellular responses that contribute to postoperative complications, including perioperative neurocognitive disorders (PND), chronic postsurgical pain, organ dysfunction, immunothrombosis, fibrosis, and cancer progression. Increasing evidence demonstrates that epigenetic mechanisms act as central regulators linking surgical trauma, inflammation, metabolic stress, ischemia–reperfusion injury, and immune activation to long-term alterations in gene expression and tissue remodeling. DNA methylation, histone modifications, chromatin remodeling, non-coding RNAs, and RNA epitranscriptomic mechanisms such as N6-methyladenosine (m6A) collectively orchestrate perioperative responses across multiple organ systems. Recent translational studies have identified histone deacetylases (HDACs), histone methyltransferases, NETosis-associated chromatin signaling, HMGB1/NF-κB activation, and epigenetic regulation of neuroimmune pathways as major contributors to postoperative cognitive dysfunction, chronic pain, cardiac dysfunction, pulmonary injury, and fibrosis. In parallel, advances in liquid biopsy, circulating tumor DNA (ctDNA), and single-cell epigenomics have opened new opportunities for biomarker-guided perioperative precision medicine. This review summarizes current evidence regarding epigenetic regulation in perioperative medicine with special emphasis on neuroepigenetics, NETosis, fibrosis, cardiac epigenetics, immune remodeling, and perioperative oncological outcomes. Furthermore, we discuss emerging therapeutic strategies targeting HDACs, DNA methylation, m6A pathways, and chromatin-associated inflammatory signaling as potential future interventions for perioperative complications. Full article

Sickness is a universal human problem. A significant proportion of the world’s population suffers from one disease or another, while some individuals have two or more chronic diseases simultaneously. The development of one disease, if not properly managed, can often lead to other coexisting health challenges, a condition known as comorbidity. Unfortunately, treating comorbidity is difficult due to overlapping symptoms and the risk of drug interactions. To overcome these challenges, it is necessary to identify active principles with broad-spectrum therapeutic properties. Therefore, this study provides an overview of the multifunctional role of lactoferrin against various human diseases. Information regarding the role of lactoferrin in combating various human diseases was gathered through a systematic literature search. Findings from a retrospective pilot study indicated that lactoferrin has the potential to alleviate symptoms of interstitial cystitis, or painful bladder syndrome. Additionally, lactoferrin has anti-inflammatory, anti-diabetic, anti-cancer, anti-obesity, and antimicrobial properties. It could be beneficial in addressing issues related to microbial drug resistance. The anti-inflammatory effects of lactoferrin are linked to the reduction in cytokines such as tumor necrosis factor-alpha (TNF-α), IL-6, and IL-1β; inhibition of Inhibitory kappa B kinase beta (IKK-β) activity; and suppression of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). Furthermore, lactoferrin may provide protection against liver, kidney, and cardiac injuries. Lactoferrin’s wide-ranging benefits indicate that it may be used in conjunction with current medications to help treat multiple health issues simultaneously. Full article

Background: Natural products with unique mechanisms remain of great interest because targeted cancer therapies frequently fail due to toxicity or resistance. Cardiac glycosides have demonstrated antitumor activity, but whether their effects involve microRNA regulation remains largely unexplored. This study investigates whether ouabain derived from Strophanthus gratus (Wall. & Hook. ex Benth.) Baill. (SGO) exerts its antitumor effects through miR-145-5p, a known tumor suppressor, using both colorectal and breast cancer models. Methods: We performed transcriptomic profiling in HCT116 colorectal cancer cells treated with SGO, followed by in vitro assays—including cell viability, caspase 3/7 activity, flow cytometry, and colony formation—in HCT116 and MCF-7 breast cancer cells. In vivo efficacy was evaluated using HCT116 xenograft models in BALB/c-nu/nu mice. miR-145-5p gain- and loss-of-function approaches were employed to determine its functional requirement. Results: SGO dose-dependently suppressed proliferation, induced apoptosis, and inhibited colony formation in both colorectal (HCT116) and breast (MCF-7) cancer cells, and significantly upregulated miR-145-5p levels in both cell types. Transcriptomic analysis identified miR-145-5p as a highly differentially expressed miRNA. In HCT116 xenograft models, SGO inhibited tumor growth by approximately 60% and elevated intratumoral miR-145-5p levels. Importantly, inhibition of miR-145-5p significantly attenuated these effects both in vitro and in vivo, establishing that the antitumor activity of SGO depends on the upregulation/activation of miR-145-5p in both cancer types. Conclusions: We have found that SGO inhibits colorectal and breast cancer growth through a miR-145-5p-dependent mechanism, revealing a previously unrecognized regulatory axis for cardiac glycosides. These findings position SGO as a promising candidate for further preclinical studies and suggest that pharmacologic re-expression of miR-145-5p may represent a viable therapeutic strategy in targeted therapy. Full article

Background/Objectives: Severe mitral regurgitation (MR) is associated with chronic atrial stretch, chamber enlargement, pulmonary pressure elevation, and atrial fibrosis, yet the relationship between tissue inflammatory/profibrotic signaling, histologically quantified fibrosis, and echocardiographic remodeling remains incompletely characterized. This study aimed to compare biatrial tissue remodeling in patients with severe MR undergoing mitral valve surgery with a practical non-valvular surgical comparator group undergoing isolated coronary artery bypass grafting (CABG). Methods: This single-center, observational, cross-sectional comparative study included 36 elective cardiac-surgery patients: 22 with severe MR and 14 undergoing isolated CABG without significant valvular disease. Left- and right-atrial tissue samples were collected intraoperatively. IL-6, TNF-α, and TGF-β expression was assessed by quantitative real-time PCR using pooled atrial samples stratified by atrial side and study group, whereas atrial fibrosis was quantified histologically on individual tissue specimens using Masson’s trichrome staining and digital image analysis. Clinical, laboratory, and echocardiographic parameters were compared between groups, and exploratory associations were assessed with cautious interpretation. Results: Compared with the CABG comparator group, patients with severe MR showed a pooled molecular profile compatible with higher aggregate atrial expression of IL-6, TNF-α, and TGF-β; because qPCR was performed on pooled tissue preparations, these molecular findings were interpreted descriptively and were not used for patient-level inferential statistics. Histologically quantified fibrosis was significantly increased in severe MR in both the left atrium (29.69 ± 12.26% vs. 12.17 ± 4.56%, p < 0.0001) and the right atrium (25.25 ± 11.33% vs. 9.01 ± 4.46%, p < 0.0001). The MR group also showed more pronounced echocardiographic remodeling, including larger estimated left atrial volume, higher pulmonary artery systolic pressure, and greater right ventricular diameter. Exploratory individual-level analyses were restricted to histological fibrosis and echocardiographic variables. Conclusions: Severe MR was associated with marked echocardiographic remodeling and significantly greater histologically quantified biatrial fibrosis compared with a CABG surgical comparator group. Pooled qPCR findings support an aggregate inflammatory/profibrotic signal, but they should be interpreted descriptively because individual-level molecular variability could not be assessed. These findings are hypothesis-generating and do not establish causality. Full article

Background: Cardiac calcified amorphous tumours (CATs) are rare non-neoplastic intracardiac masses characterized by calcified nodules within an amorphous fibrinous matrix and may clinically mimic thrombi or cardiac neoplasms. We report two uncommon cases of right atrial CAT occurring in young women and provide a narrative review of the literature. Methods: Two patients with right atrial CAT underwent multimodality imaging evaluation, including echocardiography, computed tomography, and cardiac magnetic resonance, followed by surgical excision and histopathological examination. A narrative review of published cases identified through PubMed and Embase between 1972 and 2025 was also performed. Results: The first patient presented with a calcified right atrial mass extending into the superior vena cava, associated with superior vena cava syndrome and autoimmune disease. The second patient, affected by end-stage renal disease on hemodialysis and thrombophilia, presented with a large calcified right atrial mass associated with a retained dialysis catheter fragment. Histopathological examination confirmed CAT in both cases. The literature review identified 112 published reports comprising 143 patients, including the two cases presented herein, highlighting frequent associations with end-stage renal disease, mitral annular calcification, and embolic complications. Conclusions: Cardiac CAT remains a rare and likely underrecognized entity with heterogeneous clinical presentation and significant embolic potential. Multimodality imaging is essential for diagnosis and surgical planning, while early surgical excision should be considered in symptomatic or high-risk patients. Full article

Four-dimensional cinematic rendering represents a convergence of physically based volumetric visualization and time-resolved cardiac imaging, enabling simultaneous assessment of structure and motion within a continuous spatial context. Its application to valvular pathology remains limited. We present a technical implementation of four-dimensional cinematic rendering applied to retrospectively electrocardiographically gated coronary computed tomography angiography for characterization of a presumed aortic valve papillary fibroelastoma. This approach enabled direct visualization of lesion morphology, stalk attachment, and dynamic mobility while preserving spatial relationships to valve cusps and the coronary ostium. In contrast to conventional two-dimensional and static three-dimensional techniques, four-dimensional cinematic rendering provided continuous spatial and temporal coherence, reducing interpretive fragmentation across imaging planes. Used as an adjunct to conventional cross-sectional interpretation, this method allows anatomical detail and functional behavior to be assessed concurrently, with potential implications for risk stratification and procedural planning in valvular disease. Full article

Thoracic radiotherapy, widely used in the treatment of mediastinal tumors, frequently exposes both the heart and lungs to ionizing radiation. While physiological interactions and shared vulnerability of the two organs have been known, heart and lung toxicities are assessed separately due to the lack of systematic studies and computational models demonstrating their interactions. For instance, based on the most updated NCCN guidelines for esophageal cancer, radiation prescriptions for preoperative, postoperative, and definitive intents are 41.4–50.4 Gy. Cardiopulmonary toxicities are well-known treatment side-effects in this disease site. Therefore, an exhaustive multi-layered list of dose-limits for lung and heart protection are recommended by NCCN guidelines. However, no combined or conditional (on the other organ’s status) dose-limits are considered. Furthermore, while recommendations for dosimetric consideration of substructures during planning are becoming more common, whole heart and whole lung doses stay the main references for cardiac and pulmonary toxicities. A growing body of pre-clinical and clinical studies has investigated the interaction between cardiac and pulmonary systems in the context of radiation-induced toxicity. However, an analysis of cardiopulmonary system’s collective response to radiation—particularly in predictive modeling, toxicity assessment, and treatment planning—is currently lacking. Here, we review the harmful interdependent interactions between the heart and lungs, especially in cancer patients and in response to treatment. Then we study the existing cardiopulmonary system models and conclude with potential strategies to collect the required parameters for models applicable to radiotherapy. Full article

High-fat diet (HFD)-induced hyperlipidemia is an experimental metabolic condition characterized primarily by dysregulated serum lipid levels and hepatic lipid accumulation, with associated oxidative, inflammatory, mitochondrial, and cardiovascular alterations. This study investigated the therapeutic efficacy of epigallocatechin gallate (EGCG)-functionalized selenium nanoparticles (EGCG-SeNPs) against HFD-induced metabolic and hepatic injury, in comparison with free EGCG, sodium selenite (Na₂SeO₃), and Lipanthyl. EGCG-SeNPs were characterized by dynamic light scattering, zeta potential analysis, transmission electron microscopy, X-ray diffraction, and UV–visible spectrophotometry. Forty-two adult male rats were allocated into six groups: control, HFD, HFD/Lipanthyl, HFD/EGCG, HFD/Na₂SeO₃, and HFD/EGCG-SeNPs. High-fat diet (HFD) feeding induced pronounced dyslipidemia, elevated hepatic enzymes, increased cardiac injury biomarkers, enhanced lipid peroxidation and nitrosative stress, depletion of antioxidant defenses, and disruption of the Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 (Keap1/Nrf2) regulatory axis. HFD also increased nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), while altering mitochondrial apoptotic markers, including B-cell lymphoma 2 (Bcl-2), cytochrome c, and caspase-3. At the transcriptional level, HFD increased lipogenic gene expression and reduced the expression of genes related to fatty-acid oxidation, metabolic regulation, and mitochondrial homeostasis. EGCG-SeNPs showed the greatest overall improvement among the tested interventions, as indicated by an improved lipid profile, hepato-cardiac injury biomarkers, antioxidant status, inflammatory markers, apoptotic markers, hepatic architecture, and Nrf2 immunoreactivity. Collectively, EGCG-SeNPs may mitigate HFD-induced hepatic lipotoxicity and associated cardiac stress through coordinated modulation of lipid metabolism, redox balance, inflammation, and mitochondrial homeostasis. Full article

Ring finger protein 126 (RNF126) is a RING-type E3 ubiquitin ligase that has recently emerged as a multifaceted regulator of cellular homeostasis, stress adaptation, and disease progression. Through its structurally distinct zinc-finger and catalytic RING domains, RNF126 orchestrates substrate recognition and ubiquitin transfer, generating diverse ubiquitin linkages with both proteolytic and nonproteolytic functions. Initially characterized as a component of the protein quality control (PQC) machinery, RNF126 cooperates with chaperones such as BAG6 and UBQLN1 to eliminate mislocalized and misfolded proteins, thereby maintaining proteostasis. Beyond PQC, RNF126 plays pivotal roles in DNA damage response pathways by regulating homologous recombination, non-homologous end joining, checkpoint signaling, and genome stability through substrates, including MRE11, Ku80, RNF168, and 14-3-3σ. Genetic studies have further demonstrated its importance in embryogenesis and male fertility, and accumulating evidence has identified RNF126 as a critical driver of malignancy in multiple cancers. RNF126 promotes tumor progression by degrading or modulating key regulators, such as p21, PTEN, p53, PDKs, and LKB1, thereby enhancing proliferation, metabolic reprogramming, anoikis resistance, metastasis, and chemo/radioresistance. Intriguingly, RNF126 exhibits context-dependent functions, acting as an oncogene or tumor suppressor depending on the tissue type and substrate selection. In addition to cancer, RNF126 has been implicated in neurodegeneration, cardiac pathology, antiviral immunity and adaptive immune regulation. This review summarizes the current knowledge of RNF126 structure, ubiquitin signaling mechanisms, physiological functions, and pathological roles, while discussing emerging therapeutic strategies and future challenges for targeting RNF126 in precision medicine. Full article

Background and Clinical Significance: Cardiac and mediastinal angiosarcomas are rare, aggressive malignancies that often present with nonspecific symptoms and pose significant diagnostic challenges. Tumor heterogeneity and necrosis may lead to false-negative biopsy results; Case Presentation: We report a 64-year-old man who initially presented with cardiac tamponade of unclear etiology. Despite an extensive workup, the patient remained asymptomatic for five months before re-presenting with dyspnea and a large mediastinal mass compressing the right heart, along with a lytic rib lesion. Initial ultrasound-guided biopsy of the rib lesion demonstrated a benign vascular proliferation consistent with Masson tumor (intravascular papillary endothelial hyperplasia), which was discordant with aggressive imaging findings. Further evaluation with positron emission tomography–computed tomography (PET-CT) revealed peripheral metabolic activity, and cardiac magnetic resonance imaging (MRI) demonstrated a heterogeneous mass with central necrosis and peripheral enhancement. A repeat CT-guided biopsy targeting the metabolically active region confirmed angiosarcoma, with immunohistochemical staining demonstrating diffuse positivity for ERG, CD31, and CD34. The patient was treated with palliative radiation and paclitaxel-based chemotherapy but experienced rapid clinical decline and transitioned to comfort-focused care; Conclusions: This case highlights the importance of correlating imaging with pathology and emphasizes the risk of sampling error in necrotic tumors. PET-guided biopsy targeting viable tumor regions is essential in cases with discordant findings. Full article

Background/Objectives: Tumor-infiltrating lymphocyte (TIL) therapy is an important option for patients with metastatic melanoma progressing after standard systemic therapy, but real-world data on treatment delivery, toxicity monitoring, and immune recovery remain limited. We evaluated clinical outcomes, treatment tolerance, immune reconstitution, and cardiac biomarker dynamics across three Mayo Clinic sites. Methods: We retrospectively analyzed adults with metastatic melanoma who received lymphodepleting chemotherapy followed by TIL infusion and high-dose interleukin-2 (IL-2) between April 2024 and December 2025. Clinical outcomes, treatment delivery, and adverse events were assessed. Longitudinal immune monitoring included CD4 and CD8 T-cell counts, CD4:CD8 ratio, and immunoglobulin G (IgG) at baseline and follow-up. In a prespecified cardiac sub-cohort, high-sensitivity troponin (hs-Tn) was measured during IL-2 administration to evaluate associations with cardiac events and IL-2 interruption. Results: Thirty-six patients underwent TIL infusion. The objective response rate was 50.0%, including complete responses in 13.9%, and the disease control rate was 72.2%. Median progression-free survival was 3.61 months, and median overall survival was 12.94 months. M1d disease was associated with inferior overall survival on univariable analysis (HR 6.55, 95% CI 2.03–21.17; p = 0.002), with attenuation after multivariable adjustment. Receipt of ≥3 IL-2 doses was associated with longer overall survival on univariable analysis (HR 0.20, 95% CI 0.06–0.64; p = 0.007), but this association also attenuated after adjustment. Longitudinal immune monitoring demonstrated persistent CD4 lymphopenia through 6 months, sustained inversion of the CD4:CD8 ratio, and declining IgG at months 3 and 6. In the cardiac sub-cohort (24 patients; 87 IL-2 doses), post-dose hs-Tn ≥15 ng/L was associated with clinically significant cardiac events (OR 9.6, 95% CI 1.5–60.6; p = 0.016) and IL-2 interruption (OR 3.4, 95% CI 1.1–10.7; p = 0.036). For cardiac events, hs-Tn ≥15 ng/L had 100% sensitivity and 100% negative predictive value. Conclusions: In routine practice, TIL therapy was feasible and active in metastatic melanoma. M1d disease identified a subgroup with poor survival, peri-dose hs-Tn showed promise as a tool to support safer IL-2 delivery, and prolonged CD4 suppression with IgG decline suggests that recovery after TIL therapy extends beyond initial hematologic reconstitution. These findings support prospective validation of biomarker-guided IL-2 monitoring and extended post-treatment immune surveillance. Full article

Doxorubicin (DOX) is a widely used anthracycline chemotherapeutic agent whose clinical application is limited by cardiotoxicity. In clinical settings, chemotherapy is given to tumor-bearing patients, whereas most preclinical studies of DOX-related cardiotoxicity use non-tumor-bearing animal models, potentially missing context-dependent differences. To address this, we compared DOX-induced cardiotoxicity between non-tumor-bearing and tumor-bearing mouse models. Cardiac function was assessed by echocardiography, and serum biomarkers, histopathological changes, and cardiac transcriptomic profiles were analyzed. Tumor burden exacerbated DOX-induced increases in BNP and CK-MB levels and myocardial structural damage, whereas systolic function was significantly reduced in non-tumor-bearing mice but did not further decline in tumor-bearing mice. Transcriptomic analysis revealed that DOX treatment induced 2528 and 398 differentially expressed genes (DEGs) in non-tumor-bearing and tumor-bearing mice, respectively, compared with their respective controls. A total of 206 shared DEGs were identified, most of which showed consistent directions of change under both conditions, while 16 genes exhibited opposite expression patterns. Common DEGs were mainly enriched in immune-inflammatory responses, cell adhesion, and extracellular matrix (ECM)–receptor interaction pathways. In non-tumor-bearing conditions, DOX-specific mechanisms were mainly associated with ECM remodeling, oxidative stress, metabolic dysregulation, and p53-mediated apoptosis. In contrast, tumor-bearing conditions showed predominant enrichment of immune-related pathways, including JAK-STAT, Toll-like receptor, NOD-like receptor, and chemokine signaling. These findings suggest that tumor burden may modulate the molecular mechanisms of DOX-induced cardiotoxicity, revealing context-dependent differences and offering insights for future cardioprotective strategies. Full article

Background/Objectives: Carvedilol is an adrenergic blocker FDA-approved to improve outcomes in heart failure with reduced ejection fraction. Clinical trials examining whether carvedilol may be cardioprotective in the setting of cancer therapy-induced heart failure have generated mixed results that may depend on the cancer regimen, tumor, or comorbidities. Methods: To investigate the therapeutic potential of carvedilol to mitigate doxorubicin cardiotoxicity in cardiomyocytes, myocardial tissue, and in vivo, independent of confounding factors in clinical studies, we utilized disease-free cardiac slices and cardiomyocytes from mice, dogs, and human in vitro, and in wildtype mice injected with doxorubicin in vivo. We further evaluated the impact of carvedilol in dogs with cancer receiving doxorubicin. Results: In primary canine and murine cardiac slices, carvedilol treatment restored autophagy and prevented apoptosis from doxorubicin. Carvedilol restored mitochondrial energetics in human, canine, and murine models. In wildtype mice challenged with doxorubicin, carvedilol prevented declines in cardiac function and alterations in cardiac structure. In pet dogs with cancer and undergoing doxorubicin treatment, carvedilol was beneficial in preserving cardiac function and structure. Conclusions: Carvedilol activates cardioprotective autophagy, arrests doxorubicin-induced cell death, and improves energetics and cardiac structure and function across species. Full article

Introduction: Accurate detection and characterization of intracardiac masses remain a major challenge in cardiovascular imaging due to overlapping morphological features between tumors, thrombi, and vegetations, as well as the inherent limitations of echocardiography, including operator dependency and variable image quality. Although echocardiography is the first-line imaging modality for evaluating cardiac masses, diagnostic uncertainty frequently necessitates additional multimodality imaging. Artificial intelligence (AI), including machine learning and deep learning approaches, has emerged as a promising strategy to improve image interpretation, automate feature extraction, and enhance diagnostic consistency. Objective: This narrative review aims to examine current advances in AI-enhanced echocardiography for cardiac tumor detection, with a particular focus on detection, segmentation, classification, multimodal integration, and clinical translation. Methods: A narrative literature review was conducted using PubMed, Scopus, and Google Scholar databases. Relevant English-language studies published between 2016 and 2026 were identified using keywords including “artificial intelligence”, “machine learning”, “deep learning”, “echocardiography”, “cardiac tumors”, “intracardiac masses”, “multimodal imaging”, and “ultrasomics”. Original studies, reviews, and methodological papers related to AI-assisted cardiovascular imaging were evaluated. Discussion: Current evidence suggests that AI-driven techniques, including radiomics (ultrasomics), convolutional neural networks, and multimodal learning frameworks, can improve the detection, segmentation, and classification of intracardiac masses. Experimental studies have reported high diagnostic performance, with some deep learning models achieving diagnostic accuracies exceeding 95% under controlled conditions. AI-assisted systems may also reduce interobserver variability and improve workflow efficiency. Multimodal AI approaches integrating echocardiography with cardiac magnetic resonance imaging, computed tomography, electrocardiography, and clinical data appear particularly promising for improving diagnostic discrimination. However, current models remain limited by small and imbalanced datasets, insufficient external validation, data heterogeneity, and limited generalizability across institutions and imaging protocols. Additional barriers to clinical implementation include annotation variability, limited interpretability of deep learning models, and regulatory considerations. Conclusions: AI-enhanced echocardiography has substantial potential to improve the detection and characterization of intracardiac masses by augmenting diagnostic consistency and supporting clinical decision-making. Nevertheless, current evidence remains largely based on retrospective and experimental studies. Future progress will depend on large multicenter collaborations, standardized imaging datasets, explainable AI frameworks, and prospective clinical validation to enable safe and effective integration into routine cardiovascular practice. Full article

Anthracyclines such as doxorubicin (DOX) are widely used in cancer treatment, but their benefits are offset by dose-related cardiotoxicity. Neuregulin-1β (NRG1) has been studied as a cardioprotective factor, yet its mechanisms during DOX treatment, particularly in the presence of cancer, are not well understood. This study evaluated daily recombinant NRG1 co-administered with DOX in 4T1-tumor-bearing female BALB/c mice. The mice were randomized to saline, DOX (3 mg/kg i.p. on days 0, 3, 6, 9; cumulatively 12 mg/kg) or DOX + NRG1 (20 µg/kg i.p. daily, starting one day before DOX). Body weight and tumor growth were monitored throughout treatment. Cardiac structure and function were assessed by transthoracic echocardiography at baseline and before sacrifice. Mechanistic studies included left ventricular proteomics and single-cell RNA-seq. We also used human 3D cardiac microtissues and 2D primary cardiac fibroblast-enriched cultures under defined experimental conditions, with targeted fibroblast gene perturbations. We found that early DOX exposure induced systolic dysfunction and pathological remodeling, while daily NRG1 preserved the ejection fraction and attenuated structural changes without impairing anti-tumor efficacy. Proteomic analysis identified Serping1 as one of the most strongly upregulated proteins soon after DOX exposure, an effect that was reversed by NRG1. Notably, Serping1 has not previously been implicated in anthracycline cardiotoxicity or NRG1-mediated protection. Single-cell RNA sequencing localized Serping1 expression to cardiac fibroblasts. Mechanistically, we found that Serping1 modulation was associated with altered Igfbp5 processing and fibroblast survival under DOX-induced stress; its suppression by NRG1 was linked to reduced fibroblast apoptosis and a shift toward a pro-survival-associated state. In human cardiac microtissues, NRG1 treatment or fibroblast-specific Serping1 knockdown accelerated cardiomyocyte contraction dynamics. These changes occurred without an increase in apoptosis and point to a paracrine effect of fibroblasts on cardiomyocyte function. Additionally, scRNA-seq revealed an Erbb4+ fibroblast subpopulation associated with early pro-fibrotic activation that expanded after DOX but was reduced by NRG1. Taken together, NRG1 preserved cardiac function during anthracycline treatment while maintaining anti-tumor efficacy. Our data identify fibroblast-associated signaling, particularly through Serping1, as a potential contributor to the early protective effects of NRG1. These findings add a new dimension to the understanding of NRG1 cardioprotection and suggest that fibroblast–myocyte interactions may contribute to the early cardiac response to DOX. Full article