Fusobacterium nucleatum is a Gram-negative anaerobe that occupies a central ecological niche in oral biofilms but has emerged as a trans-compartmental pathogen implicated in gastrointestinal and cardiovascular diseases. In inflammatory bowel diseases, Fusobacterium nucleatum adheres to the intestinal epithelium via adhesins such as FadA, disrupts tight junctions, and induces Toll-like receptor–mediated inflammatory cascades, amplifying epithelial permeability and sustaining mucosal inflammation. In colorectal cancer, Fusobacterium nucleatum promotes carcinogenesis through multiple mechanisms, including β-catenin activation, modulation of oncogenic microRNAs, and immune evasion via Fap2–TIGIT signaling, while also fostering a pro-inflammatory and immunosuppressive tumor microenvironment. Its enrichment correlates with advanced tumor stage, chemoresistance, and poor prognosis, underscoring its potential as a biomarker and therapeutic target. Beyond the gut, Fusobacterium nucleatum has been detected in atherosclerotic plaques and endocardial tissues, where it contributes to endothelial dysfunction, foam cell formation, oxidative stress, and plaque instability, thereby linking chronic oral infection with cardiovascular risk. Collectively, evidence suggests that Fusobacterium nucleatum acts as a pathophysiological connector across IBD, CRC, and CVD through conserved mechanisms of adhesion, immune modulation, and inflammation. Understanding these processes provides opportunities for innovative interventions, ranging from targeted antimicrobials and host-directed therapies to dietary and microbiome-based strategies, aimed at mitigating the systemic burden of this organism and improving clinical outcomes across multiple diseases.

Activating PIK3CA mutations occur in approximately 40% of hormone receptor-positive (HR+)/HER2-negative breast cancers and represent a major driver of endocrine resistance. The PI3Kα-selective inhibitor alpelisib, in combination with fulvestrant, significantly improves progression-free survival in patients with PIK3CA-mutant disease, as demonstrated in the SOLAR-1 trial. However, this therapeutic strategy is frequently complicated by treatment-induced hyperglycemia, a metabolic disturbance that promotes oxidative stress, mitochondrial dysfunction, and inflammatory signaling, thereby increasing cardiovascular vulnerability. Sodium–glucose cotransporter-2 (SGLT2) inhibitors have emerged as cardiometabolic modulators with benefits extending beyond glucose lowering. In this study, we used a human cardiomyocyte in vitro model designed to recapitulate the hyperglycemic metabolic milieu observed in breast cancer patients receiving PI3Kα-targeted therapy, to investigate whether the SGLT2 inhibitor dapagliflozin directly protects cardiomyocytes from alpelisib- and fulvestrant-induced injury. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were cultured under hyperglycemic conditions (25 mM glucose) to mimic the metabolic environment associated with PI3Kα inhibitor-induced dysglycemia. Cells were exposed to alpelisib (100 nM) and fulvestrant (100 nM), alone or in combination, in the absence or presence of dapagliflozin (1 μM). Cardiomyocyte viability was assessed using the MTS assay, mitochondrial function by TMRM-based mitochondrial membrane potential (ΔΨm) measurements, and apoptosis by caspase-3 quantification. Cardiomyocyte injury was evaluated by release of cardiac troponin I and heart-type fatty acid binding protein (H-FABP). Lipid peroxidation markers (MDA and 4-HNE) were measured to assess oxidative membrane damage. Intracellular inflammasome-related signaling (NLRP3 and MyD88) and secreted inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2) were quantified by ELISA. Exposure to alpelisib, particularly in combination with fulvestrant, significantly reduced cardiomyocyte viability, induced mitochondrial depolarization, and increased caspase-3-mediated apoptotic signaling. These alterations were accompanied by elevated lipid peroxidation (MDA and 4-HNE) and increased release of cardiac injury biomarkers (troponin I and H-FABP). Alpelisib-based treatments also activated inflammasome-related signaling, as indicated by increased intracellular NLRP3 and MyD88 levels and enhanced secretion of pro-inflammatory mediators (IL-1β, IL-18, IL-6, TNF-α, and CCL2). Co-treatment with dapagliflozin significantly attenuated these alterations, preserving mitochondrial membrane potential, reducing apoptotic signaling, limiting oxidative membrane damage, and suppressing inflammatory cytokine release. This study provides evidence that alpelisib-based therapy under hyperglycemic conditions is associated with oxidative, mitochondrial, and inflammatory stress responses in human cardiomyocytes, recapitulating key features of cardiometabolic stress relevant to PI3Kα-targeted therapy. Importantly, dapagliflozin markedly attenuated these alterations, supporting a potential cardioprotective role that may extend beyond glycemic control. These findings provide a mechanistic rationale for further investigation of SGLT2 inhibition as a cardiometabolic protective strategy in patients receiving PI3Kα inhibitor-based cancer therapy.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of oncology but are increasingly associated with cardiovascular immune-related adverse events (irAEs), including myocarditis, heart failure, arrhythmias, and vascular complications. Among these, ICI-associated myocarditis represents the most severe manifestation, often characterized by high mortality and challenging early diagnosis. Detecting subclinical myocardial injury before irreversible cardiomyocyte necrosis occurs remains a major unmet need in contemporary cardio-oncology. This narrative expert review critically examines the biological rationale, preclinical evidence, and emerging clinical data supporting the potential role of heart-type fatty acid-binding protein (H-FABP) as an adjunctive biomarker of early immune-mediated myocardial injury during ICI therapy. H-FABP is a small cytosolic lipid chaperone abundantly expressed in cardiomyocytes and rapidly released into the circulation following subtle membrane destabilization and metabolic stress, frequently preceding detectable troponin elevation in other forms of myocardial injury. Experimental studies support a mechanistic association between H-FABP release, inflammasome activation, cytokine amplification, mitochondrial dysfunction, and immune–metabolic cardiomyocyte stress. Preliminary clinical observations further suggest that H-FABP elevations may occur during ICI treatment even in the absence of overt myocarditis or concomitant increases in high-sensitivity cardiac troponins (hs-cTns). Although H-FABP cannot replace hs-cTn, which remains the cornerstone biomarker for the diagnosis of clinically significant ICI-associated myocarditis, its rapid kinetics and sensitivity to early metabolic membrane injury support its potential role as an investigational adjunctive biomarker for early surveillance and risk stratification. This approach may be particularly relevant in patients receiving high-risk combination ICI regimens or in individuals with pre-existing cardiovascular disease. However, current evidence remains limited, and large prospective multicenter studies integrating H-FABP with hs-cTns, natriuretic peptides, cardiac magnetic resonance imaging, and clinical outcomes are required before routine clinical implementation can be considered.

Immune checkpoint inhibitors (ICIs) have successfully revolutionized cancer therapy, but their immune-mediated adverse events include rare, often severe myocarditis. Although dual ICI blockade is associated with increased cardiotoxic risk, little is known about the potential effects of triplet combinations currently under clinical investigation. We developed a coculture model of human cardiomyocytes and human peripheral blood mononuclear cells (hPBMCs) to evaluate immune-mediated cytotoxicity induced by ICIs. HFCs were exposed for 48h to nivolumab plus relatlimab, ipilimumab, or atezolizumab, either alone or in triplet combinations. Cell lysis was quantified by LDH release. Cytokine secretion (IL-2, granzyme B, and additional inflammatory mediators including NLRP3 activation pathway) was measured by ELISA. Digital microscopy was used for morphological assessment. Triplet combinations of nivolumab–relatlimab with ipilimumab or atezolizumab induced significantly higher cardiomyocyte lysis than single agents or doublets ( P < 0.001). This effect correlated with a robust increase in IL-2 and granzyme B secretion, and activation of proinflammatory cytokines and NLRP3 inflammasome-related mediators. Microscopic analyses confirmed immune cell activation and reduced density of HFCs exposed to triplets. Our findings demonstrate that ICI triplets elicit potent immune activation against cardiomyocytes, providing the first preclinical evidence of direct cardiotoxic potential in this setting. These results highlight the need for enhanced clinical surveillance and cardio-oncology monitoring in patients receiving triple ICI combinations, because these regimens expand in clinical practice.