Search Results (625)

Astrocytes, once regarded primarily as structural and metabolic support cells, are now increasingly recognized as active participants in neural information processing. Within respiratory control networks, astrocytes are widely distributed throughout the brainstem and spinal cord, where they engage in bidirectional communication with neurons to regulate breathing. This review summarizes current knowledge regarding the roles of astrocytes in respiratory rhythm and pattern generation, central respiratory chemoreception, hypoxic ventilatory responses, respiratory plasticity, and respiratory pathophysiology. Recent advancements in calcium imaging, optogenetics, and pharmacology have revealed that astrocytes modulate respiratory network activity through intracellular Ca²⁺ signaling and the release of gliotransmitters, particularly ATP. In the ventrolateral medulla and the parafacial respiratory group/retrotrapezoid nucleus, astrocytes contribute to central CO₂/H⁺ chemoreception through mechanisms involving connexin hemichannels, potassium channels, and purinergic signaling. Emerging evidence further suggests that astrocytes participate in central hypoxic responses and adaptive respiratory plasticity. In addition, astrocytic dysfunction has been implicated in several disorders affecting respiratory control, including brainstem astrocytoma, Rett syndrome, sudden infant death syndrome, and sudden unexpected death in epilepsy. Collectively, accumulating evidence identifies astrocytes as integral components of respiratory control networks that contribute to both the maintenance of respiratory homeostasis and the pathogenesis of respiratory dysfunction. A deeper understanding of astrocyte–neuron interactions may provide novel therapeutic opportunities for the treatment of respiratory disorders. Full article

Glioblastoma (GBM), classified as grade 4 of high-grade glioma (HGG) under the 2021 World Health Organization (WHO) Classification of Central Nervous System Tumors (WHO CNS-2021), is the most aggressive primary brain tumor in adults. However, with maximal surgical resection, concurrent radiotherapy, and temozolomide (TMZ) chemotherapy, a median patient survival is still between 14 and 16 months. The persistent failure of current treatments is not only traceable to the molecular complexity of tumor cells but is fundamentally shaped by the tumor microenvironment (TME), in which non-neoplastic cells collectively constitute up to half of the total tumor mass. Reactive astrocytes, microglia, tumor-associated macrophages (TAMs), and oligodendrocyte precursor cells (OPCs) are no longer regarded as passive bystanders but as active architects of tumor progression, immune evasion, and therapy resistance. In this comprehensive review, we systematically describe the molecular mechanisms of glial–tumor crosstalk across all three major glial cells. Reactive astrocytes sustain tumor invasion and chemoresistance through connexin-43 gap junctions, bidirectional IL-6/JAK-STAT3 paracrine signaling, and extracellular vesicle-mediated oncogenic reprogramming. Microglia and TAMs undergo profound transcriptional reprogramming via PI3K/Akt/mTOR and CSF-1R signaling, adopting immunosuppressive states that exclude cytotoxic T cells, maintain glioma stem cell (GSC) niches, and drive angiogenesis. OPCs are now underexplored, accumulate at the tumor border, and cooperate with macrophages via Notch and Wnt/β-catenin pathways to establish a therapy-resistant GSC niche at the precise site of post-surgical recurrence. We further address glial–glial interactions as an independent regulatory layer and integrate recent spatial transcriptomic (ST) results revealing a structured, multi-glial niche that governs drug penetration. Finally, we critically evaluate emerging therapeutic strategies targeting these glial–tumor interfaces, including CSF-1R inhibitors, STAT3 modulators, CD47/SIRPα blockades, and engineered extracellular vesicle-based delivery systems. Understanding and targeting the glial ecosystem is an inseparable new field to explore. Full article

Cancer stem cell (CSC) persistence drives recurrence and therapy resistance in oral squamous cell carcinoma (OSCC), but what keeps cells locked in this stem-like state is poorly understood. In this narrative review, we propose that CSC state is sustained not by any single pathway but by joint dysregulation of three interacting cell-biological systems: membrane potential (V_mem), communication between neighbouring cells through gap junctional intercellular communication (GJIC), and the Hippo–YAP pathway. We argue that these systems act together on one common point—the YAP protein, retained in the nucleus—which switches on a SOX2-centred stemness gene programme and stabilises a self-reinforcing CSC state. Drawing on evidence from cancer genomics, developmental bioelectricity, connexin biology, and OSCC-specific studies, we reconstruct how membrane depolarisation, loss of gap junction coupling, FAT1 mutation, and Hippo pathway inactivation could converge on persistent nuclear YAP, and how betel quid—the principal risk factor across South and Southeast Asia—may engage all three systems at once. Because the model holds that each input reinforces the others, it predicts that targeting several together should displace CSC state more durably than targeting any one alone. We set out the testable predictions this framework generates. Full article

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia and is increasingly driven by cardiometabolic disease, including type 2 diabetes mellitus (T2DM), obesity, and insulin resistance. These conditions promote atrial electrical instability and a permissive substrate through mitochondrial dysfunction, oxidative stress, inflammation, calcium-handling abnormalities, and profibrotic signaling, culminating in atrial fibrosis and conduction heterogeneity. Metformin, the foundational glucose-lowering therapy for T2DM, exerts pleiotropic actions that intersect with these upstream pathways. Beyond glycemic control, metformin induces mild mitochondrial complex I modulation with reduction of reverse electron transfer-derived reactive oxygen species, activates adenosine monophosphate (AMP) activated protein kinase, and attenuates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)-mediated cytokine signaling; experimental data further suggest favorable effects on adiponectin–sarcoendoplasmic reticulum calcium adenosine triphosphatase (SERCA) 2a-dependent calcium cycling, connexin expression, small-conductance Ca²⁺-activated K+ channel remodeling, lipid handling, and transforming growth factor-β (TGF)-β-associated fibrotic remodeling. Observational cohort studies have reported associations between metformin exposure and a modest reduction in incident AF, particularly with longer treatment duration and in higher-risk metabolic phenotypes; device-based surveillance cohorts support a preventive association for new-onset AF rather than reduction of established AF burden. Data after catheter ablation suggest improved freedom from recurrence in metformin-treated patients, whereas evidence in postoperative AF is largely neutral, likely reflecting distinct acute mechanisms. Collectively, metformin may be best conceptualized as a potential substrate-modifying, upstream therapy candidate; however, confounding, exposure misclassification, and heterogeneity in comparators limit causal inference, underscoring the need for prospective randomized trials with AF endpoints. In practice, integration with comprehensive risk-factor modification (blood pressure, weight, sleep apnea, and glycemic optimization) remains essential when considering AF prevention strategies. Full article

Background: Neuroinflammation contributes to the etiopathology and symptom severity of neurodegenerative and neuropsychiatric disorders. Glial cells, especially microglia and astrocytes, play a crucial role in neuroinflammation. It has been reported that ginseng (Panax ginseng) and its bioactive component ginsenoside Rg1 exhibit anti-inflammatory effects and can improve cognitive performance in various models. However, the exact underlying mechanisms remain unclear. Methods: Astrocyte–microglia co-culture models simulating physiological (M5, 5–10% microglia) and pathological/inflammatory (M30, 30–40% microglia) conditions were treated with different concentrations of ginsenoside Rg1 (15, 30, 45 µM) or ginseng extract (derived from Korean red ginseng) at low (12.5, 25, 37.5 µg/mL) or high doses (125, 250, 375 µg/mL) for 24 h. Cell viability was assessed using the MTT assay while microglial reactivity was examined using immunocytochemistry. Astrocytic gap-junctional coupling was investigated using the scrape-loading method, and connexin 43 (Cx43) expression was analyzed using immunocytochemistry and Western blot. Results: Both Rg1 and low-dose ginseng extract reduced microglial activation under inflammatory conditions by promoting a shift in microglia from an activated to homeostatic (resting) phenotype. Rg1 preserved astrocytic gap-junctional function by preventing the inflammation-induced downregulation of Cx43 expression and enhancing Cx43-mediated gap-junctional intercellular communication. Rg1 caused a significant reduction in glial cell viability, but only at high concentrations (30 and 45 µM), under inflammatory conditions. High-dose ginseng extract showed a significant concentration-dependent reduction in glial cell viability under physiological and pathological conditions, without comparable anti-inflammatory benefits. Conclusions: This study demonstrates that low-dose ginseng and its active compound Rg1 exert anti-inflammatory effects by modulating astrocytic coupling and microglial reactivity. These results provide a novel therapeutic perspective for the use of ginseng in the treatment of neurodegenerative and neuropsychiatric diseases related to neuroinflammation. Full article

Ovarian granulosa cells (GCs) ensure proper follicular development and oocyte maturation through gap-junction-mediated intercellular communication. Zearalenone (ZEA), a mycotoxin with estrogen-like activity, specifically targets and impairs ovarian function. Most existing studies have focused on ZEA-induced apoptosis in GCs, but whether ZEA disrupts gap junctions in ovarian GCs remains unclear. Therefore, the aim of this study was to investigate whether and how ZEA induces gap junction injury in ovine ovarian GCs, with a particular focus on the roles of G protein-coupled receptor 30 (GPR30), oxidative stress, and the NLRP3 inflammasome. In the present study, primary ovine ovarian GCs were isolated, cultured, and treated with different concentrations of ZEA to establish a gap junction injury model, and specific inhibitors/antagonists were used to investigate the underlying mechanisms. The results showed that ZEA decreased granulosa cell viability and significantly inhibited the expression of the gap junction proteins Connexin 43 (Cx43) and Connexin 37 (Cx37) in a concentration-dependent manner. ZEA treatment also significantly upregulated the expression of the NOD-like receptor familypyrindomain containing 3 (NLRP3) inflammasome-related proteins (NLRP3, ASC, Cleaved Caspase-1, and the downstream pro-inflammatory cytokine IL-1β) in a concentration-dependent manner. Pretreatment with the NLRP3-specific inhibitor MCC950 significantly reversed ZEA-induced downregulation of Cx43 and Cx37 and effectively blocked NLRP3 inflammasome activation, indicating that NLRP3 is a key target in ZEA-induced gap junction injury. Further experiments confirmed that ZEA treatment significantly increased oxidative stress levels in granulosa cells; pretreatment with the reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) restored the ZEA-induced downregulation of Cx43 and Cx37 and suppressed NLRP3 inflammasome activation, suggesting that ROS acts as an upstream regulator of NLRP3 inflammasome activation. Moreover, ZEA treatment altered GPR30 expression levels, and pretreatment with the GPR30 antagonist G15 effectively inhibited ZEA-induced ROS production, NLRP3 inflammasome activation, and downregulation of Cx43/Cx37, indicating that ZEA exerts its effects through functional activation of GPR30. Collectively, ZEA activates the GPR30 receptor, induces ROS accumulation in granulosa cells, and subsequently triggers NLRP3 inflammasome activation, ultimately leading to downregulation of Cx43 and Cx37 and gap junction dysfunction. This study reveals a previously unrecognized molecular mechanism by which ZEA induces gap junction injury in ovarian GCs, providing potential therapeutic targets and a theoretical basis for preventing ZEA-induced ovarian dysfunction and improving animal reproductive health. Full article

Severe traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide. To date, there are no clinically effective neuroprotective agents. Biomaterials that combine structural support for damaged tissue with a depot for therapeutic agents may represent a key solution to this problem. To evaluate the neuroprotective potential of a collagen matrix derived from the jellyfish Rhizostoma pulmo (R. pulmo) and modified with sodium thiosulfate (Na₂S₂O₃) as an hydrogen sulfide (H₂S) donor in a bioengineered platform for the treatment of severe TBI. Comprehensive characterization of the collagen matrix (electrophoresis, fluorescence microscopy), its implantation in a mouse model of severe TBI, and subsequent morphological, histological, ultrastructural, and immunohistochemical analyses of connexin 43 (Cx43) and p53 protein (p53) were performed. In addition, molecular dynamics simulations of the interactions between sulfur-containing compounds and target proteins were conducted. The effects were compared with inhibition of endogenous H₂S synthesis using aminooxyacetic acid (AOAA). The collagen matrix retains the properties of type I collagen and forms a three-dimensional porous structure with high hydrophilicity and biocompatibility. Implantation ensures effective defect filling, reduces cystic degeneration, and preserves cortical structure. Modification with Na₂S₂O₃ results in a significant reduction in both nuclear and cytoplasmic accumulation of p53, prevention of Cx43 dysregulation, a decrease in the proportion of damaged neurons and inflammatory infiltration, and preservation of tissue ultrastructure. In contrast, inhibition of CBS with AOAA exacerbates pathological changes. Molecular modeling demonstrated that S₂O₃²⁻ is capable of forming stable electrostatic interactions with domains of p53 and Cx43 under conditions of acidosis and elevated Ca²⁺. A collagen matrix derived from R. pulmo and modified with Na₂S₂O₃ represents a promising biodegradable platform that combines structural support with local H₂S-dependent regulation of key mechanisms of secondary brain injury. This approach provides a multilevel neuroprotective effect and opens new opportunities for the development of therapeutic implants for severe TBI. Full article

Ischemic diseases are characterized by the functional collapse of endothelial cells (ECs) triggered by insufficient tissue perfusion. Given that mitochondria serve as the metabolic hub of ECs, their homeostatic imbalance, which is manifested by adenosine triphosphate (ATP) depletion, reactive oxygen species (ROS) bursts, and mitochondrial permeability transition pore opening, serves as the initiating factor driving impaired angiogenesis and tissue necrosis. In this study, we engineered an integrated nanosystem (Tan-CDs@AS-IV) by transforming Tanshinone into antioxidant carbon dots to encapsulate Astragaloside IV, achieving multi-level synergistic regulation of mitochondrial function. Our results demonstrate that Tan-CDs@AS-IV possesses superior structural stability and cellular internalization capabilities, significantly enhancing the migration and tubulogenesis of ECs under ischemic stress. Mechanistically, Tan-CDs@AS-IV effectively scavenges mitochondrial ROS and restores membrane potential and ATP production. Crucially, the nanosystem orchestrates mitochondrial biogenesis via peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) upregulation while simultaneously facilitating intercellular mitochondrial transfer through Connexin 43 (Cx43)-mediated gap junctions. This synergistic “endogenous amplification and intercellular replenishment” model establishes a robust mitochondrial quality control relay. By reconstructing cellular energy homeostasis, this study provides a novel nanoengineering strategy for the targeted therapy of ischemic diseases. Full article

Connexin-43 (CX43) lateralization in ventricular myocardium has been associated with abnormal impulse propagation and increased arrhythmia susceptibility. Its quantitative assessment in histological sections remains challenging because previous methods require segmentation of individual cardiomyocytes and rely on geometric rules applied to segmented cell profiles. Here, we present CLARISA, a segmentation-free, ROI-based deep learning framework that classifies CX43-positive regions as terminal or lateralized directly from fluorescence images. An expert-annotated dataset was generated from left-ventricular cryosections of Wistar rat hearts, in which CX43-positive regions were labeled according to their distribution pattern. A dual-stream EfficientNetV2-S classifier was trained to capture both local and contextual ROI morphology. We also developed a semi-automated whole-section inference module to generate spatial lateralization probability maps and global percent lateralization estimates. On the held-out test set, CLARISA achieved a ROC-AUC of 0.904 (95% bootstrap CI: 0.828–0.960) and a PR-AUC of 0.808 (95% bootstrap CI: 0.682–0.913), supporting the feasibility of automated ROI classification for CX43 lateralization assessment. When deployed on whole tissue sections, including an independently analyzed section not used during model development, CLARISA generated spatial maps that captured heterogeneous CX43 organization and produced a global percent lateralization estimate closely aligned with expert annotation, differing by only 1.30 percentage points over the same detected CX43-positive area. Comparison with a previously published segmentation-based method further indicated that ROI-based and cell-segmentation-based approaches provide related but non-equivalent readouts of CX43 lateralization. The ROI-based design additionally reduces annotation burden—requiring classification of discrete CX43-positive signal rather than complex cardiomyocyte delineation—and ensures that all detected CX43-positive signal contributes to the lateralization estimate regardless of cell boundaries. These results establish CLARISA as a proof-of-principle framework for scalable, segmentation-free CX43 lateralization assessment in cardiac tissue. Further validation across larger, independent, and more heterogeneous datasets will be required to assess robustness, portability across imaging conditions, and translational applicability. The complete codebase, pretrained model, image data, and expert annotation tool are publicly available. Full article

Mutations in gap junction protein β-2 (GJB2), encoding Connexin 26 (Cx26), are the most common genetic cause of hearing loss, responsible for up to 50% of inherited non-syndromic cases worldwide. This review covers Cx26 from three perspectives: protein structure, mutant disease mechanisms, and treatment approaches. Structurally, 12 Cx26 subunits assemble into a gap junction channel connecting neighboring cells, enabling exchange of ions and signaling molecules; activity is regulated by calcium, pH, and CO₂. In the cochlea, Cx26 channels are required for the development of sound-sensing hair cells, maintenance of the electrical gradient needed for hearing, and energy supply during sound processing. GJB2 mutations cause hearing loss through three mechanisms, complete loss of functional protein, failure of channel assembly or membrane delivery, and abnormal channel gating, that damage cochlear cells. Severity ranges from profound congenital deafness to gradual decline, depending on which mutations are inherited. Gene therapy, genome editing, and pharmacological approaches are under investigation; cochlear implantation remains the current standard of care. Full article

Pancreatic adenocarcinoma remains a highly lethal malignancy with limited effective treatment options, largely due to late-stage detection and rapid progression to metastatic disease. Therapeutic strategies capable of targeting both pre-metastatic and metastatic tumors are critically needed. In this study, we evaluated a combination therapy consisting of non-thermal plasma (NTP), a generator of reactive oxygen and nitrogen species, and the hypoxia-activated prodrug tirapazamine (TPZ). We further investigated whether sulforaphane (SF), a bioactive phytochemical, could further enhance therapeutic efficacy. NTP and TPZ produced strong cytotoxic effects as single agents and demonstrated additive to synergistic activity when combined, reducing viability by 87% in pre-metastatic BxPC-3 cells and achieving near-complete elimination of metastatic AsPC-1 cells. The addition of sulforaphane (10 µM) further enhanced cytotoxicity across all treatment conditions, with Bliss independence analysis indicating additive to synergistic interactions depending on cell line and treatment combination. Sulforaphane-mediated enhancement occurred without restoration of connexin 43 expression or coordinated reversal of epithelial-to-mesenchymal transition markers, and treatments did not induce N-cadherin upregulation or suggest acquisition of invasive characteristics. Together, these findings support NTP + TPZ as a potent combinatorial strategy for pancreatic adenocarcinoma and identify sulforaphane as an effective adjunct that enhances cytotoxic efficacy through mechanisms that remain to be fully elucidated. Full article

Endothelial cell dysfunction is the initial step in atherosclerosis, in which gap junction proteins such as connexin 40 (Cx40) might play an important role. Previously, we could demonstrate that miRNA-26b, a 21-nucleotide miRNA, is highly expressed in human atherosclerotic plaques and plays a key causal role in atherogenesis. There is evidence that miRNA-26b and Cx40 play crucial roles in sustaining endothelial health. However, their potential effects on atherosclerosis-related processes remain poorly understood. Therefore, this study elucidated the expression of miRNA-26b and Cx40 and studied the effect of Cx40 on inflammation and monocyte binding, which are key processes in atherosclerosis formation. In a human in vitro endothelial cell model, miRNA-26b overexpression is associated with increased Cx40 expression. Although we did not observe any anti-atherogenic effect of Cx40 on monocyte attachment or VCAM-1 transcription under static conditions, a flow-dependent expression pattern characterised by increased Cx40 and reduced VCAM-1 transcription was observed. How miRNA-26b and Cx40 are connected remains to be investigated. Furthermore, the functional role of Cx40 under flow conditions requires further investigation. Full article

Meningiomas are the most common intracranial tumours, yet the molecular programs underlying WHO grade 1 subtypes—particularly transitional diploid tumours—remain insufficiently defined, partly due to the scarcity of biologically faithful in vitro models. Here, we report the establishment of a long-term, genetically unmanipulated grade 1 meningioma cell line (H8T-MG) maintained under normoxic conditions in serum-containing, growth-factor-supplemented medium, together with a complementary long-term primary culture (H16T-MG), and provide an integrated descriptive and functional characterization of these models, combined with a subtype-restricted transcriptomic analysis of diploid transitional grade 1 tumours versus normal meninges. Both cultures preserved the dual meso-neuroectodermal identity characteristic of meningothelial cells, exhibiting stable adherent growth, preserved contact inhibition and a coherent immunocytochemical profile, expressing vimentin, α-SMA, nestin, connexin-43 and cannabinoid receptors—reported here for the first time in grade 1 meningioma cultures—highlighting cannabinoid-related pathways as potential targets for exploration. Transcriptomic analysis identified 51 differentially expressed genes, revealing a coherent inflammatory–metabolic programme characterised by downregulation of IL-17 and TNF signalling, cytokines and chemokines (IL6, CCL2, SELE, S100A8), together with reduced extracellular-matrix and cytoskeletal activity. In parallel, the enrichment of arachidonic acid metabolism, cytochrome-P450/xenobiotic pathways, retinol metabolism and oxidative/epoxygenase activity indicated a lipid/xenobiotic-oriented metabolic shift distinctive of this subtype. Protein–protein interaction analysis identified four hub genes—ASPN, SELE, ACKR1 and ABCB1—integrating ECM remodelling, endothelial–immune modulation and xenobiotic transport, reinforcing an immune-attenuated, metabolically adapted tumour landscape. Collectively, these findings provide the first integrated in vitro and transcriptomic characterisation of diploid transitional meningiomas, underscore the value of biologically stable models for early-stage meningioma research, and support the value of histological and ploidy stratification in grade 1 meningioma biology. Full article

Anticontractile factors secreted by perivascular adipose tissue (PVAT) play an important role in regulating vascular tone. This process is driven by the neurotransmitter norepinephrine (NE), but recent data show that adrenergic innervation in PVAT is sparse. How limited innervation might initiate broad responses through PVAT depots remains unknown. Here, we used Ca²⁺ imaging with genetically encoded sensors, selective drugs, immunolabeling and a conditional ablation model to test the hypothesis that gap junction coupling among PVAT adipocytes contributes to how signals initiated by NE are distributed through PVAT depots. Despite exhibiting differing sensitivities to NE, adipocytes in aortic and mesenteric PVAT and in white adipose tissue displayed robust expression of the gap junction protein connexin-43 (Cx43). Blocking gap junction coupling with the drug carbenoxolone (Cbx) limited NE-evoked Ca²⁺ responses among adipocytes, while blocking Cx43 hemichannels with the mimetic peptide 43Gap26 had no significant effect. Fluorescence recovery after photobleaching (FRAP) in mPVAT was decreased in the presence of Cbx, suggesting impaired gap junction communication. Wire myography recordings of mesenteric arteries showed that the EC₅₀ for NE was higher in samples with intact PVAT than those without; however, this effect was not significantly different in samples from mice that lacked Cx43 in adipocytes. Analysis of multiple connexins showed that adipocytes upregulate Cx26 gene expression when Cx43 is deleted. These observations support the conclusion that Cx43-mediated gap junction coupling among PVAT adipocytes contributes to distributing signals initiated by NE; however, how this mechanism contributes to regulating vessel constriction remains unclear. This, and how potential compensatory mechanisms are enacted in adipocytes lacking Cx43, should be addressed in future work. Full article

Background/Objectives: Clinical application of Doxorubicin (Doxo) is limited by cardiotoxicity, a process strongly associated with an interplay between oxidative stress and inflammatory signaling, particularly Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation and Nucleotide oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome engagement. Identifying strategies capable of mitigating these interconnected pathways is of critical importance in cardio-oncology. Simvastatin (SIM) is a promising option since it modulates oxidative stress, inflammation, and cell death through its pleiotropic effects, so this study aimed to evaluate whether SIM attenuates Doxo-induced inflammatory responses. Methods: Human Cardiomyocyte (HCM) cells were pre-treated with SIM (10 µM) for 4 h and then co-exposed to SIM and Doxo (1 µM) for 20 h. Cytofluorimetric analysis was used to evaluate inducible nitric oxide synthase (iNOS), Connexin 43 (Cx43), and Cx43 phosphorylated at Serine 368 (p^S368Cx43) levels. Real-time qPCR was performed to evaluate iNOS gene expression, while Nitric oxide (NO) release was evaluated by spectrophotometric analysis. Interleukin (IL)-1β, IL-18, IL-6, tumor necrosis factor alpha (TNF-α) production, and NLRP3 levels were evaluated by means of ELISA assay. Expression levels of inhibitor of nuclear factor kappa B alpha (IκB-α), Caspase-1, and Gasdermin D (GSDMD) were evaluated by Western Blot analysis. Nuclear translocation of NF-κB was evaluated by immunofluorescence assay. Results: In our experimental model, SIM significantly (p < 0.01) reduced Doxo-induced nitrite release, as well as iNOS gene expression (p < 0.05) and protein levels (p < 0.01). SIM also markedly attenuated Doxo-induced NF-κB signaling, pro-inflammatory cytokines production (TNF-α and IL-6, p < 0.01), and inflammosome-related responses (cleaved caspase-1, IL-1β, N-terminal domain of GSDMD), and NLRP3 expression p < 0.05). Additionally, SIM significantly attenuated the overexpression of Cx43 and its phosphorylated form (p^S368Cx43), which are responsible for impairing intercellular communication and electrical coupling in cardiomyocytes and contribute to arrhythmias and conduction abnormalities characteristic of acute Doxo-induced cardiotoxicity. Conclusions: Overall, these findings demonstrate that SIM exerts a multifaceted cardioprotective effect against Doxo-induced injury, thereby targeting interconnected inflammatory and pro-arrhythmic pathways implicated in Doxo cardiotoxicity. Full article