Search Results (7,247)

Survivin is a cancer-associated inhibitor of apoptosis protein (IAP) that can suppress both extrinsic and intrinsic apoptotic pathways. IAPs typically prevent programmed cell death by binding to caspases, but whether survivin behaves as a canonical IAP or can protect cells from death by alternative means has not been fully investigated. Here, we report a novel interaction between survivin and the mitochondrial outer membrane protein, VDAC2, which we show is an indirect association potentially mediated by Bcl2-family members. This novel finding suggests survivin can suppress mitochondrial-mediated apoptosis upstream of caspases and could open a new avenue for targeting survivin in anti-cancer therapy regimes. Full article

Mastitis remains the most economically damaging disease of dairy production, and recent molecular work has converged on the NLRP3 inflammasome as a key integrative node of its pathogenesis. This narrative review integrates evidence published largely between 2015 and 2026 to show how diverse triggers—Staphylococcus aureus and Escherichia coli, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), non-esterified fatty acids (NEFA), heat stress, environmental xenobiotics including nanoplastics, and microbiota-derived signals—may funnel into a common NLRP3–ASC–caspase-1–GSDMD axis that drives pyroptosis, blood–milk barrier disruption, and clinical disease. The review examines the potential obligatory role of reactive oxygen species (ROS), mitochondrial dysfunction, and selenoprotein-mediated redox control in licensing inflammasome assembly. It further evaluates the emerging gut–mammary and rumen–mammary axes that operate upstream of local epithelial activation. We survey a structurally diverse therapeutic landscape encompassing dietary selenium, probiotics, microbial metabolites, plant-derived nanovesicles, polyphenols, ginsenosides, and small-molecule NLRP3 antagonists, identifying recurring mechanistic motifs that suggest combinatorial regimens may yield additive benefit. Importantly, much of the evidence derives from in vitro and murine models, and we highlight the translational gaps that must be bridged before clinical application in dairy cattle. Finally, we map outstanding research gaps and propose priorities for translational work aimed at sustainable, antibiotic-sparing management of bovine mastitis. Full article

Inflammatory bowel disease (IBD) poses a significant global health burden with rising incidence, particularly in Asia. This study employed an integrative network pharmacology approach combined with molecular docking to elucidate the therapeutic mechanism of ganoderic acid A (GAA) against IBD. Potential GAA targets were retrieved from pharmacogenomic databases, while IBD-related genes were curated from OMIM and GeneCards databases. Weighted gene co-expression network analysis of IBD transcriptomic datasets (GSE38713, GSE126124) identified disease-associated modules, with the yellow module exhibiting the strongest positive correlation. Functional enrichment analyses demonstrated significant involvement of overlapping targets in lipid metabolism, the inflammatory response, and the mitogen-activated protein kinase (MAPK) signaling cascade pathway. We identified 14 IBD-GAA-ferroptosis-related genes and 54 key module genes. Intersection analysis revealed 5 overlapping targets, including tumor necrosis factor-α(TNF-α), peroxisome proliferators-activated receptor γ (PPARγ), MAPK14, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α (PIK3CA), and Caspase 3 (CASP3). Molecular docking confirmed high-affinity binding of GAA to these targets, with binding energies ranging from −7.3 to −10 kcal/mol. Crucially, experimental evaluation demonstrated the pivotal role of GAA in alleviating disease pathology. GAA treatment suppressed the significantly elevated levels of TNF-α and p-MAPK14 in the organoids using a cytokine/LPS-induced IBD model. These findings collectively suggest a potential involvement of GAA in pathways associated with ferroptosis regulation, although direct experimental evidence for ferroptosis markers remains to be established. The observed multi-target effects on immune regulation and cellular proliferation/differentiation provide a foundation for further mechanistic investigation. Full article

Photobiomodulation (PBM) is a non-invasive therapeutic strategy that uses red and near-infrared (NIR) light in the 590–950 nm range to modulate the cellular and molecular pathways involved in retinal homeostasis. At the molecular level, PBM acts primarily through photon absorption by cytochrome c oxidase (CcO, complex IV of the mitochondrial electron transport chain), whose four metal centres—two copper (CuA and CuB) and two heme groups (heme a and heme a₃)—absorb light across approximately 600–1000 nm. Photon capture promotes photodissociation of inhibitory nitric oxide (NO) from the binuclear CuB–heme a₃ centre, accelerates electron transfer, restores the proton-motive force and increases ATP synthesis. These primary events trigger a coordinated molecular programme that includes (i) transient mitochondrial reactive oxygen species (ROS) bursts that activate the Nrf2/Keap1/ARE axis and upregulate phase II antioxidant enzymes (HO-1, NQO1, GCLC, SOD2, catalase, GPx); (ii) calcium- and cAMP-dependent secondary signalling that converges on PI3K/Akt, MAPK/ERK, AMPK and mTOR pathways; (iii) suppression of NF-κB-driven cytokine production (TNF-α, IL-1β, IL-6) and of NLRP3 inflammasome activation; (iv) downregulation of the HIF-1α/VEGF axis, particularly at 590 nm; (v) anti-apoptotic remodelling of the Bcl-2/Bax ratio with reduced cytochrome c release and caspase-3/9 activation; and (vi) PGC-1α/TFAM/NRF1-driven mitochondrial biogenesis, alongside restoration of fission/fusion homeostasis (Drp1, Mfn1/2, Opa1) and PINK1/Parkin-mediated mitophagy. Wavelength specificity has a defined molecular basis: 590 nm modulates VEGF signalling and RPE pump activity, 660 nm interacts with the CuB centre and enhances O₂ binding at CcO, and 850 nm is absorbed by CuA and supports electron entry into complex IV. A second molecular axis is the bidirectional crosstalk between PBM and the circadian system: mitochondrial respiration, ATP turnover and CcO activity oscillate over the 24 h cycle under the control of the BMAL1/CLOCK and PER/CRY core machinery, the NAD⁺/SIRT1–SIRT3 axis and REV-ERBα. Preliminary preclinical and human observations suggest that NIR-induced bioenergetic and functional gains may be coupled to this rhythm, with greater benefit reported when light is delivered in the morning window (≈08:00–11:00); this time dependence should be regarded as an emerging hypothesis rather than an established clinical principle. The clinical evidence is unevenly developed across indications. It is most robust for non-exudative age-related macular degeneration, where multiwavelength PBM (590/660/850 nm; Valeda Light Delivery System) has shown disease-modifying potential in randomized controlled trials (LIGHTSITE I–III and the LIGHTSITE IIIB extension), with sustained BCVA gains and reduced incidence of geographic atrophy over 24 months and beyond. Evidence for retinitis pigmentosa, central serous chorioretinopathy and, with red-light monotherapy, childhood myopia is at present limited to small or short-term studies and remains preliminary. This narrative review synthesizes the molecular machinery engaged by PBM, integrates clinical findings across retinal diseases and discusses how chronotherapeutic delivery of light, aligned with the molecular clock, may further optimize therapeutic efficacy. Full article

Colon cancer remains a leading cause of cancer-related deaths, and drug repurposing offers a promising strategy to identify new therapies. Hydroquinidine (HQ), a class I antiarrhythmic agent, has recently been suggested to possess anticancer properties; however, its preclinical safety and efficacy in colorectal cancer are not well defined. The safety of HQ was evaluated in Wistar rats following OECD guidelines. Rats received daily intraperitoneal doses (2.5–25 mg/kg) for 90 days, with hematological, biochemical, and histopathological assessments performed. HQ was well tolerated up to 12.5 mg/kg, whereas 25 mg/kg caused signs of hepatotoxicity without lethality. A 1,2-dimethylhydrazine-induced colorectal cancer model was then used to assess HQ at safe doses (6.25 and 12.5 mg/kg) compared with cisplatin. Tissue histopathology and selected molecular markers associated with inflammation, apoptosis, epithelial–mesenchymal transition, and PI3K/AKT/mTOR pathway activity were analyzed. In the DMH-induced colon cancer model, HQ improved colonic tissue architecture and was associated with lower histopathological scores compared with untreated tumor controls. HQ also modulated tumor-associated markers by reducing IL-6 immunoreactivity, increasing caspase-3 expression, enhancing E-cadherin immunoreactivity, and decreasing vimentin expression. Moreover, HQ was associated with reduced immunoreactivity of mTOR pathway-related markers, suggesting attenuation of pathway activation in this experimental context. Overall, HQ showed an acceptable safety profile at the selected doses and exerted favorable histopathological and molecular modulatory effects, supporting further investigation as a potential repurposing candidate. Full article

Global freshwater salinization endangers aquatic species, yet its impacts on crustaceans remain poorly understood. This study investigated the hepatopancreatic response of Eriocheir sinensis to carbonate alkalinity stress (0, 4.375, 8.75, 17.5, and 35 mmol/L) over 24, 48, and 96 h, integrating histology, ultrastructure, gene expression (RT-qPCR), and non-specific immune enzyme assays. Histopathological and ultrastructural analyses revealed concentration- and time-dependent damage, including vacuolization, hepatic tubule disintegration, nuclear condensation, mitochondrial reduction, and loss of cellular integrity. Molecular analysis demonstrated upregulation of genes associated with the TLR2-MyD88-NF-κB pathway and inflammatory genes (LITAF, IL-16), alongside increased HSP70 expression, confirming severe inflammation and cellular stress. Furthermore, apoptosis was induced via upregulated Bax and Caspase-3, downregulated Bcl-2, and DNA fragmentation. Non-specific immune responses in the hepatopancreas exhibited dynamic changes: acid phosphatase (ACP) was initially activated at low alkalinity but inhibited at high concentrations, while alkaline phosphatase (AKP) activity increased at 96 h. Notably, the hepatopancreas proved more sensitive to this stress than the hemolymph. Collectively, carbonate alkalinity causes multidimensional hepatopancreatic injury in E. sinensis through structural disruption, inflammation mediated by TLR2-MyD88-NF-κB signaling pathway-related genes, apoptosis induction, and immune enzyme dysregulation, posing a significant threat to crab health in salinized waters. Full article

This study aimed to investigate the selective anticancer activity of the curcumin analog PAC (3,5-Bis-4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone). Normal gingival epithelial cells (GECs), cancerous gingival cells (Ca9-22) and tongue squamous carcinoma cells (CAL27) were exposed to increasing concentrations of PAC (0–10 µM) for 24 h. Cell viability and cytotoxicity were evaluated using MTT and LDH assays, while apoptosis and caspase activation were analyzed by Annexin V/PI staining and flow cytometry. Gene-expression profiling was performed using RT² Profiler PCR arrays. PAC significantly inhibited Ca9-22 and CAL27 cell proliferation in a concentration-dependent manner, with an IC₅₀ value of 5 µM, while exerting no noticeable cytotoxic effects on normal GEC. PAC treatment induced significant early and late apoptosis associated with increased caspase activity in both oral cancer cell lines. Transcriptomic analyses revealed extensive modulation of apoptosis-related genes. In Ca9-22 cells, PAC predominantly suppressed anti-apoptotic and survival-associated genes, including BCL2, BIRC3, BIRC5, XIAP, CFLAR, and NFKB1. In contrast, CAL27 cells exhibited a more pronounced pro-apoptotic transcriptional profile characterized by upregulation of TP53, APAF1, CASP1, BID, and TNF. Gene interaction network analyses further demonstrated that PAC targets highly interconnected apoptotic signaling pathways. Collectively, these findings demonstrate that PAC exerts potent selective anticancer activity against OSCC cells through modulation of intrinsic and extrinsic apoptotic pathways. These results further support the therapeutic potential of PAC as a promising multitarget candidate for oral cancer treatment. Full article

Background: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal barrier disruption and dysregulated immune responses. While Intravenous Immunoglobulin (IVIG) is widely used for its immunomodulatory effects in various autoimmune conditions, its specific therapeutic mechanisms and molecular targets in colitis remain to be fully elucidated. Objective: To elucidate the therapeutic mechanisms of IVIG in dextran sodium sulfate (DSS)-induced colitis, with a focus on pyroptosis regulation via the NOD-like receptor (NLR) signaling pathway. Methods: Colitis was induced in mice via DSS administration. IVIG was administered intravenously during disease progression. Colon tissues underwent proteomic profiling, and key targets (GBP5, NLRP3, Pro-Caspase-1, GSDMD) were validated by Western blotting (WB), while interleukin (IL)-1β and IL-18 levels were quantified via ELISA. Results: IVIG significantly attenuated weight loss, Disease Activity Index (DAI) scores, colon shortening, and histopathological damage. Proteomics analysis identified 172 differentially expressed proteins between DSS and DSS + IVIG groups, with pronounced downregulation of GBP5 and NLR pathway components. IVIG suppressed GBP5/NLRP3/CASP1 activation, reduced GSDMD cleavage, and significantly decreased IL-1β production (while showing a decreasing trend for IL-18). Conclusions: IVIG ameliorates colitis by inhibiting the GBP5/NLRP3/CASP1-mediated pyroptosis pathway, highlighting its potential as a targeted therapy for ulcerative colitis. Full article

Fisetin is a bioactive flavanol with reported anticancer activity, although its mechanisms in leukaemia and potential for combination therapy remain incompletely understood. This study investigated the cytotoxic and mechanistic effects of fisetin, alone and combined with pinocembrin, in human leukaemia cells. Cell viability, apoptosis, and cell cycle progression were assessed by flow cytometry; protein expression in Jurkat cells was assessed by Western blotting; and molecular docking was used to evaluate interactions with the Fas receptor. Drug interactions were quantified using ZIP synergy analysis, and cytotoxicity and clonogenic survival were evaluated using soft-agar colony formation assays in K562 cells. Fisetin significantly reduced cell viability and induced apoptosis, accompanied by caspase-8 cleavage, p62 accumulation, and CDK4 downregulation, consistent with activation of extrinsic apoptosis, impaired autophagic flux, and cell cycle inhibition in Jurkat cells. Docking analysis supported a potential interaction with the Fas receptor, which was confirmed using the Fas receptor antagonist Met-12. Co-treatment with pinocembrin enhanced fisetin-mediated cytotoxicity and produced synergistic effects, particularly in Jurkat cells (ZIP score > 10), while synergistic interactions at specific sub-IC₅₀ concentrations were also observed in K562 cells. Combination treatment further enhanced caspase-8 activation, reduced CDK4 expression in Jurkat cells, and significantly suppressed clonogenic survival in K562 cells compared with single-agent treatments. These findings suggest that fisetin promotes caspase-8-dependent apoptosis, potentially involving Fas-associated signalling, and highlight fisetin–pinocembrin combination therapy as a promising strategy for leukaemia treatment. Full article

Objectives: This study aimed to develop curcumin nanoparticles (Cur@PCL-PEG-MF/cRGDfc) with retinal-targeting capability and to evaluate their biological effects and pharmacological mechanisms in vitro. Methods: After synthesis of the carrier framework, metformin (MF) and cRGDfc were conjugated to the carrier material using the carbodiimide method and Michael addition reaction, respectively. Subsequently, self-assembled nanoparticles were formed from the carrier and curcumin under specific conditions. The materials were characterized by spectroscopy, chromatography, elemental analysis, energy-dispersive spectroscopy and X-ray diffraction. The efficacy of the formulation was evaluated in two cell lines, ARPE-19 and HUVEC-T1. In addition, the pharmacological mechanism was explored using transcriptome sequencing as a complementary approach. Key Findings: Self-assembled nanoparticles were successfully prepared by combining the two modified carrier materials, PCL-PEG-MF and PCL-PEG-cRGDfc, with curcumin. The nanoparticles exhibited an encapsulation efficiency of 78.09%, a particle size of 162.33 nm, and a zeta potential of −23.28 mV and displayed a spherical morphology. They showed sustained release in simulated physiological conditions and stronger affinity for ARPE-19 cells under oxidative stress. Nearly 100% of the nanoparticles were internalized by the cells, which was accompanied by reduced ROS and LDH release and decreased DNA fragmentation. In addition, the nanoparticles inhibited neovascularization by reducing VEGF-A release, thereby potentially protecting the retina in macular degeneration and reducing choroidal hemorrhage. Further analyses showed that curcumin and its nanoformulations significantly reduced the expression of inflammatory factors such as IL-1β and IL-18, lowered the protein levels of Caspase-1, GSDMD-N, and NLRP3, and increased AMPK levels. Conclusions: Using PCL-PEG as the carrier framework, MF and cRGDfc were conjugated to construct a curcumin-loaded nanoparticle with retinal-targeting capability. This nanoparticle, characterized by a small particle size, sustained release, and targeted delivery to retinal pigment epithelium (RPE) cells under oxidative stress, alleviated oxidative stress-induced damage. Its therapeutic effect may be mediated, at least in part, by interference with the AMPK/mTOR pathway and activation of the NLRP3/Caspase-1/GSDMD pathway. Full article

The Asteraceae family represents one of the largest groups of medicinal plants, widely used in traditional medicine and increasingly investigated for its pharmacological potential. This review summarizes current evidence on the botanicals derived from Asteraceae plant species and their molecular mechanisms of action against inflammation and cancer. Major classes of bioactive compounds in extracts are discussed in relation to their modulation of key signaling pathways and therapeutic targets such as NF-κB, MAPK, PI3K/Akt, COX-2, iNOS, and apoptotic regulators (Bax/Bcl-2, caspases). A literature search covering studies published between 2022 and 2026 was conducted. Evidence from in vitro, in vivo, and in silico studies demonstrates that Asteraceae-derived botanicals exert therapeutic effects through antioxidant activity, cytokine suppression, enzyme inhibition, and regulation of gene expression. Overall, the mechanistic insights presented herein support the rational use of Asteraceae medicinal plants and identify promising lead compounds for drug discovery and development. Full article

Deep dermatophytosis is a rare, life-threatening fungal infection characterised by the invasion of dermatophytes beyond the superficial layers of keratinised tissue into the dermis and subcutaneous tissues. The present review aimed to identify the current knowledge on the role of Caspase Recruitment Domain-containing protein 9 (CARD9) deficiency in the pathogenesis, clinical spectrum, diagnosis, and management of deep dermatophytosis. For innate immune activation, CARD9 acts as an adaptor molecule. Basically, CARD9 helps mediate the connection between the fungal pattern recognition receptor (Dectin-1) and the NF-κB and MAPK signalling pathways, and it mediates cytokine production, thereby activating phagocytic activities. Thereby, any change or mutation in the CARD9 gene may disrupt these pathways, leading to dysfunctional neutrophils and impaired Th17-mediated antifungal immunity. Clinically, patients with CARD9 deficiency are immunocompetent but susceptible to recurrent and/or severe fungal infections [Candida, dermatophytes (Trichophyton spp.), and phaeohyphomycetes]. Deep dermatophytosis in these patients is usually chronic, treatment-resistant, and characterized by erythematous papules, nodules, plaques, ulcers, or necrotic lesions, most of which occur on the lower limbs. It usually occurs in adulthood and is more common in males. There have been instances of geographic clustering of CARD9 deficiency in Asia, North Africa, and the Middle East. Early recognition and genetic diagnosis of CARD9 mutations in patients with recurrent or atypical deep dermatophytosis. Although antifungal therapy is essential, hematopoietic stem cell transplantation can be a definitive treatment for selected patients with CARD9 deficiency. Thus, CARD9 deficiency is a critical factor in the better management of patients but remains an underrecognized cause of severe, treatment-resistant deep dermatophytosis, and early genetic diagnosis is essential for guiding targeted management and improving patient outcomes. This review emphasises the importance of CARD9 in antifungal immunity and underscores the need for greater clinical awareness and the incorporation of genetic evaluation into the management of deep dermatophytosis. Full article

Melittin (Mel) is a membrane-active peptide with potential anticancer activity, but its direct therapeutic application may be limited by nonspecific toxicity and delivery-related challenges. The study aimed to assess melittin-functionalized magnetic nanoparticles (MNPs-Mel) as a strategy to enhance antitumor activity in Caco-2 cells, with/without magnetic hyperthermia (MH) association. BJ fibroblasts were used as a normal human in vitro cellular model. The effects of free Mel (2.5 µg/mL), MNPs, and MNPs-Mel (50 µg/mL both) + MH (30 min at 355 kHz and 25 kA/m) were assessed using colorimetry (for viability), luminescence (ATP), and spectrophotometry (lactate) following different exposure conditions. The mechanism of apoptosis induction was evaluated by ELISA (caspase 8 and 9 levels). Transmission electron microscopy (TEM) was also used to evaluate nanoparticle morphology and treatment-associated cellular ultrastructural changes. Free Mel reduced viability in both cell lines, with Caco-2 cells showing greater sensitivity at lower concentrations. MNPs (with/without MH) produced limited and less consistent effects, whereas MNPs-Mel significantly reduced Caco-2 viability and ATP levels and increased LDH and caspase 9. MH further enhanced the effects of MNPs-Mel: reduced viability (57–58% of the control at 24 h and 72 h), decreased ATP levels (67% of the control at 24 h and 53% at 72 h), increased LDH levels (206% of the control at 24 h and 301% at 72 h), and induced the mitochondrial apoptotic pathway (caspase 9 increased with 2164% of the control at 72 h). TEM proved the internalization of both MNPs and MNPs-Mel and revealed extensive ultrastructural alterations concerning mitochondria and lysosomes produced by MNPs-Mel, particularly in the Caco-2 cells. These modifications were heavily increased by MNPs-Mel + MH exposure. Overall, these findings demonstrate that Mel functionalization increases the antitumor activity of Mel at lower doses and that MH further potentiates this effect in Caco-2 cells. Full article

Background/Objectives: DNA-targeting small molecules that induce replication stress represent a promising strategy in anticancer drug development. 1,8-Naphthalimide (NI) derivatives are well-established DNA-intercalating agents, and heterocyclic annulation offers a rational approach to enhancing their potency and tumor selectivity. Here, we report the synthesis and biological evaluation of a novel series of benzofuran-containing naphthalimide derivatives, with particular focus on the lead dinitro-substituted compound 5d. Methods: Cytotoxic activity was assessed using the MTT assay in A549 (p53 wild-type), H1299 (p53-null), and MRC-5 cells. Long-term antiproliferative effects were evaluated by clonogenic survival assay. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Replication stress and DNA damage were quantified by EdU incorporation and γH2AX immunofluorescence, respectively. Apoptosis was assessed by Annexin V/PI staining and caspase-3/7 activation assay. p53 nuclear accumulation and autophagy induction were evaluated by immunofluorescence and Western blot, using LC3 as an autophagic marker. Results: All compounds exhibited cytotoxic activity in the nanomolar range, with 5d emerging as the most potent and selective. Clonogenic survival was significantly reduced, indicating durable suppression of proliferative capacity. Treatment with 5d induced G₁ arrest in A549 cells and the accumulation of H1299 cells in G₂/M, consistent with p53-dependent and p53-independent checkpoint activation, respectively. EdU incorporation was markedly reduced, while γH2AX intensity increased, collectively supporting a replication stress-driven mechanism of DNA damage. Apoptosis was confirmed by increased Annexin V-positive populations and caspase-3/7 activation. LC3 puncta formation and LC3-I/LC3-II conversion were increased, indicating LC3 processing and autophagosome accumulation consistent with the activation of autophagy-related processes. Conclusions: 5d induces a cellular phenotype consistent with replication stress, including reduced EdU incorporation, γH2AX accumulation, cell cycle arrest, and apoptotic cell death in a p53 status-dependent manner. These findings establish benzofuran-annulated naphthalimides as a promising scaffold for the development of anticancer agents that exploit replication stress vulnerabilities in tumor cells. Full article

Background/Objectives: Diabetic cardiomyopathy (DCM) is largely driven by severe oxidative stress and calcium dyshomeostasis. We examined the targeted antioxidant and therapeutic effects of zinc sulfate (ZnSO₄) on contractile dynamics, oxidative damage, calcium turnover, and apoptosis/fibrosis in aged female rats with type 2 diabetes. Methods: Thirty-two aged female Wistar rats were divided into Control, Control + ZnSO₄, Diabetes (DM), and DM + ZnSO₄ groups. DM was induced via high-fat diet and 30 mg/kg streptozotocin. After a 4-week complication period, treatment groups received 10 mg/kg/day ZnSO₄ (i.p.) for 6 weeks. Left ventricular papillary muscle contraction, oxidative/antioxidant markers (MDA/GSH), and gene expressions (SIRT1, GLUT4, SERCA2a, RyR2, Cav1.2, PLN) were evaluated. Myocardial architecture, fibrosis, and apoptosis were analyzed immunohistochemically. In DM rats, contractile force (CF) and velocities (±dF/dtmax) significantly declined. Results: Concurrently, SIRT1, GLUT4, SERCA2a, RyR2, Cav1.2, and antioxidant GSH decreased, while oxidative lipid damage (MDA), PLN, Caspase-3 activity, Collagen I, and fibrosis increased (p < 0.001). ZnSO₄ treatment in diabetic rats acted as a potent antioxidant modulator; it restored redox balance, activated the SIRT1/GLUT4 pathway, protected calcium-handling proteins from oxidative degradation, and significantly improved contractile dynamics. It also preserved myocardial architecture by reducing apoptosis and fibrosis. In healthy rats, ZnSO₄ caused mild stress and early fibrosis. Conclusions: In conclusion, while inducing mild stress in healthy myocardium, zinc supplementation provides robust antioxidant protection in diabetic hearts. It activates SIRT1, suppresses oxidative damage, maintains calcium homeostasis, and restores contractile dynamics, demonstrating strong antioxidant therapeutic potential against DCM. Full article