Search Results (2,470)

Background/Objectives: Malignant melanoma is characterized by constitutive PI3K/Akt/mTOR and MAPK activation, driving aggressive behavior and therapeutic resistance. Alpha-lipoic acid (αLA), a naturally occurring dithiol compound with an established clinical safety profile, has shown anticancer potential; however, its integrated molecular mechanisms in melanoma remain poorly defined. This study aimed to comprehensively evaluate the cytotoxic and mechanistic effects of αLA in B16F10 murine melanoma cells. Methods: Antiproliferative effects were assessed by MTT assay at four concentrations (250, 500, 750, 1000 µM) over 48 h. Protein levels of apoptotic markers (Bax, Bcl-2, Caspase-3, AIF), kinase signaling components (p-Akt, p-mTOR, p-ERK, p-JNK), ER stress markers (GRP78, GADD153/CHOP), and cell cycle regulator Wee1 were quantified by ELISA at a specifically selected sub-lethal concentration of 750 µM (inducing ~38% growth inhibition). Results: αLA dose-dependently inhibited B16F10 proliferation. At 750 µM, it triggered robust intrinsic apoptotic signaling, evidenced by a nearly 10-fold shift in the Bax/Bcl-2 ratio and greater than 9-fold Caspase-3 activation. Elevated AIF suggested profound mitochondrial stress and the potential priming of concurrent caspase-independent cell death mechanisms. αLA suppressed survival signaling by reducing p-Akt (44%), p-mTOR, p-ERK, and p-JNK. Treatment triggered lethal ER stress via GRP78 and GADD153/CHOP upregulation and upregulated Wee1, suggesting the induction of stress-responsive checkpoint signaling. The simultaneous CHOP upregulation and p-Akt suppression highlight a concurrent dysregulation of stress and survival pathways, suggesting a potential pro-apoptotic interplay. Conclusions: αLA exerts potent multi-target anticancer effects by inducing a broad spectrum of associated molecular changes, including the suppression of PI3K/Akt/mTOR and MAPK networks, induction of ER stress, engagement of cell cycle checkpoints, and activation of the mitochondrial Bax/Bcl-2/Caspase-3 axis. Importantly, these correlative findings do not establish proven pathway dependencies. Nevertheless, this concurrent dysregulation positions αLA as a potential disruptor of inter-pathway resilience underlying drug resistance. Full article

Redox homeostasis is the balance between oxidative processes and antioxidant defenses and is fundamental to cellular integrity. This review critically synthesizes current evidence on the phytochemical composition, redox-modulating mechanisms, and therapeutic bioactivities of Fagonia cretica L. (F. cretica), with the aim of evaluating its translational potential as a natural antioxidant and anticancer agent. F. cretica has emerged as a phytochemically rich candidate containing highly bioactive secondary metabolite for redox-targeted therapeutic applications. Its diverse secondary metabolite profile, including alkaloids, flavonoids, tannins, saponins, terpenoids, glycosides, and phenolic compounds, confers broad biological activity. Bioactive constituents, particularly kaempferol, catechin, quercetin, and arbutin, directly neutralize reactive oxygen species (ROS) and modulate inflammatory pathways through inhibition of COX-1, COX-2, and nitric oxide production. These compounds influence important major ROS-sensitive redox signaling pathways: activation of the Keap1/Nrf2/ARE axis to upregulate cytoprotective genes such as HO-1, NQO1, and GCL, suppression of the NF-κB pathway to attenuate pro-inflammatory cytokine transcription, including TNF-α, IL-1β, and IL-6, and interference with the MAPK-PI3K/Akt cascade to disrupt aberrant cancer cell survival and proliferation. Bioactive compound-rich extracts of F. cretica exhibit anticancer activity in MCF-7 breast cancer cells by inducing DNA damage, cell cycle arrest, and apoptotic signaling through the FOXO3a/p53 pathways. Similar effects have been reported in colorectal (HCT-116) and prostate (PC-3) cancer cells through DNA (cytosine-5)-methyltransferase 1 (DNMT1) downregulation, oxidative stress induction, and ER-β activation. Moreover, these extracts demonstrate cytotoxic effects in HepG2 and Caco-2 intestinal cancer cells, often associated with topoisomerase inhibition and caspase activation. Despite encouraging preclinical evidence, systematic studies encompassing pharmacokinetic profiling, toxicological characterization, and human clinical trials remain essential to translate these findings into safe, evidence-based therapeutic applications. Full article

Methotrexate (MTX) is widely used in the treatment of malignancies and inflammatory disorders, but nephrotoxicity remains a major adverse effect. Naringenin (NAR), a natural flavonoid, has antioxidant, anti-inflammatory, and nephroprotective properties. This study investigated the potential protective effects of NAR against MTX-induced nephrotoxicity at biochemical, molecular, and histopathological levels. Forty-two adult male Wistar albino rats were assigned to seven groups (n = 6): Control, CMC (carboxymethyl cellulose), NAR100, MTX, and MTX combined with NAR (25, 50, or 100 mg/kg/day). NAR was administered for 7 days, with MTX given on day 3. Renal function, histopathology, and genes associated with oxidative stress, apoptosis, endoplasmic reticulum stress, and inflammation were evaluated. MTX administration caused marked renal damage, increased creatinine and BUN levels, elevated apoptosis-, inflammation-, and ER stress-related gene expression, and suppressed antioxidant defense-related genes. However, 50 and 100 mg/kg/day NAR attenuated these alterations, with greater effects at 100 mg/kg/day. Histopathological damage was attenuated by NAR treatment, although complete recovery was not observed. These findings suggest that NAR may protect against MTX-induced nephrotoxicity through the modulation of pathways associated with oxidative stress, inflammation, apoptosis, and ER stress. However, the persistence of certain histopathological alterations indicates that structural recovery of renal tissue may take a longer period compared with molecular changes. Full article

Serotonin transporter Slc6a4a functions as a transporter in serotonin reuptake and is tightly linked with serotonergic regulation and stress responses. However, few studies have investigated its role in copper homeostasis and organogenesis in an in vivo vertebrate model. In this study, we demonstrate that slc6a4a deficiency (slc6a4a^−/−) leads to copper accumulation, retinal developmental defects, and locomotor dysfunction in zebrafish specifically. Mechanistically, slc6a4a deficiency is associated with reduced atp7b and copper accumulation, which lead to reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress, and results in Caspase-3-mediated apoptosis and retinal degeneration. Specifically, tetrathiomolybdate (TTM), a pharmacological copper chelator, partially reduces ER stress and restores retinal defects. Additionally, ectopic expression of full-length atp7b mRNA partially restores retinal defects. These findings identify serotonin transporter Slc6a4a as a novel regulator in copper homeostasis and retinal development via the regulation of Atp7b in an in vivo vertebrate model. This study supports a mechanistic link between slc6a4a deficiency, copper overload, and retinal defects and highlights copper chelation as an alternative therapeutic strategy in individuals with Slc6a4 deficiency. Full article

Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction remain incompletely understood. Here, we combine cellular models of inducible Gfpt1 knockdown and a skeletal muscle-specific Gfpt1 knockout mouse (Gfpt1^Tm1d/Tm1d) with whole-cell proteomics, immunoblot studies and secretomics to define glycosylation-dependent defects in intracellular trafficking, ER stress signaling and autophagy. Global proteomic profiling of Gfpt1-deficient myoblasts revealed marked downregulation of protein trafficking pathways and impaired secretion of key muscle cargo proteins, including serglycin (Srgn). Loss of GFPT1 reduced both high-molecular-weight glycosylated serglycin and its core protein, accompanied by intracellular retention and decreased secretion. These trafficking defects coincide with robust activation of the unfolded protein response (UPR), evidenced by increased Xbp1 expression and accumulation of spliced Xbp1s across pharmacologic, cellular, and mouse models of GFPT1 deficiency. Converging evidence from proteomics, immunoblotting, and immunofluorescence demonstrated impaired autophagy, including increased LC3-II accumulation, elevated p62/Sqstm1 levels, and enhanced p62-positive puncta in both Gfpt1-deficient C2C12 myoblasts and skeletal muscle. Soluble/insoluble fractionation further confirmed p62 accumulation, indicating defective autophagic flux and buildup of aggregated cargo. Together, these findings identify a glycosylation-dependent failure in protein trafficking that triggers ER stress, UPR activation, and autophagy impairment in Gfpt1-deficient skeletal muscle. This mechanistic cascade provides a unifying explanation for muscle pathology in GFPT1-CMS and suggests that restoring glycosylation or improving proteostasis may represent viable therapeutic approaches. Full article

Reticulon-like proteins shape the endoplasmic reticulum (ER) membrane network, yet the developmental and physiological roles of individual plant reticulon isoforms remain poorly understood. Here, we characterize an Arabidopsis RTNLB16 T-DNA allele, rtnlb16-1, that exhibits severe photoperiod-dependent growth retardation and chlorosis. Molecular analysis revealed that rtnlb16-1 is not a simple loss-of-function mutant: the T-DNA insertion deletes the 5′ region required for RTNLB16 splice variant 7, while a CaMV35S enhancer associated with the insertion drives overexpression of the remaining splice variants. This misexpression is enhanced under long-day photoperiods and reduced under continuous low light, paralleling the severity of the mutant phenotype and its partial rescue. RTNLB16.5-GFP localized mainly to the tubular ER network and punctate cell-boundary structures consistent with plasmodesmata-associated ER. Neither overexpression of RTNLB16 isoforms 1–6 nor CRISPR-Cas9 disruption of major RTNLB16 isoforms reproduced the rtnlb16-1 phenotype, supporting a model in which altered splice-variant stoichiometry, rather than simple loss or gain of function, underlies the developmental defects. Transcriptome profiling showed that rtnlb16-1 undergoes extensive photoperiod-dependent transcriptional reprogramming, including changes in defense, hormone-response, senescence, photosynthesis, and iron/redox-associated gene networks. Physiologically, rtnlb16-1 displayed enhanced recovery from dark-induced senescence, while both rtnlb16-1 and rtnlb16-2 showed reduced sensitivity to exogenous abscisic acid during germination. Together, these findings suggest that balanced expression of RTNLB16 splice variants is important for normal growth and for coordinating ER-associated stress, hormone, and senescence responses in Arabidopsis. Full article

Virus infection requires coordinated activation of pathogen-sensing, innate immune, and cellular stress response pathways to mount an effective antiviral defense. Recognition of nucleic acid pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) initiates signaling cascades that drive the production of type I interferons (IFNs) and proinflammatory cytokines. These responses are often accompanied by the activation of integrated stress response pathways that help optimize host defense. Cytosolic double-stranded dsDNA, generated during viral infection or released from damaged mitochondria, is sensed by cyclic GMP-AMP synthase (cGAS), which generates 2′3′-cGAMP to activate stimulator of interferon genes (STING). Activated STING translocates from the endoplasmic reticulum to the Golgi, where it drives TBK1-dependent IFN and cytokine production. Previous reports show that cGAS activity is enhanced by Ras-GAP SH3 domain binding protein 1 (G3BP1), a key nucleator of stress granules (SGs), independent of its role in SG assembly. Here, we identify a non-canonical role of G3BP1 as a regulator of DNA sensing responses at multiple levels, including STING intracellular trafficking, in addition to potentiating cGAS activity. Loss of G3BP1 impaired STING-dependent IFN and cytokine responses to HSV-1 infection and viral DNA. G3BP1-deficient cells showed reduced cGAMP-induced STING translocation to the Golgi, induction of type I IFN and proinflammatory cytokines, and activation of the ER stress kinase PERK and stress granule formation. Together, these findings demonstrate G3BP1-STING as a node linking DNA sensing, innate immunity, and stress signaling with broad implications for antiviral defense and diseases characterized by aberrant DNA sensing and stress responses, including neurodegeneration, fibrosis, and autoimmunity. Full article

Background: Minimal change disease (MCD) is a leading cause of childhood nephrotic syndrome. Endoplasmic reticulum stress (ERS) and autophagy are implicated in its pathogenesis, but the precise mechanisms remain unclear. This study aimed to identify ERS and autophagy-related key genes (ERS-RGs and ARGs) in MCD using bioinformatic and experimental approaches. Methods: Transcriptomic data from GSE216841 and GSE246206 were analyzed. ERS-RGs and ARGs were obtained from prior literature. Candidate genes were selected by integrating weighted gene coexpression network analysis and differential expression analysis. Feature genes were identified via protein–protein interaction network analysis and machine learning (Least Absolute Shrinkage and Selection Operator and Boruta). Key genes were validated by expression analysis and receiver operating characteristic evaluation. A multilayer perceptron (MLP) model was constructed, and regulatory networks, immune infiltration, and chemical compound prediction were analyzed. The expression levels of the identified key genes were preliminarily assessed in peripheral blood samples using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: LIG4 and ZRANB3 were identified as key genes, both significantly downregulated in the MCD group, and the gene-based MLP model effectively predicted MCD probability. Overall, 13 significantly different immune cell types (e.g., CD56⁺ natural killer and activated dendritic cells) were detected. Regulatory networks (transcription factor-messenger RNA (mRNA) and long non-coding RNA-microRNA-mRNA) and 8 common chemical compounds (e.g., bisphenol A, acetaminophen) targeting these genes were predicted. Notably, peripheral blood RT-qPCR analysis revealed significant LIG4 and ZRANB3 downregulation, suggesting a systemic expression signature. Conclusion: LIG4 and ZRANB3 are key genes associated with ERS and autophagy in MCD, providing insights for diagnosis and targeted therapy. Full article

Ryanodine receptor-like (RyR-like) is a key endoplasmic reticulum (ER) Ca²⁺ release channel governing intracellular Ca²⁺ homeostasis and cellular stress responses in invertebrates. However, its function in bivalves under high-temperature stress remains unclear. In the present study, one RyR-like was identified from Yesso scallop Patinopecten yessoensis (PyRyR-like). Its function in regulating intracellular Ca²⁺, IRE1α-mediated unfolded protein response (UPR) and apoptosis in the mantle after high-temperature (25 °C) treatment was investigated using molecular cloning, qRT-PCR, Western blot, pull-down assay, cellular calcium imaging, TUNEL and histology assays; High temperature treatment significantly increased intracellular Ca²⁺ content at 1 and 6 h (p < 0.05), but decreased it at 3, 12 and 24 h (p < 0.05); meanwhile, the cAMP level, PyPKA activity, mRNA expression level of PyRyR-like, and protein expression levels of PyFKBP12 and PyGRP78 were significantly increased at different times. However, high temperature did not affect the expression level of PyNVL and PyXBP1(S). The SPRY and RYR domains of PyRyR-like separately interacted with PyFKBP12 and PyPKA. Moreover, RyR antagonist Dantrolene reversed high-temperature-induced alterations in Ca concentration, PKA activity, and core UPR- and apoptosis-related molecules, and suppressed Caspase-3 activity. These findings suggest that PyRyR-like plays an important role in the high-temperature response of scallops by regulating intracellular Ca²⁺ homeostasis and mediating UPR activation and apoptosis, providing new insight into the molecular mechanism underlying scallop adaptation to high temperature. Full article

Obesity exhibits pronounced sex-dependent differences in susceptibility and progression; however, the molecular mechanisms coordinating central energy sensing with peripheral thermogenic responses remain incompletely defined. Selenoprotein F (SELENOF), an endoplasmic reticulum (ER)-resident member of the selenoprotein family involved in protein quality control and redox-sensitive metabolic regulation, has not previously been investigated in the context of diet-induced obesity. In the present study, WT and SELENOF-deficient mice subjected to a 16-week high-fat diet (HFD) were combined with primary brown adipocyte experiments to determine the role of SELENOF in systemic metabolic homeostasis. SELENOF deficiency markedly aggravated HFD-induced weight gain, adipose tissue expansion, dyslipidemia, and hyperleptinemia selectively in female mice, whereas no genotype-dependent effects were observed in males. Mechanistically, SELENOF deficiency intensified hypothalamic ER stress and leptin resistance, as reflected by increased GRP78, p-IRE1α, and p-PERK expression together with SOCS3 upregulation, reduced STAT3 phosphorylation, and activation of the IKK/NF-κB inflammatory pathway. In parallel, SELENOF deficiency reduced circulating free triiodothyronine (FT₃) levels and the ratio of free triiodothyronine to free thyroxine (FT₃/FT₄ ratio), and suppressed DIO2 and UCP1 expression in brown adipose tissue (BAT). Experiments in primary brown adipocytes further showed that SELENOF deficiency did not disrupt proximal β3-adrenergic signaling but attenuated the downstream induction of DIO2 and UCP1. Collectively, these findings provide preliminary evidence that SELENOF is associated with sex-dependent metabolic adaptation during HFD-induced stress by linking hypothalamic proteostasis with the thyroid hormone-related thermogenic signaling program in BAT. Full article

Endoplasmic reticulum (ER) stress is a common state of cellular adversity experienced by tumor cells under unfavorable conditions such as hypoxia, nutrient deprivation, and oncogene activation. As the most conserved signaling branch of the unfolded protein response (UPR), the inositol-requiring enzyme 1α (IRE1α)- X-box-binding protein 1 (XBP1) pathway plays a central role in sustaining tumor cell survival, driving malignant progression, and remodeling the tumor microenvironment (TME). XBP1, the terminal transcription factor of this pathway, finely orchestrates tumor cell fate through both its canonical and non-canonical functions. This review systematically summarizes the dual mechanisms of XBP1 in cancer: within cancer cells, XBP1 promotes proliferation, metastasis, and chemoresistance via metabolic reprogramming, anti-apoptotic proteins, and DNA repair; within immune cells (macrophages, dendritic cells, T cells), XBP1 fosters an immunosuppressive microenvironment, while also modulating cancer-associated fibroblasts, endothelial cells, and osteoclasts. Despite its therapeutic promise, several major unresolved questions remain, including the precise molecular switch governing XBP1’s pro-tumorigenic versus anti-tumorigenic functions, the functional divergence between XBP1u and XBP1s isoforms in different cellular contexts, and the lack of reliable predictive biomarkers for patient stratification. Key translational challenges involve the on-target toxicity of systemic XBP1/IRE1α inhibition due to its essential roles in normal tissues, the cell-type-specific and context-dependent effects that complicate therapeutic outcomes, and the limited selectivity and off-target effects of current inhibitors, as well as compensatory activation of other UPR branches that may drive adaptive resistance. Finally, this review discusses XBP1-targeted therapeutic strategies, including small-molecule inhibitors, nucleic acid-based drugs, immunotherapeutic combination approaches, and XBP1-based tumor vaccines, and provides perspectives on future research directions, aiming to establish a theoretical foundation for the development of more effective and precise XBP1-targeted therapies for tumorigenesis and cancer progression. Full article

Ferroptosis has emerged as a critical mechanism linking iron dysregulation, oxidative stress, and neurodegeneration in amyloid-associated pathologies. Building on our previous work, which identified compound 20 as a promising antioxidant and neuroprotective agent, the present study investigates the molecular mechanisms underlying its protective activity against amyloid-induced ferroptosis in human neuroblastoma SH-SY5Y cells exposed to Aβ(25–35). Compound 20 (3-(((4-hydroxybenzyl)(methyl)amino)methyl)-1-methyl-N-(2-(piperazin-1-yl)ethyl)-1H-indole-5-carboxamide) markedly counteracted Aβ(25–35)-induced ferroptotic damage by restoring intracellular glutathione levels, depleting the labile iron pool, and suppressing lipid peroxidation. In parallel, the compound significantly rescued mitochondrial membrane potential and attenuated endoplasmic reticulum (ER) expansion associated with ER stress, thereby preserving cellular homeostasis under oxidative challenge. These protective effects were further corroborated by real-time PCR analysis, which revealed the modulation of key genes involved in the oxidative stress response, endoplasmic reticulum stress, and inflammatory pathways. To gain a systems-level insight into these mechanisms, untargeted ¹H-NMR metabolomic profiling was performed. This analysis confirmed the activation of antioxidant pathways and disclosed a significant modulation of energy metabolism and GABA-related pathways, both of which are closely linked to redox balance and neuronal resilience. Overall, these findings demonstrate that compound 20 drives metabolic reprogramming that orchestrates its multifactorial protective effect against Aβ(25–35)-induced ferroptosis by coordinating antioxidant defense, iron homeostasis, and ER stress mitigation. Full article

Palmatine chloride (berbericinine, C₂₁H₂₂ClNO₄) is a protoberberine alkaloid found in several plants, including Rhizoma Coptidis, Cortex Phellodendri, Rhizoma Corydalis, Guduchi (Tinospora cordifolia), and Tinospora sagittata roots. Palmatine chloride (PA) is known as an inhibitor of dopamine generation. However, its effect on endoplasmic reticulum (ER) stress-related macrophage activation caused by endotoxin (lipopolysaccharide) is not yet well known. In this study, the effects of PA on pyroptotic responses of mouse macrophages (RAW 264.7) activated by endotoxin were investigated using Griess reagent assay for nitric oxide (NO) production, fluo-4 assay for cytosolic calcium release, dihydrorhodamine 123 assay for hydrogen peroxide production, multiple cytokine assay for cytokine production, real-time PCR for inflammatory gene transcriptions, and flow cytometry assay for p38 MAPK activation. Preliminary experiments using THP-1 human monocytic cells demonstrated that PA was not cytotoxic and significantly reduced basal NO production. Results revealed that PA significantly reduced excessive production levels of NO, hydrogen peroxide, pro-inflammatory cytokines (such as interleukin (IL)-6, CCL3 (MIP-1α), and CSF2 (GM-CSF)), and cytosolic calcium release in endotoxin-stimulated RAW 264.7, but significantly increased the production of anti-inflammatory cytokine IL-10. PA inhibited endotoxin-induced transcripts of Chop, Stat1, Fas, and c-Fos in activated RAW 264.7. It also decreased p38 MAPK phosphorylation and level of Fas in RAW 264.7 stimulated by endotoxin. To further interpret these findings, a network pharmacology-informed analysis based on large-scale literature mining was performed, supporting the multi-target regulatory role of PA in ER stress-related pathways. Briefly, PA exerts anti-inflammatory effects on endotoxin-stimulated RAW 264.7 via the calcium-CHOP pathway, consequently reducing endotoxin-induced production of pro-inflammatory mediators (NO, cytokines, etc.) and relieving ER stress-related pyroptotic cascade. Full article

Persisting ethnic disparities in pre-eclampsia (PE), cardiovascular disease (CVD), and maternal mortality call for a paradigm shift in how ethnicity is understood as a risk factor for PE. Starting from a migrant perspective, we argue that the transgenerational experience of maternal stress within shared, yet dynamic ecosocial contexts can be linked to core pathophysiological features of PE. A growing body of evidence suggests how a vicious cycle of chronic maternal stress, cardiovascular dysfunction, placental ER stress, and endothelial dysfunction may serve as a catalyst for the transmission of altered cardiovascular and neuro-endocrine stress reactivity patterns across generations, with a seemingly important role for foetal programming and epigenetics. As these alterations in stress reactivity patterns have in turn been associated with an increased risk of PE and CVD later in life, the resulting transgenerational chain reaction may ultimately allow for ethnic disparities in PE to be traced back to historic, stressful moments in the shared ecosocial contexts of ethnic minority women. Reconceptualising ethnicity as a proxy for the stratified and embodied experience of transgenerational maternal stress within its unique ecosocial contexts, rather than a stand-alone, non-modifiable risk factor, will therefore open new directions for future research, clinical care, and policy interventions aimed at advancing maternal health equity. Full article

Background: Gentamicin-induced nephrotoxicity limits clinical pharmacotherapy and involves multiple converging stress-response pathways. Ellagic acid (EA) has renoprotective potential, yet its role in coordinating endoplasmic reticulum (ER) stress-mediated apoptosis, autophagy, and inflammation remains unclear. We hypothesized that EA co-treatment would protect the kidney by modulating ER stress-dependent pathways and associated inflammatory and adaptive signaling. Methods: For an integrated mechanistic analysis in a rat model of gentamicin nephrotoxicity, 40 male Sprague-Dawley rats were assigned to control, gentamicin (100 mg/kg), EA (100 mg/kg), and gentamicin + EA groups for 14 days. Renal function, oxidative stress, inflammatory mediators, ER stress markers, apoptosis, autophagy, tubular injury markers, and histopathological changes were assessed. Results: Gentamicin induced renal dysfunction, tubular injury, and ER stress across all unfolded protein response (UPR) branches (IRE1α, PERK, ATF6), C/EBP homologous protein (CHOP)-associated apoptosis, dysregulated autophagy, and upregulated kidney injury molecule-1 (KIM-1). A selective inflammatory signature was observed, with increased cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6), whereas tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) remained unchanged. Co-administration of ellagic acid with gentamicin significantly improved renal function markers compared to the gentamicin group. In contrast, ellagic acid alone did not show significant differences compared to the control group. Notably, gentamicin induced compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) expression, while ellagic acid co-treatment attenuated this compensatory upregulation, likely secondary to reduced oxidative stress burden. Conclusions: This study provides integrated evidence that ER stress is closely associated with gentamicin nephrotoxicity. The key novel findings include selective suppression of IL-6, modulation of the apoptosis-autophagy balance, and attenuation of Nrf2/HO-1 signaling without direct reactive oxygen species (ROS) scavenging, demonstrating a multi-target framework for EA’s renoprotective effects. These findings suggest that ellagic acid mitigates renal injury in a context-dependent manner rather than confirming a direct causal mechanism. Full article