Stress Signaling Research Articles

Activation of cytosolic nucleic acid-sensing pathways represents a promising strategy to convert immunologically "cold" tumors into inflamed ones. Iron-sulfur (Fe-S) enzymes are critical regulators of innate immunity and nucleic acid sensing, yet their roles in cancer remain poorly defined. Here, ferredoxin-1 (FDX1), a mitochondrial Fe-S protein frequently downregulated in clear cell renal cell carcinoma (ccRCC), is identified as a dual regulator of ferroptosis and antitumor immunity. FDX1 overexpression triggers mitochondrial permeability transition pore opening, leading to cytosolic release of mitochondrial DNA (mtDNA) and double-stranded RNA (mt-dsRNA). This reveals an independent function of FDX1 as a tumor-intrinsic immunity activator linked to mitochondrial stress signaling. These damage-associated molecular patterns (DAMPs) engage cytosolic nucleic acid sensors-specifically cGAS and RIG-I/MDA5-triggering TBK1 phosphorylation and a robust type I interferon response that occurs prior to overt ferroptosis. This innate immune cascade reshapes the tumor microenvironment by enhancing MHC I/II antigen presentation, recruiting CD8+ T cells, and suppressing tumor growth and metastasis in orthotopic syngeneic models. These findings uncover a previously unrecognized antitumor axis through which FDX1 synergizes with mitochondrial nucleic acid release with ferroptosis to promote immunogenic inflammation and T cell infiltration in ccRCC, offering novel therapeutic opportunities targeting mitochondrial-immune crosstalk.

Drug-Induced Liver Injury (DILI) is the leading cause of late-stage drug failure and withdrawal of medications from the market. This underscores the urgent need for newin vitroliver models that better recapitulate physiologically relevant conditions and provide controlled physical and biochemical parameters for drug toxicity testing. While advanced, complex liver-on-a-chip systems have been in use for some years, this study presents a simplified microfluidic model for technically comparing static and dynamic culture conditions using a hepatocyte-like cell line for drug toxicity testing. In this study, a dual-compartment microfluidic device comprising a dynamic flow channel and a cell culture chamber was designed to mimic the liver's microstructure. The device's membrane-based design enabled the investigation of cell-media interactions and replication of hepatic Disse space, with comparisons made between static and dynamic conditions. The chip design was evaluated using computational models of glucose consumption and shear stress, which yielded an optimal flow rate of 50 μL/h. HepG2 cells cultured within the chip were assessed via live/dead staining and metabolic function assays, including responses to three antiepileptic drugs at physiological doses, to evaluate hepatotoxicity. Under dynamic conditions, cell viability and function improved significantly, simulating a continuous supply of nutrients and oxygen, as well as mechanical shear stress signaling. Among the tested drugs, sodium valproate (500 μM) induced the least hepatotoxicity, whereas carbamazepine and phenytoin led to a ∼60% reduction in hepatic function over one week. Although structurally and functionally less complex than existing liver-on-a-chip platforms, these findings suggest that this liver-chip platform is a simple yet useful tool for drug screening and hepatotoxicity assessment.

Salt stress is a critical abiotic factor that impairs crop seed germination and limits agricultural productivity. Elucidating the mechanisms governing salt tolerance is essential for development of salt-tolerant crop varieties. In this investigation, 217 accessions of highland barley ( Hordeum vulgare var. coeleste Linnaeus ) were evaluated. Germination assays conducted under 200 mmol/L and 500 mmol/L NaCl conditions identified a salt-tolerant variety 37 and a salt-sensitive variety 44. By integrating transcriptome sequencing, 16S rRNA sequencing, and Na + /K + content analysis, we systematically investigated the molecular mechanisms underlying salt-tolerant germination in highland barley seeds. Our findings revealed that the salt-tolerant variety 37 maintained a high germination rate of 98% under 500 mmol/L NaCl stress, with lower Na + accumulation (4.24 g/kg) and a lower Na + /K + ratio (2.59) compared to the salt-sensitive variety 44 (Na + accumulation: 4.89 g/kg, Na + /K + ratio: 3.62). Analysis of 16S rRNA sequencing data showed a significant increase in the abundance of the endophytic bacterium Brevundimonas in salt-tolerant variety 37 under high-salt conditions, which was positively correlated with K + content. In contrast, the dominant bacterium Rhodococcus in salt-sensitive variety 44 exhibited a positive correlation with Na + content and the Na + /K + ratio. Transcriptome sequencing identified 1,467 and 1,644 differentially expressed genes (DEGs) in salt-tolerant variety 37 and salt-sensitive variety 44, respectively. Pathway enrichment analysis indicated that DEGs in salt-tolerant variety 37 were primarily associated with “potassium ion homeostasis” and “response to oxidative stress”. Weighted gene co-expression network analysis (WGCNA) identified 5 co-expression modules, among which the MEyellow module was correlated with Na + content (r = 0.59). Ten core genes were identified, including WRKY transcription factor ( HORVU.MOREX.r3.3HG0268090 ) and receptor protein kinase (RPK; HORVU.MOREX.r3.4HG0331910 ). A total of 174 HvRPK genes were identified, distributed across 7 chromosomes with a predominant localization on chromosome 2. These genes exhibited functional conservation and were involved in salt stress signaling pathways. Phylogenetic, collinearity, and cis-element analyses further supported their regulatory role in salt stress responses. This study clarifies the key mechanisms underlying salt-tolerant germination in highland barley seeds, providing valuable insights and genetic resources for the molecular breeding of salt-tolerant crops.

FCA Contributes to Root Thermomorphogenesis by Attenuating SOG1-Mediated Stress Signaling in Arabidopsis

In response to various intracellular stress or damage-associated signals, inflammasomes can be activated and trigger a pyroptotic cell death process through the sequential assembly of structurally compatible and interacting filamentous oligomers involving the pyrin domains (PYD) of important inflammasome components. The PYD-containing interferon-inducible protein 16 (IFI16) has been suggested as a viral DNA sensor that can induce inflammasome formation, but it also has other inflammasome-independent functions, including interferon production. Here, the cryo-EM structure of the filament assembled by the PYD of human IFI16 reveals a helical architecture distinct from inflammasome PYD filaments. In silico interface energy calculations suggest that the helical architecture of the IFI16PYD filament prevents interactions with inflammasome PYD filaments. Biochemical and cell biology experiments consistently demonstrate that IFI16 does not directly interact with inflammasome pyrin domains. Together, our results provide insights into the structural basis of the inflammasome-independent functions of IFI16, and also show that strict architectural compatibility requirements for interactions contribute to the signal transduction specificity in inflammasome signaling.

Endometriosis is increasingly recognized as a systemic inflammatory disease rather than a localized gynecological disorder. This review integrates recent molecular and clinical evidence demonstrating how chronic inflammation, oxidative stress, and extracellular vesicle (EV) signaling interact to shape both local and systemic pathophysiology. Elevated cytokines such as IL-1β, IL-6, TNF-α, IL-8, MCP-1, and VEGF sustain angiogenesis, immune activation, and lesion persistence, while diminished IL-10 impairs immunoregulation. Concurrently, oxidative stress arising from peritoneal iron overload and mitochondrial dysfunction amplifies inflammatory signaling through NF-κB and TGF-β/SMAD pathways, promoting fibrosis, apoptosis resistance, and nociceptor sensitization. Recent discoveries highlight EVs as mediators of systemic communication, transferring microRNAs and proteins that modulate immune, endothelial, and neural targets, thereby linking pelvic inflammation to cardiovascular, metabolic, and autoimmune comorbidities. Evidence from multiple studies indicates that endometriosis confers elevated risks of hypertension, dyslipidemia, autoimmune disorders, and mood disturbances—hallmarks of systemic immune and vascular dysregulation. Furthermore, chronic oxidative and inflammatory exposure fosters genomic instability, explaining the observed association with ovarian clear-cell and endometrioid carcinomas. Recognizing endometriosis as a multisystemic disorder supports the development of integrative diagnostic and therapeutic strategies, including cytokine and exosomal biomarker panels and targeted anti-inflammatory, antioxidant, and anti-angiogenic treatments. Contributions from Mexico, Colombia, and Ecuador emphasize the need for regionally inclusive research and precision-medicine approaches. Endometriosis thus emerges as a model of systemic inflammation, exemplifying how immune, oxidative, and endocrine networks converge to produce both reproductive and extra-pelvic disease manifestations.

Background: Fragility of the ascending aortic wall has been observed in patients with aortic regurgitation (AR), possibly due to turbulent retrograde flow. However, the underlying cellular and structural mechanisms remain unclear. To investigate the effects of AR-induced retrograde flow on endothelial cells (ECs) and smooth muscle cells (SMCs) in the ascending aorta, we developed a catheter-based AR model in rats and performed histological and single-cell analyses. Methods: AR was induced in 10-week-old Sprague–Dawley rats by echocardiography-guided perforation of the aortic valve via the right common carotid artery. Sham-operated controls underwent the same procedure without valve injury. Ascending aortic tissues were collected at 1, 2, and 4 weeks for histological analysis. EC polarity was assessed by whole-mount immunohistochemistry at one week. Single-cell RNA sequencing (scRNA-seq) was performed on aortic tissues, with differential gene expression and pathway enrichment analyzed using Seurat and clusterProfiler. Results: Confocal imaging revealed that ECs in AR rats showed disrupted polarity and a more rounded morphology compared to controls. Quantitative analysis demonstrated significantly reduced aspect ratio and cell orientation angle in the AR group. Histological analysis showed progressive medial degeneration by 4 weeks, including elastic fiber fragmentation, mucopolysaccharide accumulation, and fibrosis. Picro-Sirius Red staining demonstrated a significant increase in fibrotic area at 4 weeks. Furthermore, serial echocardiography revealed time-dependent dilation of the ascending aorta in AR rats. ScRNA-seq revealed that ECs downregulated shear stress–responsive and anti-inflammatory genes. SMCs showed decreased expression of contractile markers and extracellular matrix (ECM) remodeling genes. Gene Ontology analysis revealed upregulation of inflammatory signaling and suppression of shear stress–responsive pathways in ECs. ECs also exhibited increased Wnt and TGF-β signaling—pathways known to drive SMC phenotypic switching—which was accompanied by phenotypic modulation and impaired ECM remodeling in SMCs. Conclusion: AR-induced retrograde flow leads to early EC polarity disruption and progressive medial degeneration in the ascending aorta. These structural changes are accompanied by shear stress–dependent transcriptional suppression in ECs and phenotypic modulation in SMCs, potentially contributing to aortic wall fragility.

Background: Cancer treatment is increasingly recognized as a contributor to elevated cardiovascular disease risk. Ceramides, small bioactive lipids, play a critical role in various cellular processes, including apoptosis, oxidative stress, and inflammatory signaling pathways. Elevated circulating levels of ceramides have been associated with heart failure, underscoring their potential relevance in cancer therapy-related cardiac complications. Objective: We sought to assess whether circulating ceramides were associated with the risk of left ventricular dysfunction in women with breast cancer undergoing potentially cardiotoxic chemotherapy. Methods: This study is a secondary analysis of the UPBEAT trial (WF97415), which enrolled adult women with stage I to III breast cancer undergoing cancer therapy. Plasma ceramide levels were measured at baseline and again three months after the initiation of chemotherapy. Ceramide abundance was quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cardiovascular magnetic resonance imaging was used to evaluate left ventricular ejection fraction (LVEF), allowing for the stratification of participants into two groups: those who experienced an LVEF decline of ≥10%, and those who did not. Results: We studied 170 women, 56±11 years old; patients with ≥10% decline in LVEF showed an increase in C18:1/C16:0 ceramide ratio over 3 months of therapy compared to patients without LVEF decline (OR, 1.736, 95% CI, 1.164 – 2.590). These changes were independently associated with an increased risk of LVEF decline even after adjustment for age, race, cancer stage (OR, 1.689, 95% CI, 1.125 – 2.537), total cholesterol and triglyceride level (OR, 1.799, 95% CI, 1.194 – 2.717, C-Reactive Protein (OR, 1.671, 95% CI, 1.133 – 2.465), underlying comorbidities, such as hypertension, hyperlipidemia, diabetes, stroke, coronary artery disease, and smoking (OR, 1.652, 95% CI, 1.122 – 2.432), or receipt of potentially cardioprotective drugs (OR, 1.664, 95% CI, 1.127 – 2.457). Conclusions: This finding suggests that disruptions of the relative abundance of the different species of ceramides may play a significant role in the development of chemotherapy-induced cardiotoxicity. Ceramide profiling could offer a promising avenue for early identification of patients at higher risk for cardiac dysfunction, potentially guiding more personalized monitoring and cardioprotective strategies.

Introduction: Liver dysfunction contributes to cardiovascular disease (CVD) and metabolic dysfunction-associated steatohepatitis (MASH), characterized by fat accumulation, inflammation, and fibrosis. MASH co-occurs with obesity and diabetes, increasing mortality and CVD risk. As the final reversible stage before cirrhosis, MASH lacks effective treatments. Temporal dynamics and cell-cell crosstalk mechanisms remain unclear. Methods: We used a mouse MASH model induced by a choline-low, high-fat, high-sucrose diet, collecting liver tissues at weeks 1, 4, 8, and 12. Histologic, immunologic, physiologic, and single-cell transcriptomic analyses tracked disease progression. Custom quantification tools detected chronic-phase changes. Results: Progressive liver pathology developed in MASH-fed mice. Week 4 showed liver dysfunction and hepatomegaly; week 8 revealed steatosis and fibrosis, mirroring human MASH. Single-cell transcriptomics revealed hepatic and immune compartments remodeling. Kupffer cells recruited monocytes maturing into macrophages by week 1. T cell infiltration peaked at weeks 8-12. Hepatocyte stress and fibrotic signaling began at week 8. Trajectory analysis and MacSpectrum showed both monocytes and Kupffer cells contributed to inflammatory macrophages. By week 8, both expanded and expressed pro-inflammatory, fibrogenic genes. Cell-cell interactions intensified weeks 8–12, with greater immune signaling diversity and strength. Macrophages became key signal recipients, integrating an expanding ligand repertoire. Hepatocytes signaled immune cells by week 1 and assumed a coordinating role by week 8. Lgals9, Tgfb1, and Thbs1 showed temporal activation, shifting from immune-restricted to broader hepatocyte/myeloid targets. These interactions paralleled fibrosis and revealed a temporally orchestrating signaling network. Conclusion: Temporal transcriptomic and physiologic profiling reveals dynamic liver cell shifts with early myeloid infiltration and evolving immune-parenchymal interactions. The weeks 8–12 transition aligns with metabolic stress, immune dysregulation, and fibrosis. As a CVD risk factor, MASH involves chronic inflammation and macrophage reprogramming—offering insight into systemic disease.

Prostate cancer (PCa) has long been classified as an androgen-driven malignancy; however, mounting evidence underscores the pivotal role of estrogen in its initiation, progression, and therapeutic resistance. This review establishes that PCa exhibits intrinsic estrogen dependence through intratumoral aromatization, positioning it within the spectrum of estrogen-driven malignancies. Through integrative molecular analyses, we elucidate how estrogen orchestrates metabolic reprogramming, shifting prostate tumors toward enhanced lipid oxidation and glucose uptake a hallmark of glucolipotoxicity. Mechanistically, estrogen signaling, primarily via the PI3K/AKT pathway, drives the upregulation of carnitine palmitoyltransferase 1 and glucose transporter 1, fueling a metabolic storm characterized by oxidative stress, mitochondrial dysfunction, and chronic inflammatory signaling. This metabolic adaptation enables androgenindependent survival, presenting a critical vulnerability overlooked by conventional androgen-targeted therapies. Our findings necessitate a paradigm shift in the classification and treatment of PCa, advocating for a novel therapeutic framework targeting the estrogen–metabolic axis. We propose a precision strategy integrating aromatase inhibition, estrogen receptor blockade, and metabolic stress modulation to counteract castration-resistant disease. Recognizing PCa as an estrogen-driven, metabolically adaptive malignancy transforms its clinical understanding and therapeutic approach, demanding urgent reconsideration of current oncologic paradigms.

Backround: There is a life expectancy disparity of nearly 20 years in sickle cell disease (SCD) patients. Cardiovascular and pulmonary complications are major contributors to mortality with acute chest syndrome (ACS) being one of the most common causes of death. Hemin, the oxidized moiety of hemoglobin and a product of SCD-associated hemolysis, has been implicated in the pathogenesis of ACS in our work due to its effects on endothelial barrier integrity through induction of necroptosis. Hypothesis: We hypothesized that hemin treatment in human pulmonary arterial endothelial cells (hPAECs) would induce important transcriptomic changes that can be linked to mechanisms of ACS in SCD. Methods: HPAECs were treated with hemin (40 uM) or control saline for 4 hours. RNA was processed, purified, and submitted for RNA sequencing (Illumina NovaSeq X). 15,042 genes were counted and were determined to be significantly differentially expressed if false discovery rate was <0.1. Pathway analysis was done with STRING Protein-Protein Interaction Network and Ingenuity Pathway Analysis (IPA). Significant genes were clustered with Markov clustering (inflation parameter = 3). Results: Hemin treatment leads to upregulation of the necroptosis-associated protein MLKL and endothelial barrier dysfunction is confirmed by a drop in trans-endothelial resistance. RNA sequencing identified 147 differentially expressed genes. Heme oxygenase-1 ( HMOX1 ) was the most significantly upregulated gene (fold change >20). Caspase 8 Associated Protein 2 ( CASP8AP2 ) was a top five downregulated gene. The top Gene Ontology pathway was response to lipopolysaccharide (LPS). The top KEGG pathway and STRING cluster was TNF signaling and included key inflammatory chemokines ( CXCL1 , CXCL2 , CXCL3 , CCL2 ), cytokines ( IL-1A , IL-6 ) and transcription factors ( NRF2 ). Using IPA, oxidative stress signaling and NRF2-mediated oxidative stress response pathways were identified as key toxicology and disease process pathways. Conclusions: RNA sequencing analysis identifies multiple pathways by which hemolysis may contribute to the pathogenesis of ACS in SCD. Hemin-treated hPAECs demonstrate differential expression of key mediators in necroptosis ( CASP8AP2, NRF2 ), the inflammatory response ( CXCL1, IL1A, IL-6) and response to LPS, which is TLR4 mediated . Increased oxidative stress signaling may suggest a role for targeting necroptosis through anti-inflammatory mediators, including heme oxygenase and NRF2, in the treatment of ACS.

Objective: Heart failure with preserved ejection fraction (HFpEF) is a major global health problem with limited therapeutic options. Despite its high prevalence, the molecular mechanisms underlying HFpEF remain poorly understood. We hypothesize that disruption of calcium homeostasis induces endoplasmic reticulum (ER) stress via localized intracellular β-adrenergic receptor (βAR) interaction with phosphodiesterases 4D (PDE4D) in HFpEF. Methods and Results: Wild-type mice were fed a high-fat diet (HFD) and N(ω)-nitro-L-arginine methyl ester (L-NAME) to induce HFpEF. Echocardiography was used to assess diastolic function via the E/E' ratio (early diastolic transmitral flow velocity to early diastolic mitral annular velocity). Treatment with the PDE4D inhibitor Zatolmilast significantly reduced E/E' compared to saline-treated HFpEF controls, indicating improved diastolic function. Sirius Red staining showed marked interstitial and perivascular fibrosis in HFpEF hearts, which was attenuated by Zatolmilast. Adult cardiomyocytes were isolated from normal chow (NC), HFpEF, and HFpEF+Zatolmilast mice and analyzed using FRET-based PKA biosensors and excitation-contraction coupling (ECC) assays. In HFpEF cardiomyocytes, PDE4D was upregulated and showed increased association with β1AR at the ER/SR, resulting in localized cAMP degradation. PDE4D inhibition restored β1AR-mediated PKA activity and improved calcium handling, as evidenced by shortened decay tau during calcium reuptake. Moreover, ER stress markers were assessed by qPCR and Western blot. HFpEF hearts displayed elevated PERK, ATF4, and CHOP expression, which were reduced following Zatolmilast treatment. The phosphorylation of IRE-α was increased after PDE4D inhibition. Conversely, PDE4D overexpression alone was sufficient to elevate PERK, ATF4, and CHOP while decreasing IRE-α phosphorylation, implicating PDE4D as a direct modulator of ER stress signaling. To further validate these findings, we generated cardiac-specific PDE4D knockout (cKO) mice and induced HFpEF. Compared to floxed controls, PDE4D cKO mice showed improved diastolic function (lower E/E’), supporting the therapeutic relevance of PDE4D deletion in HFpEF. Conclusion: These findings identify PDE4D as a key mediator of ER stress and cardiac dysfunction in HFpEF. Inhibition or genetic deletion of cardiac PDE4D alleviates ER stress, improves calcium handling, and restores diastolic function, highlighting PDE4D as a promising therapeutic target in HFpEF.

Amyloid-beta (Aβ) aggregation is the key component of neuritic plaques that drives Alzheimer's disease (AD) progression and cognitive decline. Although synaptic dysfunction strongly correlates with cognitive impairment, its underlying mechanisms remain unclear. Recently, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key contributor to AD pathology, and xanthurenic acid (XA), a naturally occurring end-product of the KP, has been implicated in neuroprotection. In this study, we investigated the neuroprotective effects of intranasally administered XA in an Aβ-induced AD mouse model. AD-like pathology was induced in mice by intracerebroventricular injection of Aβ1-42. The mice received daily intranasal instillation of XA (0.5 μg/5 μL per nostril) for 6 weeks. After XA treatment was completed, the cognitive performance was assessed in behavioral tests, then the mice were euthanized, and the brain were collected for molecular and biochemical analyses. We showed that XA treatment significantly improved the cognitive function of AD mice, and reduced AD-related pathological markers such as APP, Aβ and BACE-1 in the cortex, hippocampus and olfactory bulb. XA treatment also attenuated Aβ-induced oxidative stress through upregulation of the Nrf2/HO-1/SOD1 and key enzymatic antioxidants (GSH, GST, CAT, SOD), while concurrently reducing lipid peroxidation. Furthermore, XA treatment preserved synaptic integrity, evidenced by restoring both pre- and postsynaptic markers (SNAP-25, SYP, SNAP-23, PSD-95) and enhancing signaling via the cAMP-PKA-CREB pathway. Notably, XA differentially modulated metabotropic glutamate receptors, decreasing mGluR2 and increasing mGluR3 expression. In vitro experiments were conducted in APPswe/ind-transfected SH-SY5Y neuroblastoma cells. XA (3-100 µM) dose-dependently improved the cell viability while reducing cytotoxicity and apoptosis. Overall, these results demonstrate that XA confers multifaceted neuroprotection by modulating Aβ pathology, oxidative stress, synaptic function, and glutamatergic signaling, suggesting its potential as a novel therapeutic strategy to mitigate cognitive decline and pathological progression in AD.

Dry eye disease (DED) is a highly prevalent multifactorial disorder of the ocular surface that extends beyond local tear film pathology to involve systemic immune, neuroendocrine, and neurosensory mechanisms. Increasing evidence reveals a strong and bidirectional association between DED and psychiatric disorders, particularly depression, anxiety, post-traumatic stress disorder (PTSD), and sleep disturbances. This review synthesises the current knowledge on shared molecular, neuroimmune, and neuropathic pathways that underlie this comorbidity. Key mechanisms include hypothalamic–pituitary–adrenal (HPA) axis dysregulation, systemic and ocular inflammation, oxidative stress, mitochondrial dysfunction, and impaired neurotrophic signaling, especially reduced brain-derived neurotrophic factor (BDNF). Dysregulation of monoaminergic neurotransmitters such as serotonin and norepinephrine not only contributes to mood disturbances but also alters tear secretion and corneal pain perception. Corneal nerve changes and trigeminal–limbic sensitisation further reinforce the overlap between neuropathic ocular pain and affective dysregulation. Psychotropic medications, while essential for psychiatric care, may exacerbate ocular surface dysfunction through anticholinergic effects, altered neurotransmission, and tear film instability, highlighting the iatrogenic dimension of this interface. Conversely, tear-based biomarkers, including cytokines, serotonin, and BDNF, offer promising translational tools for patient stratification, diagnosis, and treatment monitoring across ocular and psychiatric domains. Recognising DED as part of a systemic, biopsychosocial continuum is critical for effective management. Multidisciplinary strategies that integrate ophthalmologic and psychiatric care, alongside novel therapies targeting shared molecular pathways, provide a framework for improving outcomes. Future research should prioritise longitudinal studies, biomarker validation, and personalised interventions to address this complex comorbidity.

Background: Skeletal muscle is essential not only for structural integrity but also metabolic homeostasis. Muscle atrophy, the loss of muscle mass and function, is closely linked to chronic and metabolic disorders and is driven by chronic inflammation, oxidative stress, impaired myogenesis, and disrupted protein homeostasis. The present study aimed to evaluate the protective effects and underlying mechanisms of Rosa canina extract (RCE), a polyphenol-rich plant known for its antioxidant and anti-inflammatory properties, in vitro and in vivo models of muscle atrophy. Methods: We investigated the effects of RCE in TNF-α-treated L6 myotubes and a mouse model (eight-week-old male C57BL/6N) of immobilization-induced muscle atrophy. Markers of inflammation, oxidative stress, myogenesis, protein turnover, and anabolic signaling were analyzed via RT-PCR, Western blotting and ELISA. Muscle mass, performance, micro-CT imaging, and histological cross-sectional area were assessed in vivo. Results: RCE suppressed pro-inflammatory cytokines, restored antioxidant enzyme expression, and preserved myogenic markers. It inhibited muscle proteolysis by downregulating the genes involved in protein degradation and promoted protein synthesis by via activation of the PI3K/Akt/mTOR pathway. In mice, RCE mitigated muscle mass loss, preserved fiber cross-sectional area, improved strength and endurance, and restored muscle volume. Conclusions: RCE attenuated muscle atrophy by targeting inflammation, oxidative stress, proteolysis, and impaired anabolism. These findings highlight RCE as a promising natural therapeutic for preserving muscle health and metabolic homeostasis.

Stress signaling via glucocorticoid receptor disrupts ovarian development in Japanese eel (Anguilla japonica) through HPI-HPG axis crosstalk.

Calcium-dependent protein Kinases: Bridging growth and stress responses in plants.

Doxorubicin-mediated retardation of aggresome formation enhances Carfilzomib-induced cell death synergistically by augmenting ER stress and proapoptotic signaling.

Rewiring amino acids in cancer.

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping researchers promote themselves alongside their papers. Dushyant Gautam is first author on ‘ Methotrexate alleviates chronic inflammation in a Drosophila model’, published in JCS. Dushyant conducted the research described in this article while a PhD student in Dr Indira Paddibhatla and Professor Ravi Kumar Gutti's lab at University of Hyderabad, Hyderabad, India. He is now a postdoc in the lab of Emmanouil Tampakakis at Johns Hopkins University, Baltimore, MD, USA, investigating how stress, inflammation and immune signalling networks intersect with metabolism to shape cell fate and preserve tissue homeostasis.