Fibroblast-like synoviocytes (FLSs) are crucial in driving synovial inflammation and joint damage in rheumatoid arthritis (RA). This study explored the functions and underlying mechanisms of GALNT1-mediated O-glycosylation, which is markedly upregulated in RA FLSs, in synovial aggression and subsequent experimental joint damage. Targeted suppression of GALNT1 effectively curtailed migration and invasion in RA FLSs and mitigated arthritis severity in a rat collagen-induced arthritis (CIA) model. Mechanistically, NEK9 was identified as a pivotal substrate and downstream effector of GALNT1, affecting the aggressive phenotype of RA FLSs. In vitro experiments further demonstrated that O-glycosylation of NEK9, mediated by GALNT1, promotes the pathogenic phenotype of RA FLSs by promoting cytoskeleton reorganization and restraining excessive endoplasmic reticulum (ER) stress activation. Our study provides mechanistic insights into the activation of RA FLSs and identifies GALNT1 as a potential therapeutic target for RA.

Islet transplantation offers a promising therapy for type 1 diabetes, but early β-cell loss due to stress-induced cell death limits graft survival and function. Although apoptosis has been extensively studied, necroptosis, a regulated form of necrotic cell death, remains an underexplored contributor to β-cell dysfunction. Herein, we evaluated sustained necrostatin-1 (Nec-1) delivery via poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) to protect islets from stress-induced damage in vitro. Nec-1-loaded PLGA MPs were synthesized by single-emulsion solvent evaporation and characterized by scanning electron microscopy and high-performance liquid chromatography for size, morphology, and drug encapsulation. Mouse islets were coincubated with Nec-1 or empty MPs for 24 h, followed by induction of endoplasmic reticulum stress with thapsigargin. Glucose-stimulated insulin secretion and cytokine release were quantified to assess β-cell function and inflammatory response. Nec-1 MPs were spherical with a median diameter of 10.34 μm (interquartile range [IQR], 6.55-15.17 μm) and an encapsulation efficiency of 36.2% (IQR, 31.1%-40.0%). Release studies demonstrated an initial burst of 24.8% (IQR, 21.8%-30.3%) by day 3, followed by sustained delivery up to 53.6% (IQR, 52.3%-57.4%) by day 14, with minimal impact on media pH. Under thapsigargin-induced stress, Nec-1 MP-treated mouse islets maintained glucose-stimulated insulin secretion, with insulin release increasing from 2.63% (IQR, 1.42%-5.74%) to 8.63% (IQR, 7.97%-14.42%, P = 0.0006) compared with 3.36% (IQR, 0.53%-9.08%) in stressed controls (P = 0.0117). The Stimulation Index was similarly preserved (3.23; IQR, 2.51-4.77 versus 1.18; IQR, 0.65-1.62; P = 0.0002). Nec-1 MPs partially attenuated IL-12p70 secretion (103.3 pg/mL; IQR, 67.7-162.4 versus 217.1 pg/mL; IQR, 86.2-367.6; P = 0.0381) while maintaining low levels of other proinflammatory cytokines. Nec-1-loaded PLGA MPs provide sustained, localized protection of β-cells from necroptotic and inflammatory stress in vitro. Given the sustained and targeted drug delivery, these findings provide a foundation for future in vivo translation to provide graft-localized therapeutic intervention and improve islet survival, engraftment, and long-term function.

Classic Hodgkin lymphoma (cHL) shares mutations with primary mediastinal B cell lymphoma (PMBL) but differs in histology, clinical behavior, and phenotype. To define transcriptional programs underlying these differences, we performed flow cytometric cell sorting and low-input RNA sequencing of Hodgkin and Reed-Sternberg (HRS) cells from eighteen primary tumors, paired intra-tumoral B cells, and four cHL cell lines, and compared them with RNA-sequencing data from 40 PMBL cases. Transcriptomic profiling revealed that HRS cells undergo abortive plasma cell differentiation with robust activation of the unfolded protein response (UPR), a feature shared with multiple myeloma but absent in diffuse large B cell lymphoma and PMBL. HRS cells also demonstrated profound immune evasion, including suppression of B cell identity genes and loss of natural killer cell recognition through downregulation of SLAM family ligands such as CD48. Comparative analysis with PMBL highlighted shared oncogenic programs and key distinctions: HRS cells exhibited greater loss of B cell identity, absence of GCB- and plasma cell markers, and unique upregulation of cytoskeletal and mitotic pathways consistent with their multinucleated morphology. These findings establish HRS cells as aberrantly differentiated GCB cells with partial plasmacytic features, UPR activation and distinct immune evasion strategies.

Platinum-based drugs exhibit potent anti-tumor efficacy but are limited by low bioavailability, severe toxicity, and resistance. Current therapeutic strategies lack effective solutions due to the unclear molecular mechanisms. Autophagy, with its dual protective/destructive roles, offers potential to enhance platinum-based chemotherapy, yet its clinical translation for optimizing therapeutic outcomes remains underexplored. To address this challenge, we screened a Natural Compounds Library (NCL) to identify low-toxicity agents that synergize with Cisplatin (Cis). Among 285 autophagy-related candidates, Catharanthine (CA) emerged as a specific autophagy activator model molecule that reduced toxicity and synergistically suppressed gastric cancer (GC) when combined with Cis. Mechanistically, CA promoted organ protection via endoplasmic reticulum stress (ERS)/AMPKα-dependent autophagy activation. The CA-Cis combination induced tumor-suppressive effects, including ERS, autophagosome accumulation, and cytoskeletal impairment in cancer cells. Conversely, CA-mediated autophagy protected normal cells, as AMPKα knockdown abolished this protection, resulting in DNA damage and apoptosis. These results highlight the dual autophagic flux regulation: tumor cells undergo destructive autophagy, while normal cells experience protective autophagy, establishing a favorable therapeutic balance. We confirmed that the CA-Cis combination activates autophagy through the AMPKα-ULK1 pathway in both tumor and non-tumor tissues and differentially regulates phosphorylation at serine 757 of ULK1, this differentiation can dramatically modulate autophagy activity, thereby mediating context-dependent dual outcomes of autophagic protection and detrimental effects. These findings elucidate a mechanism whereby CA enhances platinum efficacy by remodeling of autophagic homeostasis in organisms, providing a theoretical basis for optimizing platinum-based regimens. Our study bridges autophagy's dual functionality with clinical strategy, proposing the combination of specific autophagy activators as a promising approach to overcome platinum resistance and toxicity in GC treatment.

Zinc homeostasis is crucial for various biological processes, including gene regulation, signal transduction, and proteostasis. ZIP7 is a membrane transporter that exports zinc ions (Zn2+) from the lumen of the endoplasmic reticulum (ER) to the cytosol, and its dysfunction causes ER stress, although the underlying mechanism remains unclear. Here, we show that ZIP7 inhibition increases the labile Zn2+ concentration in the ER to micromolar levels, approximately 106 times higher than its steady-state level. Such abnormally high Zn2+ concentrations disrupt the function and trafficking of the Zn2+-dependent chaperone ERp44 at the ER-Golgi interface. In vitro assays using recombinant proteins demonstrated that Zn2+ inhibits the Ero1α-PDI oxidative system, and that ERp44 enhances this inhibitory effect. Consequently, the ER redox environment becomes more reducing, severely impairing the oxidative folding of key membrane receptors such as Notch1 and EGFR. These findings reveal the essential role of zinc homeostasis in redox-dependent proteostasis within the ER.

Zn is an essential micronutrient for all organisms. Understanding how Zn homeostasis is controlled in plants is crucial for agriculture and human health. In the present study, we characterized a transporter in rice (Oryza sativa), ZRT/IRT-LIKE PROTEIN10 (OsZIP10), which is primarily expressed in the roots and localized in the endoplasmic reticulum (ER) membrane. OsZIP10 transports Zn from the ER lumen into the cytoplasm and facilitates the radial delivery of Zn via the symplastic pathway in rice roots. Notably, both OsZIP10 knockout mutants and overexpression lines enhanced Zn accumulation by upregulating Zn uptake in roots and the root-to-shoot transfer of Zn, albeit through different mechanisms. Overexpression of OsZIP10 triggered an unfolded protein response and induced the expression of the ER stress-responsive transcription factor BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR74 (bZIP74), producing an unconventional alternatively spliced isoform. This isoform of OsbZIP74 then activated the expression of ZRT/IRT-LIKE PROTEIN7 (OsZIP7) and ZRT/IRT-LIKE PROTEIN9 (OsZIP9), enhancing Zn uptake and translocation. Through a distinctive mechanism, the knockout of OsZIP10 promotes the translocation of BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR50 (bZIP50) from the cytosol to the nucleus, where it activates the expression of OsZIP7 and OsZIP9. Our findings fill a gap in the understanding of Zn transfer in rice roots and establish two distinct signaling pathways linking Zn homeostasis control in the ER with the regulation of Zn uptake, transport, and accumulation.

Saturated fatty acids, which increase during high-fat diets and metabolic disease, disrupt lipid homoeostasis, leading to hepatic dysfunction. Understanding how hepatocytes adapt to this stress is essential for delineating the early events of fatty liver disease and its progression to more severe inflammation and fibrosis. Here, we show that the transcription factor TCF19 acts as a central regulator that helps hepatocytes manage lipid overload and cellular stress in both MAFLD mice model and human clinical samples. Combining lipidomic and transcriptomic analysis, we found that TCF19 controls genes involved in fatty-acid elongation and protein-folding responses, thereby linking lipid metabolism with endoplasmic-reticulum stress-response pathways. Elevated TCF19 levels are associated with lipid accumulation, whereas reducing TCF19 worsens inflammation and fibrotic features of the liver. Together, our findings identify TCF19 as a protective regulator during the transition from early hepatic fat accumulation to inflammatory liver disease, highlighting a potential target for early therapeutic intervention.

Autophagy is an evolutionarily conserved process that degrades and recycles intracellular components through lysosomes, thereby maintaining cellular homeostasis under stress conditions. Although radiation is known to influence autophagy, most previous studies have relied on static marker expression rather than quantitative evaluation of autophagic flux. In the present study, we quantitatively analyzed autophagic flux in hTERT/RPE-1 cells exposed to γ-rays (0.5-4Gy) using both bafilomycin A1-based assays and HaloTag reporter systems that visualize lysosomal degradation. LC3-based total autophagic flux remained unchanged even at 4Gy, indicating that lysosomal function is preserved after irradiation. In contrast, SQSTM1-dependent selective autophagy increased significantly at doses of 2Gy or higher, suggesting enhanced clearance of radiation-induced protein aggregates. HaloTag-based analyses further revealed that γ-irradiation induced mitophagy and ER-phagy in a dose-dependent manner, consistent with activation of oxidative stress and unfolded protein response pathways. These findings demonstrate that ionizing radiation does not globally suppress autophagy but selectively activates organelle-specific autophagy, particularly SQSTM1-mediated ER-phagy. The selective activation of these quality-control pathways likely contributes to maintaining cellular integrity and stress adaptation following irradiation. Quantitative flux analysis thus provides new insight into the hierarchical regulation of autophagy and its role in cellular survival and repair mechanisms after radiation exposure.

Cadmium-induced hepatotoxicity: interconnecting molecular and cellular pathways.

This investigation sought to assess the potential protective function of the phosphodiesterase-4 (PDE) enzyme inhibitor rolipram (ROL) against paracetamol (PARA) induced liver damage, as well as any potential underlying mechanism through modulation of endoplasmic reticulum (ER) stress via cAMP signaling. Fifty-six rats were randomly divided into 7 groups (n = 8). Following 24 h of fasting, animals received three different dosages of ROL (1.25, 2.5, and 5 mg/kg, i.p.) or N-acetylcysteine (140 mg/kg, orally). One hour later, 2 g/kg PARA orally was administered to induce hepatotoxicity. The ELISA method was used to evaluate GSH, PDE4D, and cAMP levels in liver tissue, as well as PDE4D and cAMP levels in serum. In addition, serum levels of liver injury biomarkers, including ALT and AST, were measured. GRP78, IRE1, and CHOP mRNA expressions in tissue samples were assessed using the Real Time PCR technique. The liver tissue's histopathological parameters, including necrosis, bleeding, and mononuclear cell infiltration, were evaluated. The PARA group had higher serum and tissue PDE4 levels, lower cAMP and GSH levels, higher ALT and AST levels, and higher expressions of the ER stress markers GRP78, IRE1, and CHOP mRNA. Histopathological evaluation also revealed severe histopathological damage with PARA toxicity. These changes improved with dose dependent increase of ROL dose. It was evaluated that the protective effect of PDE4 enzyme inhibition on liver injury caused by PARA toxicity could be regulated by intracellular secondary communication signals and ER stress inhibition. These findings also suggested that these pathways might be studied in relation to other liver injuries.

Unfolded protein response (UPR) is a conserved cellular strategy that enhances the protein folding capacity of cells under stress conditions. In Saccharomyces cerevisiae, the dual kinase RNase IRE1 initiates the UPR by catalyzing the cytosolic splicing of HAC1 mRNA, a process conserved in humans where IRE1 splices XBP1 mRNA. The spliced HAC1/XBP1 mRNA yields a transcription factor that upregulates the expression of protein-folding enzymes and chaperones, thereby boosting the cell's ability to cope with unfolded proteins. Our study demonstrates that the UPR involves two distinct phases. The early phase operates predominantly through the canonical IRE1 signaling pathway, while the later phase involves additional regulation by the MAP kinase Slt2 or its human ortholog ERK1/ERK2/ERK5 and the downstream target the MADS-box transcription factor Rlm1 (an ortholog of human MEF2C). We further show that Slt2 promotes IRE1 expression through Rlm1. Together, these findings reveal a previously unrecognized crosstalk between the MAPK and IRE1-mediated arm of the UPR.

Cellular proteostasis is essential for cellular proteome integrity, which is exquisitely sensitive to the redox environment. Heat shock proteins (HSPs) are the central chaperones that sense and adapt to these redox fluctuations. Emerging evidence demonstrates dysregulation of cellular HSPs-modulated redox-proteostasis in protein aggregation diseases, including cancers, senescence, neurodegenerative diseases, limb-girdle muscular dystrophy type D1, and β-thalassemia, making HSPs promising therapeutic targets in disease treatment. Redox post-translational modifications (PTMs) serve as master switchboards to dynamically modulate the structure and chaperone function of HSPs. Redox PTMs allow HSPs to participate in protein synthesis and folding, conformational maintenance, and degradation, thereby maintaining cellular proteostasis. Beyond their chaperone functions, HSPs also play critical roles in organelle-specific stress responses, such as mitochondrial unfolded protein response, endoplasmic reticulum (ER) stress, and unfolded protein response. Despite the well-known contributions of HSPs to redox-proteostasis, the double-edged functions of HSPs in protein aggregation diseases remain unclear. The main issues covered in this review include the regulation of HSPs by redox PTMs, the important role of HSPs in proteostasis and organelle-specific stress responses, dual modulation of HSPs in protein aggregation diseases, and pharmacological agents targeting HSPs.Further Directions:The functional diversity of HSPs in redox-proteostasis makes them promising therapeutic targets in disease treatment. Further studies should focus on exploiting agents that precisely target cysteine residues modifications on HSPs with good blood-brain barrier (BBB) penetration and low toxicity. Antioxid. Redox Signal. 00, 000-000.

Abstract Background Central nervous system (CNS) disorders arise from many initiating factors, yet they repeatedly culminate in shared cellular stress-response programs. We organize this phenomenon by defining a comprehensive stress adaptation network as a set of coupled sensing and eff ector loops spanning oxidative–mitochondrial control, neuroimmune regulation, excitability regulation, and proteostasis maintenance. Methods We review how two major phytocannabinoids, cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), modulate these adaptive modules. CBD is non-intoxicating and acts as a pleiotropic modulator that shapes stress-linked signaling through diverse molecular targets, including cannabinoid receptor 1 (CB1), cannabinoid receptor 2 (CB2), and various non-cannabinoid receptors, whereas THC is an intoxicating partial agonist at CB1/CB2, with neurobehavioral effects that depend strongly on state and dose. Results Clinical evidence is strongest for purifi ed CBD in epilepsy and for standardized formulations of purified THC and CBD combinations in multiple sclerosis (MS) spasticity, while evidence in other neurodegenerative and sleepdisorders remains preliminary. Across these four adaptive domains, cannabinoids can alter redox tone, glial stateprograms, circuit stability, and autophagy or unfolded protein response (UPR) signaling. However, many mechanisticclaims are based mainly on preclinical systems and may vary with exposure, cell type, and disease stage. Conclusion We highlight translational priorities that include standardized chemotypes and formulations, exposure–response biomarkers, cell-type-specific biomarkers and functional endpoints, and trial designs that separate symptomatic effects from disease modification. Graphical Abstract

Valproate medications are a leading cause of drug-associated acute pancreatitis. This study examines how sodium valproate (Na-VPA) induces pancreatic injury and contributes to acute pancreatitis (AP). Murine pancreatic acinar cells (PACs) were treated with Na-VPA or major VPA metabolites, and cytotoxicity was assessed by spectrofluorometry and confocal imaging. In vivo, C57BL/6 mice, with or without caerulein-induced pancreatitis (CER-AP), were administered Na-VPA and pancreatic injury was evaluated. Intracellular methionine-cycle metabolites were quantified by LC-MS/MS, whereas one-carbon metabolism enzyme expression was determined by RT-qPCR and western blotting. AutoDock Vina was employed to predict binding affinities of VPA to key metabolic enzymes. Na-VPA and its metabolites induced concentration- and time-dependent PAC death, independent of toxic calcium signalling. In vivo, Na-VPA aggravated CER-AP, increasing pancreatic histology scores and biochemical parameters. Transcriptomic and metabolomic analyses showed dysregulated one-carbon metabolism, validated by altered mRNA and protein expression analysis of key rate-limiting enzymes. Molecular docking indicated direct interactions between VPA and several metabolic enzymes. Na-VPA also activated the pancreatic endoplasmic reticulum (ER) stress pathway. In PACs, Na-VPA reduced methionine and S-adenosylmethionine (SAM) levels, whereas supplementation with methionine or SAM markedly attenuated cell injury; conversely, ethionine exacerbated it. Moreover, SAM supplementation in vivo significantly ameliorated pancreatic damage and biochemical alterations in Na-VPA-exacerbated CER-AP. Na-VPA disrupts one-carbon metabolism, triggering ER stress and acinar cell injury and exacerbating experimental pancreatitis. These findings provide new mechanistic insight into valproate-associated AP and identify metabolic targets for potential prevention or therapy.

Triple-negative breast cancer (TNBC) poses a significant therapeutic challenge due to the lack of defined molecular targets. While ceramide synthase 2 (CerS2) has a complex role in oncology, enhancing its enzymatic activity to produce pro-apoptotic, very long-chain ceramides (VLCCs) is a potential anti-cancer strategy. Here, we identify and characterize DH20931, a novel biisoquinoline derivative, as a newly identified small-molecule activator of CerS2. We provide genetic and biochemical evidence that CerS2 is the direct target of DH20931, which shows an effective, receptor-independent cytotoxicity across diverse breast cancer cell lines while sparing normal cells. In vivo, DH20931 demonstrates consistent tumor growth inhibition in both orthotopic xenograft and clinically relevant TNBC patient-derived xenograft (PDX) models, supported by a favorable safety and pharmacokinetic profile. Mechanistically, DH20931 triggers an effective dual mechanism of apoptosis. First, the accumulation of VLCCs induces lipotoxic endoplasmic reticulum (ER) stress, activating the pro-apoptotic ATF4-CHOP pathway. Second, we uncovered a previously unknown physical interaction between CerS2 and the ER calcium channel IP3R1. DH20931 promotes this interaction, enhancing ER-mitochondria proximity and facilitating a marked flux of Ca²⁺ into the mitochondria, which serves as an effective, secondary apoptotic signal. These findings validate CerS2 as a bona fide druggable target and present DH20931 as a promising clinical candidate. This unique synergistic mechanism, coupling lipotoxicity with calcium dysregulation, offers a convincing new strategy for treating aggressive and therapy-resistant breast cancers.

Microbial pathogens frequently manipulate host protein homeostasis to undermine immunity by targeting protein synthesis, folding, trafficking, and degradation. Conversely, effective immune responses themselves impose substantial proteostatic demands, as the rapid production of antimicrobial effectors increases the burden on cellular quality-control systems. This bidirectional pressure has likely driven the evolution of surveillance mechanisms that sense disruptions in protein homeostasis as indicators of infection. Using Caenorhabditis elegans as a genetically tractable model, recent studies have revealed that perturbations in proteostasis across multiple cellular compartments, including the cytosol, endoplasmic reticulum (ER), mitochondria, proteasome, and extracellular space, are actively integrated with innate immune signaling. Stress-response pathways such as the heat shock response, translational regulation, and the unfolded protein responses of the ER and mitochondria function not only to restore proteome integrity but also to directly shape immune gene expression and pathogen resistance in a context-dependent manner. This review highlights proteostasis as an evolutionarily conserved immune surveillance system, linking cellular stress sensing to host defense and offering broader insights into the coupling of stress adaptation, immunity, and organismal health.

Disrupted sleep is increasingly recognized as a factor influencing vaccine efficacy, yet the mechanisms by which sleep disruption affects vaccine-induced immunity remain incompletely understood. Sleep fragmentation, a hallmark of several common sleep disorders, may interfere with immune processes required for effective vaccination. Here, we show that chronic sleep fragmentation (CSF) markedly impairs immune responses to influenza vaccination. In a mouse model, two weeks of CSF before and during influenza vaccination significantly compromises antibody responses and reduces protection against lethal challenge, with lower neutralizing antibody titers, diminished IgG subclass responses, and decreased survival despite preserved antibody avidity. Single-cell RNA sequencing revealed transcriptional signatures associated with altered B cell maturation, impaired germinal center programs, and stress in antibody-producing plasma cells, including activation of unfolded protein response and oxidative stress pathways, alongside altered interactions between B and T cells. Clinically, analysis of 916,307 influenza-vaccinated adults shows that obstructive sleep apnea, a disorder characterized by recurrent sleep fragmentation, is associated with a higher risk of influenza infection than matched controls (0.7% vs. 0.4%; risk ratio 1.70). Taken together, this study demonstrates that CSF compromises vaccine-induced immune responses and highlights sleep health as a modifiable determinant of vaccine-associated protection.

Endoplasmic reticulum (ER) stress and hypoxia interaction in the progression of glioblastomas and other malignant tumors has not yet been sufficiently studied. Both PSAT1, as the ER stress-responsive phosphoserine aminotransferase, and сyclin D1 are shown to participate in tumor progression and chemoresistance. Therefore, this study aimed to elucidate the effect of endoplasmic reticulum stress on PSAT1 and CCND1 (сyclin D1) genes expression in normal human astrocytes of NHA/TS line, and U87MG glioblastoma cells. Hypoxia was created with the HIF1A prolyl hydroxylase inhibitor dimethyloxalylglycine. Tunicamycin and thapsigargin were used for ER stress induction. PSAT1 and cyclin D1 expression were examined by quantitative real-time RT-PCR. It has been established that hypoxia and tunicamycin had a similar suppressive effect on PSAT1 and CCND1 expression in normal astrocytes, but increased both genes expression in glioblastoma cells. Thapsigargin enhanced PSAT1 expression in both cell lines, but suppressed CCND1 expression in normal astrocytes without any effect on its expression in glioblastoma cells. Hypoxia modified the effect of tunicamycin and thapsigargin when these ER stress inducers were combined with hypoxia, but in different ways in normal and glioblastoma cells. These results indicate that hypoxia and ER stress relationship in the control of the studied genes expression differs in normal and tumor cells. Keywords: cyclin D1, endoplasmic reticulum stress, gene expression, glioblastoma cells, hypoxia, normal human astrocytes, PSAT1

The ketogenic diet (KD), a high-fat, low-carbohydrate diet, can effectively regulate energy metabolism in the brain. The regulation of cerebral energy metabolism in patients with Alzheimer's disease (AD) has attracted the attention of researchers. Recent studies have shown that ubiquitin carboxyl terminal hydrolase L1 (Uch-L1) deficiency leads to neurodegeneration by increasing energy demand and endoplasmic reticulum stress. However, the effect of Uch-L1 on AD remains to be explored. This study first combined Uch-L1 with cerebral energy metabolism to explore its role in long-term KD in AD. We found that AD mice with long-term KD showed better spatial recognition and working memory. KD promoted Uch-L1(C) and Mfn2 expression by inhibiting oxidative stress in the hippocampus of mice, improved mitochondrial function, increased ATP content, and significantly reduced neuronal apoptosis. In conclusion, KD can increase Uch-L1(C) and Mfn2 expression in the brain, and improve cerebral energy metabolism and cognitive function in AD mice.

Surgery is the first choice of treatment for oral squamous cell carcinoma (OSCC), including primary tumor resection and neck dissection. However, neck dissection of early-stage OSCC patients is still controversial. Exploration of mechanisms of early-stage OSCC metastasis might help to guide treatment choice. Our previous research has demonstrated that matrix stiffness activated the PERK-associated unfolded protein response (UPR), thereby contributing to early-stage OSCC metastasis. Since stress granules (SGs) are also regulated by PERK-mediated UPR, our study aimed to identify stiffness-related SGs and decipher their function of modulating early-stage OSCC metastasis. At first, we evaluated matrix stiffness and SGs level in early-stage OSCC tissues. Then enhanced matrix stiffness was simulated in vivo and its effect on metastasis and SGs expression was observed. Furthermore, A force loading model was adopted to identify the stiffness-related SGs in vitro and the effects of stiffness-related SGs on metastasis were further evaluated in vitro and in vivo. We identified the unique type of SGs which was stiffness-related to adopt mechanical stimuli. The stiffness-related SGs may boost metastasis cascade through promotion of anoikis resistance. At last, we investigated the containing mRNAs of stiffness-related SGs through RNA Immunoprecipitation Sequencing. The stiffness-related SGs were identified which may boost metastasis cascade through promotion of anoikis resistance. The unique SGs were rich in mRNA related to negative regulation of apoptosis, partly explained the anoikis resistance associated with stiffness-related SGs. The stiffness-related SGs may protect the disseminated cancer cells from anoikis resistance by harboring the set of specific mRNAs. Matrix stiffness promotes the formation of SGs in OSCC, getting prepared for metastasis in the early stage.