Search Results (1,682)

Endoplasmic reticulum (ER) stress represents a critical pathophysiological condition that plays a central role in the development of various human diseases, including protein misfolding diseases. While the small molecule Vx-445 (Elexacaftor) exhibits robust cellular bioactivity, its cryptic intracellular targets and off-label mechanisms of action remain poorly defined. This study investigates the cytoprotective efficacy and molecular targets of Vx-445 in Thapsigargin-induced ER stress in a neuronal cell model. Integrating biochemical assays, gene expression proteomics, and label-free functional proteomics, we demonstrate that Vx-445 significantly mitigates oxidative stress by reducing intracellular levels of reactive oxygen species, restores calcium homeostasis to baseline levels, and prevents apoptosis by inhibiting cytochrome c release. These phenotypic modifications correlated with changes in proteomic expression and were validated by Drug Affinity Responsive Target Stability (DARTS) analysis to map restored cellular pathways and identify potential protein interaction partners. Together, these findings uncover alternative molecular targets for Vx-445, providing a mechanistic basis for drug repurposing strategies in endoplasmic reticulum stress-related diseases. Full article

Cancer cells are able to survive under conditions of high endoplasmic reticulum (ER) stress by activating the adaptive unfolded protein response (UPR), which is closely linked with autophagy. On the other hand, excessive and prolonged ER stress leads to apoptosis. However, the relationships between different UPR branches and apoptosis or autophagy vary in cancer cells of different origins and depend on the extent and nature of the stress signal. This study was designed to establish the role of ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring enzyme 1 (IRE1α) in apoptosis or autophagy signaling in T-lymphoblastic leukemia MOLT-3 cells via the RNA interference method. The cells were transfected with small interfering RNAs (si-PERK, si-IRE1α, or si-Cont) for 6 h and further cultured under normal conditions for 72 h to provide an insight into chronic effects of the gene silencing. The expression of apoptosis and autophagy effectors at the mRNA and protein levels was compared using RT-PCR and Western blot assays, respectively. Transfection of the cells with PERK siRNA led to a significant decrease in PERK protein and gene expression, and decreased phosphorylation of its downstream effector eukaryotic initiation factor 2α (eIF2α). PERK silencing was accompanied by activation of apoptosis-related genes and proteins—BCL2-associated X (Bax), caspase-3, C/EBP homologous protein (CHOP), while the levels of autophagy markers (Unc-51 like autophagy activating kinase 1 (ULK1), Beclin-1, and microtubule-associated proteins 1A/1B light chain 3 (LC3A/B)) remained stable. In contrast, treatment of the cells with si-IRE1α reduced the content of IRE1α, X-box-binding protein 1 (sXBP1), and glucose-regulated protein 78 (GRP78) proteins, but increased ERN1 gene expression. IRE1α RNA interference did not affect the levels of the pro-apoptotic marker Bax, but suppressed caspase-3, CHOP, c-Jun N-terminal kinase (JNK), and autophagy signaling molecules (ULK1, Beclin-1, LC3A/B) at both the transcriptional and translational levels. These results indicate that the PERK pathway is an important contributor to the survival of MOLT-3 cells under basal ER stress, while PERK depletion compromises the resistance of cells to UPR-mediated apoptosis. The IRE1α UPR branch is directly linked with autophagy-dependent signaling, although IRE1α knockdown exerted a more complicated influence on the cells, probably via activation of multiple pro-death and compensatory pro-survival regulatory mechanisms. Full article

Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). The PLP1 gene, predominantly expressed in OLs, encodes proteolipid protein (PLP), a major structural component of CNS myelin that also regulates oligodendrocyte precursor cell (OPC) proliferation, differentiation, and maturation. Pelizaeus–Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by PLP1 mutations and characterized by defective myelination. Clinical manifestations range from severe connatal PMD to classic PMD and the milder spastic paraplegia type 2 (SPG2), reflecting substantial phenotypic heterogeneity. Beyond disrupting myelin structure, PLP1 mutations impair oligodendrocyte development and function. Increasing evidence indicates that PMD is fundamentally a proteostasis disorder, in which misfolded PLP accumulates within the endoplasmic reticulum (ER), overwhelms ER quality control mechanisms, and triggers chronic unfolded protein response (UPR) activation. Persistent ER stress and maladaptive UPR signaling ultimately promote oligodendrocyte dysfunction and degeneration. Using PMD as a representative model, this review summarizes the relationships between PLP1 mutations and disease phenotypes and discusses the cellular mechanisms by which ER stress and UPR signaling contribute to oligodendrocyte pathology. Full article

The progression and immune escape of HCC are closely regulated by endoplasmic reticulum stress (ERS). However, the associated ceRNA regulatory networks and their prognostic value remain to be systematically elucidated. Here, we sought to establish a prognostic signature derived from an ERS-associated ceRNA network and to investigate its relationship with the tumor immune microenvironment. We integrated TCGA-LIHC transcriptomic data with the MSigDB ERS gene set to identify ERS-associated differentially expressed genes and construct a ceRNA regulatory network. Using a forward search strategy with 10-fold cross-validation, we screened candidate genes to select the optimal prognostic combination and constructed a multigene Cox regression signature. External validation was performed in the independent microarray cohort GSE14520. By integrating single-cell transcriptomics, CIBERSORT, ESTIMATE, TIDE, and drug sensitivity analyses, we revealed immune microenvironment characteristics associated with this signature. Based on the ceRNA network’s eight core ERS mRNAs, an optimal three-gene signature comprising STC2, CKS1B, and PSAT1 was selected via forward search. The signature demonstrated robust prognostic discrimination in the TCGA training cohort (C-index = 0.653) and was independently corroborated in the external GSE14520 dataset (C-index = 0.584, log-rank p = 0.008). The signature was confirmed as an independent prognostic indicator by multivariable Cox regression. Functional enrichment analysis demonstrated a marked accumulation of cell-cycle-related pathways in the high-risk group, notably DNA replication and the spindle assembly checkpoint. Single-cell transcriptomic profiling showed that STC2 and CKS1B were predominantly expressed by tumor epithelial cells, whereas CCL2 and ATF3 were mainly detected in macrophages and fibroblasts. Drug sensitivity analysis indicated that the high-risk group was more sensitive to drugs such as docetaxel and AZD5582, consistent with the upregulation of proliferation pathways in this group; in the low-risk group, VE-822 exhibited selective sensitivity. This study established a three-gene prognostic signature based on the ERS-associated ceRNA network. The signature demonstrated robust prognostic stratification capabilities in cross-platform validation and revealed molecular characteristics centered on uncontrolled cell-cycle progression, as well as an immunosuppressive microenvironment, in the high-risk group, providing an exploratory tool for prognostic assessment and treatment strategy selection in hepatocellular carcinoma (HCC). Full article

Background/Objectives: Prostate cancer is one of the most common malignancies among men worldwide, and clinical outcomes following androgen deprivation therapy (ADT) vary considerably. Given that endoplasmic reticulum (ER) stress and the unfolded protein response mediate processes such as apoptosis, tumor adaptation, and disease progression, we aimed to investigate whether genetic variants in ER stress-related genes are associated with survival outcomes in patients with prostate cancer receiving ADT. Methods: This study enrolled 630 patients with prostate cancer who underwent ADT across three medical centers in Taiwan. A genetic association analysis of 89 haplotype-tagged single-nucleotide polymorphisms (SNPs) across 12 ER stress-related genes was performed. The primary clinical endpoint was overall survival (OS). Kaplan–Meier survival analysis and Cox proportional hazards models were used to evaluate prognostic associations. Furthermore, publicly available databases were integrated to analyze gene expression, clinical relevance, gene set enrichment, and tumor immune infiltration to elucidate the underlying biological mechanisms. Results: Among the analyzed SNPs, BAX rs182509214 showed the strongest association with OS. The minor G allele of BAX rs182509214 was significantly associated with poorer OS. Prostate tumor tissues exhibited markedly elevated BAX expression compared with normal prostate tissues, and this elevated expression was associated with worse survival outcomes. Multiple public gene expression datasets confirmed the overexpression of BAX in prostate cancer. Functional analyses revealed that genes associated with BAX expression were predominantly enriched in ribosomal, oxidative phosphorylation, and proteasomal pathways. Furthermore, the BAX copy number variation was significantly associated with the infiltration levels of multiple immune cell types, and BAX expression was negatively correlated with CD8⁺ T-cell infiltration, implying a potential marker role for the tumor immune microenvironment. Conclusions: The ER stress-related genetic variant, BAX rs182509214, may influence survival outcomes in patients with prostate cancer receiving ADT. BAX alterations are associated with disease progression and linked to mitochondria-related metabolic pathways and the tumor immune microenvironment. These results highlight BAX as a potential prognostic biomarker for prostate cancer treated with ADT; however, further validation in larger cohorts and functional studies is warranted. Full article

Transforming Growth Factor-beta (TGF-β) promotes lens epithelial–mesenchymal transition (EMT) and fibrosis, contributing to anterior subcapsular cataract (ASC) formation. Transgenic mice overexpressing TGF-β1 in the lens have been studied for over three decades, and yet the impact of active TGF-β1-overexpression on the lens epithelial transcriptome is undefined. We have addressed this knowledge gap by examining the gene expression landscape of these unique lens epithelia. High-throughput RNA-sequencing was performed on isolated lens epithelia from three-week-old TGF-β1-overexpression transgenic mice from two independent lines, OVE853 and OVE918, and wild-type mice. Downstream analyses included comparisons with lens datasets (e.g., cataract surgery model) and investigations using various resources/tools (e.g., Gene Ontology, CompBio, and iSyTE). Compared to wild-type murine lens epithelia, 384 differentially expressed genes (DEGs) were commonly identified in the lens of both transgenic lines. Candidates involved in EMT, inflammatory response, extracellular matrix organization, and mechano-sensation were elevated, while those involved in lipid metabolism, Wnt-suppression, Bmp- and Notch-activation were reduced. Comparative analyses with temporal transcriptomes on a mouse cataract surgery model identified overlapping pathological pathways, and some elevated genes, for example, endoplasmic reticulum stress genes, were consistent with human ASC data. This study provides the first comprehensive transcriptomic characterization of two independent TGF-β1 transgenic ASC models and identifies novel candidate downstream genes and pathways associated with TGF-β1 overexpression. All our data is made user-friendly and accessible through iSyTE. Full article

The Warburg effect is better understood as regulated metabolic plasticity rather than mitochondrial failure. Many malignant cells retain functional mitochondria while increasing aerobic glycolysis, lactate production, and redox remodeling to support growth, immune escape, and adaptation to microenvironmental stress. Within the context of the cancer microenvironment, this review examines xylitol as a hypothetical metabolic modifier within a broader host-microbe-mitochondria framework. Xylitol, a five-carbon sugar alcohol, is derived endogenously through the pentose phosphate pathway (PPP) and the glucuronate–xylulose pathway, and is metabolized efficiently in humans, rats, and pigs through xylitol dehydrogenase (XDH) in hepatic mitochondria and the cytosol; whereas, it is less tolerated by obligate carnivores who lack this enzyme. Preclinical studies show that partial substitution of glucose with xylitol can reduce proliferation and glycolytic markers in oral squamous carcinoma models, and preliminary studies link xylitol to glutathione depletion, endoplasmic reticulum (ER) stress, autophagy-associated death, and altered tumor metabolomics. On the other hand, oral pathogens such as Fusobacterium nucleatum and Porphyromonas gingivalis promote tumor stemness, extracellular vesicle signaling, metastasis, and immune evasion. In addition, Streptococcus mutans, the primary cariogenic pathogen, contributes to systemic bacteremia and epithelial–mesenchymal transition. Oral and gut microbiomes modulate macrophage polarization, T cell activity, and the senescence-associated secretory phenotype (SASP), possibly promoting cancer immune evasion. The anti-adhesive properties of xylitol may limit pathogen attachment to immune cell receptors, reducing the generation of pro-tumorigenic senescent immune cells. Xylitol also offers metabolic benefits, a low glycemic index, partial insulin-independent metabolism, and potential diabetes-prevention activity that are relevant, considering the established link between metabolic disease and cancer risk. A recent study reported that higher levels of endogenous xylitol were associated with adverse cardiovascular events, but confirmation of this requires large scale prospective studies. The evolutionary dietary context of MIS 6, during which hominin populations in sub-Saharan Africa depended on polyol-rich underground storage organs, provides a biological basis for human tolerance of xylitol. As a result, we hypothesize that xylitol may be a context-dependent metabolic modifier within an integrated host–microbe–mitochondria–cancer stem cell network. 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

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. Conclusions: 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