The present study used an in-vivo inflammation-induced colorectal cancer (CRC) model to evaluate the additive effect of thapsigargin (TG) with the standard chemotherapy drug irinotecan (IRN). CRC was induced by AOM/DSS, and after 10th weeks, animals were treated with five weekly cycles of either IRN or TG or a combination of both drugs. All the animals were sacrificed after the 16th week, and the data were analysed. Coadministration of both IRN and TG substantially reduced both tumor numbers and occurrence of aberrant crypt foci (ACF) in the colon tissues as compared to only IRN/TG-treated animal groups. Further analyses revealed that IRN and TG together alleviated ultrastructural abnormalities of the colon with a recovered overall histoarchitecture, enhanced ER stress and mitochondrial dysfunction, reduction of PCNA positive cells indicating low rate of cellular proliferation, increased DNA fragmentation and apoptosis supported by higher intensity of γH2AX and cleaved caspase-3 immunohistochemistry. Gene expression analyses of key oncogenic biomarkers also suggest that the addition of TG with IRN is more effective in inhibiting carcinogenic transformation in the colon of AOM/DSS-treated mice. This study provides direct evidence of the superior therapeutic potential of a combination of both drugs compared to conventional monotherapy in the management of CRC.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-34567-2.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder characterized by metabolic imbalance, oxidative stress, and granulosa cell (GC) dysfunction. Given the established role of BRCA1 in maintaining genomic stability and regulating stress responses, its potential involvement in PCOS pathogenesis warrants investigation. We examined the impact of BRCA1 on PCOS using a dehydroepiandrosterone (DHEA)-induced mouse model and testosterone-stimulated KGN cells. Lentiviral vectors overexpressing BRCA1 were administered by ovarian injection in PCOS mice or used to infect KGN cells. The IL-1β, TNF-α, and IL-6 levels were measured using enzyme-linked immunosorbent assay. Western blotting was performed to evaluate the expression levels of BRCA1 and other proteins related to inflammation, apoptosis, and endoplasmic reticulum stress (ERS). A TUNEL assay and flow cytometry were used to assess cell apoptosis. Spectrophotometry was used to measure the levels of reactive oxygen species, malondialdehyde, superoxide dismutase, and catalase. Cell survival was evaluated using a CCK-8 assay. Hematoxylin and eosin staining was used to assess the pathological alterations in the ovaries of PCOS mice. Additionally, rescue experiments were conducted on KGN cells treated with the ERS inducer thapsigargin (TG) to determine whether the protective effects of BRCA1 overexpression could be reversed through reactivating ERS. BRCA1 expression was reduced in PCOS. BRCA1 overexpression normalized sex hormone levels, improved ovarian morphology, and attenuated inflammatory signaling, oxidative stress, apoptosis, and ERS in vivo and in vitro. Notably, the ERS inducer TG reversed these protective effects, indicating ERS dependence. These findings suggest that BRCA1 mitigates PCOS phenotypes primarily by suppressing ERS and downstream inflammatory/oxidative and apoptotic pathways, thereby highlighting BRCA1 as a potential molecular target for PCOS therapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40001-025-03734-6.

Vascular smooth muscle cells (VSMCs) plays an important role in maintaining vascular function by responding to various vasoactive stimuli within blood vessels. Far-infrared (FIR) rays has been shown to possess a variety of physiological effects including vasodilation, while the underlying molecular mechanism remains elusive. Here, we explored the molecular mechanism by which FIR irradiation suppresses vascular contraction using rat VSMCs and aortas. FIR irradiation enhanced the transport of intracellular Ca2+ from the cytosol to the sarcoendoplasmic reticulum (SER) via activation of sarcoendoplasmic reticulum Ca2+-ATPase (SERCA), which accompanied a decrease in intracellular ATP levels. Pretreatment with thapsigargin (TG), a specific SERCA inhibitor, or knockdown of SERCA2 gene expression reversed FIR irradiation-induced translocation of Ca2+ into the SER. Notably, FIR irradiation promoted the dissociation of SERCA2 and phospholamban (PLN), an endogenous SERCA inhibitor, without altering their total protein expression levels. The array of effects elicited by FIR irradiation was not observed under hyperthermic conditions (39°C). Moreover, FIR irradiation, but not hyperthermal condition, decreased the phosphorylation of myosin light chain (MLC) at Ser19, which was restored by pretreatment with TG or the knockdown of SERCA2 gene expression. FIR irradiation attenuated phenylephrine-induced vessel contraction in endothelium-deprived rat aortas. Consistent with the in vitro results, the reduction in MLC phosphorylation caused by FIR irradiation was reversed following pretreatment with TG in isolated aortas. Additionally, FIR irradiation increased blood flow in the carotid arteries of mice. Collectively, these results suggest that FIR irradiation activates SERCA2 by promoting its dissociation from PLN, independent of hyperthermic effects. This activation lowers cytosolic Ca²⁺ and ATP levels, reducing MLC phosphorylation and vascular smooth muscle contraction. These findings provide scientific evidence for the therapeutic potential of FIR therapy in the treatment and prevention of arterial narrowing conditions such as pathological vasospasm, and peripheral artery disease.

Colorectal cancer (CRC) incidence is a significant cancer globally, and radiotherapy resistance is a serious problem. Cucurbitacin D (CBD), extracted from many plants such as the tubers of Trichosanthes kirilowii and the fruits of Ecballium elaterium (squirting cucumber), has various therapeutic effects, such as anti-cancer, -inflammation, -diabetes, and -viral infection effects. Since reports have indicated that CBD exhibits effective anti-cancer activity across various cancer types, our hypothesis is that CBD will overcome radioresistance in CRC radiotherapy. In the present study, we identified that CBD, a triterpenoid compound isolated from Trichosanthes kirilowii and Ecballium elaterium, has an anti-cancer and anti-inflammatory effect in vivo and in vitro. In LPS-induced murine models, CBD suppresses LPS-mediated cytokines, including TNFα, IL-6, IL-1β, and COX-2. In CRC xenograft mouse models, CBD treatment results in significantly smaller tumor volumes than the control. In HCT116 and HT29 cells, CBD treatment suppresses cell viability and increases LDH cytotoxicity and caspase-3 activity and cleavage. However, combined treatment of CBD and Z-VAD-FMK inhibits caspase-dependent apoptosis and cell death. Since CBD induces intracellular calcium (Ca2+) and reactive oxygen species (ROS) generation, it mediates ER stress-induced apoptotic cell death through the PERK-ATF4-CHOP axis. Moreover, ER stress inducer thapsigargin (TG) mediates synergistic apoptotic cell death in CBD-treated HCT116 and HT29 cells. However, PERK or CHOP knockdown suppresses ER stress-mediated apoptosis in CBD-treated HCT116 and HT29 cells. CBD treatment induces oxidative stress through the NADPH Oxidase 4 (NOX4) and also increases ROS generation. However, NOX4 knockdown and ROS inhibitor NAC or DPI block ER stress-induced apoptotic cell death by inhibiting the suppression of cell viability and the elevation of caspase-3 activity, LDH cytotoxicity, and intracellular ROS activity in CBD-mediated HCT116 and HT29 cells. We established radioresistant CRC models (HCT116R and HT29R); subsequently, radiation (2 Gy) in combination with CBD treatment overcame radioresistance via the modulation of the epithelial–mesenchymal transition (EMT) phenomenon, including the increase in N-cadherin and vimentin and the reduction in E-cadherin. Thus, these results show that CBD may be a new powerful therapeutic approach for CRC radiotherapy.

DDX3X facilitates adaption to proteotoxic stress by regulating the translation of MAPKAPK2 and the stability of TMCO1 via stress granules in multiple myeloma

GDF11 mitigates liver injury associated with pancreatitis by inhibiting endoplasmic reticulum (ER) stress and the activation of the TXNIP/NLRP3 inflammasome.

Mechanistic study of ANXA3-mediated endoplasmic reticulum stress promoting M1 macrophage polarization in pulmonary arterial hypertension based on bioinformatics and nine machine learning algorithms.

Previous studies have demonstrated that high-yielding dairy cows experience endoplasmic reticulum (ER) stress in the liver during early lactation. To date, most insights into the role of ER stress in metabolism and disease pathophysiology have been derived from rodent and human models. In dairy cattle, however, the specific impact of ER stress on metabolic pathways and its contribution to disease development remain insufficiently characterized. The objective of this study was therefore to investigate the molecular effects of ER stress using a bovine liver cell model (BFH12 cells). ER stress was induced by incubation with Tunicamycin (TM) and Thapsigargin (TG). Molecular responses to ER stress were assessed via a whole-genome array analysis and PCR targeting genes involved in selected metabolic pathways. Incubation with both ER stress inducers resulted in a marked upregulation of genes associated with the unfolded protein response (UPR) within a 4 to 24-h time frame, indicative of the production of robust ER stress in these cells. Unexpectedly, treatment with TM led to a downregulation of numerous genes involved in lipid biosynthesis, including those related to lipogenesis and cholesterol synthesis. Furthermore, incubation with TM and TG induced upregulation of genes involved in fatty acid oxidation and was accompanied by a reduction in intracellular triglyceride concentrations. Genes associated with inflammatory responses were upregulated by both TM and TG, whereas genes encoding antioxidant enzymes were downregulated. Genes involved in ketogenesis did not exhibit a consistent pattern of regulation. Overall, several effects of ER stress previously described in rodent models could not be replicated in this bovine liver cell system. Extrapolating these findings to dairy cows suggests that while ER stress may contribute to hepatic inflammation, it is unlikely to play a significant role in the development of hepatic lipidosis or ketosis.

Obesity is characterized by chronic low-grade inflammation and oxidative stress, conditions that disrupt metabolic homeostasis and promote vascular endothelial growth factor (VEGF) expression. While hypoxia and fatty acid-induced oxidative stress are known regulators of VEGF, the contribution of endoplasmic reticulum (ER) stress in monocytic cells remains unclear. In this study, we investigated the interplay between ER stress and metabolic stress in regulating VEGF expression using THP-1 monocytic cells. Metabolic stress was induced by palmitic acid (PA) and ER stress by thapsigargin (TG). Co-treatment with PA and TG significantly increased VEGF mRNA and protein levels compared to PA alone. This effect was accompanied by enhanced reactive oxygen species (ROS) production and upregulation of ER stress markers, including CHOP, ATF6, and IRE1. Pretreatment with the antioxidant curcumin markedly reduced VEGF expression and ROS levels, indicating a ROS-dependent mechanism. Additionally, PA+TG co-treatment elevated transcripts of antioxidant defense genes such as SOD2 and NRF2, suggesting a compensatory cellular response to oxidative stress. These findings demonstrate that ER stress amplifies VEGF induction in monocytic cells under lipotoxic conditions through ROS-mediated pathways, highlighting a potential mechanism linking metabolic stress, inflammation, and angiogenesis in obesity-related disorders.

Celastrol modulates calcium signaling in mouse taste bud cells and gustatory preference for a dietary fatty acid in the mouse.

Intracellular Ca2+ homeostasis is essential to regulate the molecular mechanisms underlying platelet physiology and aggregation. Store-operated Ca2+ entry (SOCE) is the main mechanism of extracellular Ca2+ influx in platelets and it has been involved in platelet aggregation.We reported the function of the uncharacterized protein EFCAB13 as a positive regulator of SOCE in megakaryoblastic cells and platelets from either mothers and their newborns. Alternatively, MEG-01 and HEK293 cells were used as sourrogated of platelets to perform changes in the expression of EFCAB13, which was ensured by immunoprecipitations and Western Blotting techniques. Once EFCAB13 was genetically modifies and to achive its role in Ca2+ homeostasis we used fluorescence microscope under single cells configuration. Finally, MEG-01 maturation was assay using flow-cytometry and specific fluorescent antibodies or cell cycle dies. Intracellular distribution and protein interaction was also evaluated by confocal microscopy.EFCAB13 is underexpressed in neonatal platelets as compared with adults, indicating an age-dependent expression. Silencing of EFCAB13 expression reduced the colocalization of STIM1 with Orai1 and, subsequently, impairs SOCE in megakaryoblastic MEG-01 cells stimulated with thapsigargin (TG). Coimmunoprecipitation experiments showed that EFCAB13 interacts with Orai1, and colocalization between both proteins increases during TG-evoked SOCE. Indeed, EFCAB13 localized nearby the ER during TG-evoked SOCE activation. Finally, PMA-induced MEG-01 maturation was altered in EFCAB13-silenced cells.Altogether, we conclude that EFCAB13 binds to Orai1 to stabilize and regulate the STIM1/Orai1 complex formation, which is necessary to support SOCE in adults. However, its function is less important in neonatal platelets. This regulatory function may also be important for megakaryocytic physiology during maturation. Therefore, EFCAB13 could be an interesting target for specific treatment of maternal hemostatic disorders during pregnancy.

Diabetic foot ulcers (DFUs) are a leading cause of disability and mortality, with endothelial dysfunction playing a key role in the development of non-healing ulcers. A primary driver of endothelial cell impairment in this context is endoplasmic reticulum (ER) stress, triggered by glycolipotoxicity, though the underlying mechanisms are not fully understood. In this study, we observed that diabetic mice displayed poor ulcer healing associated with reduced angiogenesis and downregulated Reticulocalbin 1 (RCN1) expression. Proteomic analysis in human umbilical vein endothelial cells (HUVECs) identified a strong link between RCN1 and the damaging effects of glycolipotoxicity on endothelial cell function, leading to impaired tubule formation, reduced migratory capacity, and increased apoptosis in endothelial cells. Mechanistic RNA sequencing analysis highlighted a significant role for RCN1 in regulating ER function. RCN1 overexpression alleviated ER stress by reducing Protein kinase R-like endoplasmic reticulum kinase (PERK) phosphorylation and C/EBP homologous protein (CHOP) expression, both induced by glycolipotoxicity or Thapsigargin (TG), while RCN1 silencing intensified these effects. Additionally, TRIM11-mediated ubiquitination, influenced by glycolipotoxicity, regulated RCN1 stability, specifically promoting angiogenesis through RCN1 modulation. RCN1 overexpression accelerated ulcer healing in diabetic mice by suppressing ER stress proteins and enhancing angiogenesis, whereas RCN1 inhibition further delayed ulcer healing. In human DFU samples, proteomic analysis revealed that low RCN1 levels were linked to disrupted ER functional proteins, with RCN1 serum levels decreasing as diabetes progressed to DFU. Following surgical debridement treatment, RCN1 levels increased in patients with improved DFU healing outcomes. These findings suggest that ER stress, initiated by RCN1 inhibition in response to glycolipotoxicity, leads to endothelial dysfunction and apoptosis, ultimately contributing to the non-healing of DFUs.

From the perspective of competitive endogenous RNA(ceRNA) constructed by metastasy-associated lung adenocarcinoma transcript 1(Malat1) and microRNA 16-5p(miR-16-5p), the improvement mechanism of Tonggu Xiaotong Capsules(TGXTC) on the imbalance and disorder of "cholesterol-iron" metabolism in chondrocytes of osteoarthritis(OA) was explored. In vivo experiments, 60 8-week-old C57BL/6 mice were acclimatized and fed for 1 week and then randomly divided into two groups: blank group(12 mice) and modeling group(48 mice). The animals in modeling group were anesthetized by 5% isoflurane inhalation, which was followed by the construction of OA model. They were then randomly divided into model group, TGXTC group, Malat1 overexpression group, and TGXTC+Malat1 overexpression(TGXTC+Malat1-OE) group, with 12 mice in each group. The structural changes of mouse cartilage tissues were observed by Masson staining after the intervention in each group. RT-PCR was employed to detect the mRNA levels of Malat1 and miR-16-5p in cartilage tissues. Western blot was used to analyze the protein expression of ATP-binding cassette transporter A1(ABCA1), sterol regulatory element-binding protein(SREBP), cytochrome P450 family 7 subfamily B member 1(CYP7B1), CCAAT/enhancer-binding protein homologous protein(CHOP), acyl-CoA synthetase long-chain family member 4(ACSL4), and glutathione peroxidase 4(GPX4) in cartilage tissues. In vitro experiments, mouse chondrocytes were induced by thapsigargin(TG), and the combination of Malat1 and miR-16-5p was detected by double luciferase assay. The fluorescence intensity of Malat1 in chondrocytes was determined by fluorescence in situ hybridization. The miR-16-5p inhibitory chondrocyte model was constructed. RT-PCR was used to analyze the levels of Malat1 and miR-16-5p in chondrocytes under the inhibition of miR-16-5p. Western blot was adopted to analyze the regulation of TG-induced chondrocyte proteins ABCA1, SREBP, CYP7B1, CHOP, ACSL4, and GPX4 by TGXTC under the inhibition of miR-16-5p. The results of in vivo experiments showed that,(1) compared with model group, TGXTC group exhibited a relatively complete cartilage layer structure. Compared with Malat1-OE group, TGXTC+Malat1-OE group showed alleviated cartilage surface damage.(2) Compared with model group, TGXTC group had a significantly decreased Malat1 mRNA level and an increased miR-16-5p mRNA level in mouse cartilage tissues(P<0.01).(3) Compared with the model group, the protein levels of ABCA1 and GPX4 in the cartilage tissue of mice in the TGXTC group increased, while the protein levels of SREBP, CYP7B1, CHOP and ACSL4 decreased(P<0.01). The results of in vitro experiments show that,(1) dual-luciferase was used to evaluate that miR-16-5p has a targeting effect on the Malat1 gene.(2)Compared with TG+miR-16-5p inhibition group, TG+miR-16-5p inhibition+TGXTC group had an increased mRNA level of miR-16-5p and an decreased mRNA level of Malat1(P<0.01).(3) Compared with TG+miR-16-5p inhibition group, TG+miR-16-5p inhibition+TGXTC group exhibited increased expression of ABCA1 and GPX4 proteins and decreased expression of SREBP, CYP7B1, CHOP, and ACSL4 proteins(P<0.01). The reasults showed that TGXTC can regulate the ceRNA of Malat1 and miR-16-5p to alleviate the "cholesterol-iron" metabolism disorder of osteoarthritis chondrocytes.

Avian reovirus induces autophagy-mediated cargo of progeny viruses to extracellular vesicles and enhancement of virus release.

Background: Pannexins are a family of channel proteins involved in a variety of biological processes, including cell death signaling and immune functions. Pannexin 2 has been proposed as a large pore ATP-permeable channel with critical roles in various physiological processes. However, its exact role in the regulation of cardiomyocyte still poses a question. A prior study showed that Panx2 deficiency sensitizes pancreatic beta cells to cytokine-induced apoptosis. The aim of this study was to investigate how does Panx2 deficiency affects cardiomyocyte function followed by its mechanistic pathway. Methods: Cardiomyocytes were stained with sarcoplasmic reticulum (SR) and mitochondria markers along with Panx2 to determine its subcellular localization and imaged using confocal microscope. Cardiomyocytes were treated with thapsigargin (TG), an ER stress inducer and cell viability was measured by lactate dehydrogenase assay (LDH) and 3- (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Furthermore, the protein expression levels of UPR markers like PERK and IRE1α, and proptosis markers including cleaved caspase 1, NLRP3, and cleaved gasdermin were evaluated in our knockout cells and compared them to the control group. Cardiomyocytes were overexpressed with Panx2 and treated with TG to see whether it assists in cell survival or not. Results: Our confocal imaging results indicated that Panx2 is located intracellulary and is in close proximity to the SR. Our cell viability data shows that deficiency of Panx2 in cardiomyocytes significantly reduces its survival. We also observed that Panx2 knockout cells had more p-PERK and p-IRE1α expression indicating more ER stress compared to control cells. Deficiency of Panx2 resulted in inflammatory response that lead the cells to pyroptosis, which were indicated by elevated cleaved caspase1, NLRP3, and cleaved gasdermin protein expression. However, overexpressing the cells with Panx2 resulted in increased cell viability and reduced UPR and pyroptosis markers. Conclusion: Panx2 deficiency worsens thapsigargin induced injury in cardiomyocytes.

Stem cells from apical papillae (SCAPs) are promising seed cells for angiogenesis, neurogenesis and dental pulp regeneration, which are contingent upon endoplasmic reticulum (ER) homeostasis. Due to the narrow anatomical structure of the root canal system and slow ingrowth of vasculatures, the presence of hypoxia and nutrient-deficient microenvironment within the sterilised root canal space may induce ER stress in the transplanted cells and affect their differentiation into neural lineages. This study aimed to investigate the role of ER stress in the neuronal differentiation of human SCAPs and its underlying mechanisms. Thapsigargin (TG) was employed to induce ER stress in SCAPs. ER Ca2+ level was quantified by Mag-Fluo 4 AM. Quantitative real-time PCR (qRT-PCR) and western blot were conducted to detect ER stress markers. SCAPs, with or without ER stress, were guided towards neuronal differentiation. We measured the expression of neuronal markers and the activation of the extracellular signal-regulated kinase (ERK1/2) and the unfolded protein response (UPR) signalling. Immunofluorescence staining was applied to observe SCAP-derived neuron-like cells. The kinetic Ca2+ influx of SCAP-derived neuron-like cells was monitored using a fluorescence microscope. SCH772984 and MKC8866 were used to selectively inhibit ERK1/2 and inositol-requiring enzyme 1α (IRE1α) activation, respectively. Statistical analyses were conducted using the GraphPad Prism 10 software. After TG stimulation, ER Ca2+ levels in all TG-treated SCAP groups were markedly reduced, the ER stress markers were significantly upregulated and UPR activation was found. Following neuronal induction, ER stress induced by 20 nM TG did not inhibit SCAP neuronal differentiation. However, ER stress induced by 40 or 80 nM TG significantly inhibited neuronal marker expression, neurite outgrowth and Ca2+ influx in SCAP-derived neuron-like cells. The phosphorylated ERK1/2 decreased during neuronal differentiation, along with the reduction of phosphorylated-IRE1α (p-IRE1α). Inhibition of ERK1/2 activation led to neuronal marker protein reduction, neurite outgrowth restraint and p-IRE1α decrease. Selective inhibition of IRE1α activity suppressed NeuN expression and neurite outgrowth. Severe ER stress inhibits the neuronal differentiation of SCAPs via decreasing ERK1/2 and IRE1α activity, whereas ER stress at an appropriate level is essential for the neuronal differentiation of SCAPs.

Thapsigargin (TG), a potent inhibitor of the sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA), is widely used to study intracellular Ca²⁺ homeostasis and has shown—along prodrug derivatives—promise as an anticancer agent. While TG is traditionally considered an inducer of apoptosis, the precise mode of cell death it triggers remains incompletely defined. Here, we investigated the effects of TG on rat basophilic leukaemia (RBL-1) cells using advanced 2D and 3D transmission electron microscopy, confocal laser scanning microscopy, and functional cell death assays. TG treatment led to marked ultrastructural alterations, including pronounced ballooning of the perinuclear space, extensive vacuolization, mitochondrial enlargement and degradation, and structural anomalies of the endoplasmic reticulum. Notably, classical apoptotic features such as nuclear fragmentation, chromatin condensation and apoptotic body formation were absent. Functional assays revealed minimal caspase-3/7 activation and low Annexin V staining, indicating a caspase-independent, non-apoptotic form of programmed cell death (PCD). Morphological and quantitative analyses demonstrated that TG-induced cell death in RBL-1 cells closely resembles autosis, a non-apoptotic, autophagy-dependent PCD characterized by perinuclear space ballooning and increased autophagolysosome formation. These autosis-like features were also observed in TG-treated murine macrophages and human mast cells, suggesting a conserved mechanism across cell types. Digoxin, a Na⁺/K⁺-ATPase inhibitor, partially reversed TG-induced ultrastructural damage, supporting the involvement of Na⁺/K⁺-ATPase in this process. Ca²⁺ imaging confirmed that TG-induced cytosolic Ca²⁺ elevation is primarily driven by ER Ca²⁺ release, with extracellular Ca²⁺ amplifying the response. Our findings establish that TG induces a non-apoptotic, caspase-independent PCD matching autosis, challenging the prevailing view of TG as a classical apoptosis inducer. This insight has important implications for research on intracellular Ca2+ homeostasis as well as for the therapeutic exploitation of TG and its derivatives in targeting apoptosis-resistant cancer cells.

Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer.

Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer that portends a poor prognosis and limited treatment. PTPN2 is a member of the non-receptor protein tyrosine phosphatase family that regulates biological processes by dephosphorylating various signaling molecules. Endoplasmic reticulum stress (ERS) plays a dual regulatory role by promoting both survival and apoptosis. This study aims to elucidate the role of PTPN2 in mediating the pro-apoptotic effects of ERS induced by Thapsigargin (TG), and its influence on the fate of TNBC cells, utilizing both loss-of-function and gain-of-function methodologies. Our findings indicate that PTPN2 modulates TG-induced ERS via the IRE1-XBP1 and PERK/EIF2α/ATF-4 signaling pathways. Furthermore, PTPN2 mitigates the TG-induced reduction in cell proliferation and the concomitant increase in apoptosis. Specifically, PTPN2 appears to inhibit several facets of TG-induced apoptosis, including: (1) Ca2+ elevation in mitochondria, (2) the production of reactive oxygen species (ROS), and (3) Bax/Bcl-2 augmentation which dictates mitochondria-mediated apoptosis. Additionally, we observed that the knockdown of PTPN2 enhances TG-induced autophagy; however, our results suggest that autophagy may serve a protective role against TG-induced apoptosis. Consequently, targeting PTPN2 in conjunction with ERS-inducing agents may represent a promising therapeutic strategy for the treatment of TNBC.

Endoplasmic reticulum stress induces trophoblast pyroptosis via regulating CYLD during labor initiation.