Experimental cell research最新文献

{"title":"CDC6 promotes keratinocyte senescence through the CCND1/P53 signaling in ischemia-reperfusion injury-induced pressure injury","authors":"Chenming Wang ,&nbsp;Shanshan Zhu ,&nbsp;Meige Dai ,&nbsp;Hui Chen","doi":"10.1016/j.yexcr.2026.114903","DOIUrl":"10.1016/j.yexcr.2026.114903","url":null,"abstract":"<div><div>Pressure injuries develop when prolonged compression of the skin and subcutaneous tissue impairs blood circulation, leading to localized tissue ischemia, degeneration, and ultimately necrosis. Ischemia-reperfusion(I/R) injury is one of the key pathological mechanisms underlying pressure injury formation. While cellular senescence has been implicated in I/R-related pathologies, its role in pressure injury development remains unclear. We aimed to elucidate the mechanisms of keratinocyte senescence in cutaneous I/R injury. An in vitro hypoxia/reoxygenation (H/R) model was employed to simulate I/R injury using human immortalized keratinocytes (HaCaT). H/R induction significantly exacerbated the senescence response, as characterized by reduced cell proliferation, increased apoptosis, elevated SA-β-galactosidase (SA-β-gal) activity, and upregulated expression of senescence markers (p16 and p21). Quantitative proteomic analysis identified CDC6 as a prominently upregulated protein under H/R conditions. siRNA-mediated CDC6 knockdown attenuated keratinocyte senescence, restored G1/S phase cyclin-D1 (CCND1) expression, and suppressed p53 levels, demonstrating its regulatory role in senescence via the p53/CCND1 pathway. Furthermore, protein interaction network analysis and experimental validation revealed CDC6's direct binding with origin recognition complex 2 (ORC2), evidenced by nuclear colocalization (immunofluorescence) and physical interaction (co-immunoprecipitation). Collectively, our findings pioneers the mechanistic elucidation of CDC6 in pressure injury pathology, proposing senescence-targeted interventions as a novel therapeutic strategy for ulcer management.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 2","pages":"Article 114903"},"PeriodicalIF":3.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146043768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLA2R1-mediated ERK-Dependent ferroptosis: A key pathogenic mechanism in epileptic neuronal injury","authors":"Hong Chen ,&nbsp;Guohang Wu ,&nbsp;Qiannan Song","doi":"10.1016/j.yexcr.2026.114904","DOIUrl":"10.1016/j.yexcr.2026.114904","url":null,"abstract":"<div><h3>Background</h3><div>Phospholipase A2 receptor 1 (PLA2R1) plays a regulatory role in pathological processes, but its mechanism in epileptic neuronal injury remains unclear. This study aimed to elucidate how PLA2R1 promotes epileptic neuronal injury through ERK-dependent ferroptosis.</div></div><div><h3>Methods</h3><div>A kainic acid-induced epilepsy mouse model was employed. PLA2R1 expression was detected using qRT-PCR, Western blot, and immunofluorescence. PLA2R1 knockdown and overexpression vectors were constructed to observe effects on seizure severity and neuronal injury. Ferroptosis indicators (GPX4, ACSL4, PTGS2, MDA, ROS, GSH) were analyzed. HT22 cells were used for in vitro validation with glutamate and Erastin-induced ferroptosis. ERK pathway involvement was verified using inhibitor SCH772984.</div></div><div><h3>Results</h3><div>PLA2R1 was upregulated in epileptic tissues. PLA2R1 knockdown prolonged seizure latency, reduced seizure intensity, decreased neuronal injury, and inhibited ERK activation. It upregulated GPX4 and GSH while downregulating ACSL4, PTGS2, MDA, and ROS. PLA2R1 overexpression exacerbated ferroptosis-related neuronal injury. In vitro experiments confirmed that ferroptosis inducers upregulated PLA2R1, while knockdown improved neuronal survival. ERK inhibitor SCH772984 reversed PLA2R1 overexpression-induced neuronal injury.</div></div><div><h3>Conclusion</h3><div>This study identified the PLA2R1-MEK-ERK-ferroptosis signaling axis, suggesting that PLA2R1 contributes to neuronal ferroptosis through ERK pathway activation in epilepsy. PLA2R1's druggability and ERK inhibitors' clinical safety provide foundation for therapeutic translation.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 1","pages":"Article 114904"},"PeriodicalIF":3.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of Gfi1 induced by LSD1 inhibitor protects against cisplatin-induced ototoxicity through attenuating pyroptosis","authors":"Zihe Zhao ,&nbsp;Jingjing Luo ,&nbsp;Dengbin Ma ,&nbsp;Siyu Li ,&nbsp;Shaoqin Cen ,&nbsp;Hanqi Fan ,&nbsp;Zhenxing Hou ,&nbsp;Junze Lu ,&nbsp;Cheng Cheng ,&nbsp;Xiaoyun Qian ,&nbsp;Xia Gao ,&nbsp;Ao Li","doi":"10.1016/j.yexcr.2026.114902","DOIUrl":"10.1016/j.yexcr.2026.114902","url":null,"abstract":"<div><div>Cisplatin, a widely used chemotherapeutic agent, is associated with significant ototoxicity. Identifying potential therapeutic targets to mitigate cisplatin-induced hearing loss has become a crucial goal. In this study, we demonstrated that the LSD1 inhibitor S2101 could protect against cisplatin-induced ototoxicity (CIO) by upregulating Gfi1 expression. Mechanistically, we investigated the regulatory relationship between Gfi1 and Trim27. Our findings indicated that Gfi1 could bind to the Trim27 promoter region, activating its transcription. The subsequent upregulation of Trim27 significantly attenuated hair cell pyroptosis, highlighting the therapeutic potential of the Gfi1-Trim27 pathway. These results collectively underscore the critical function of Gfi1 in protecting against cisplatin-induced hearing loss and provide novel insights into potential therapeutic strategies.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 2","pages":"Article 114902"},"PeriodicalIF":3.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146017972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AHNAK inhibits osteoporosis progression by stabilizing Smad1 protein","authors":"Weifei Zhang ,&nbsp;Hua Chen ,&nbsp;Tiantian Qi ,&nbsp;Dengbo Yao ,&nbsp;Hang Liu ,&nbsp;Hui Zeng ,&nbsp;Fei Yu ,&nbsp;Wenyu Zhou","doi":"10.1016/j.yexcr.2026.114899","DOIUrl":"10.1016/j.yexcr.2026.114899","url":null,"abstract":"<div><div>AHNAK is a structural scaffold protein implicated in a wide array of physiological functions. AHNAK mutations are highly prevalent in patients with osteoporosis, However, it is currently unknown whether AHNAK affects the progression of osteoporosis and the specific mechanism behind this effect. This study detected decreased AHNAK (AHNAK1) expression in bone tissues and bone marrow mesenchymal stem cells (BMSCs) of osteoporotic mice. Genetic knockdown of AHNAK inhibited osteogenic differentiation of BMSCs. Mechanistic investigations indicated that AHNAK functions through stabilizing Smad1 protein levels. Overexpression of Smad1 in AHNAK-knockdown BMSCs restored their osteogenic differentiation capacity. Furthermore, in vivo mouse experiments further confirmed these findings. Collectively, these findings indicate that AHNAK inhibits the progression of osteoporosis by stabilizing Smad1 protein.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 2","pages":"Article 114899"},"PeriodicalIF":3.5,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"USP18 promotes cell proliferation and inhibits ferroptosis by stabilizing HDAC3 in endometrial carcinoma","authors":"Fang Tong ,&nbsp;Xue Gao ,&nbsp;Yuhong Shang","doi":"10.1016/j.yexcr.2026.114900","DOIUrl":"10.1016/j.yexcr.2026.114900","url":null,"abstract":"<div><div>Endometrial cancer (EC) represents one of the most prevalent malignancies of the female reproductive system. Ferroptosis, a recently identified form of programmed cell death, has garnered increasing attention in cancer research. Ubiquitin-specific peptidase 18 (USP18), a member of the deubiquitinating enzyme family, has been recognized as an oncoprotein in various cancers; however, its functional role and underlying mechanisms in EC remain largely unexplored. In this study, we found that USP18 was markedly upregulated in EC patients (n = 15, stage I; n = 4, stage II and n = 1, stage III), and elevated USP18 expression correlated with unfavorable prognosis. Functional assays demonstrated that knockdown of USP18 significantly inhibited EC cell proliferation. Moreover, USP18 silencing promoted the accumulation of lipid reactive oxygen species (ROS), malondialdehyde (MDA), and Fe²⁺, thereby enhancing erastin-induced ferroptosis. In contrast, USP18 overexpression produced opposing effects. These in vitro findings were further validated <em>in vivo</em>, where USP18 knockdown suppressed tumor growth and promoted ferroptosis. Mechanistic investigations revealed that USP18 interacted with and deubiquitinated histone deacetylase 3 (HDAC3), thus leading to its stabilization. Subsequent rescue experiments confirmed that the tumor-promoting effects of USP18 were abrogated upon HDAC3 knockdown. Taken together, our results identify the USP18/HDAC3 axis as a key regulator of EC cell proliferation and ferroptosis suppression, underscoring the potential of USP18 as a therapeutic target in EC.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 1","pages":"Article 114900"},"PeriodicalIF":3.5,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upregulation of EphA2 by Src counteracts Src-induced loss of cell adhesion","authors":"Misuzu Takada ,&nbsp;Mayu Murata ,&nbsp;Shuhei Soeda ,&nbsp;Takuya Honda ,&nbsp;Ryuzaburo Yuki ,&nbsp;Yuji Nakayama","doi":"10.1016/j.yexcr.2026.114898","DOIUrl":"10.1016/j.yexcr.2026.114898","url":null,"abstract":"<div><div>The receptor tyrosine kinase EphA2 is highly expressed in various cancers, and its elevated levels are associated with poor prognosis. Although Src has been shown to increase EphA2 expression partly through ERK signaling, the functional consequences of EphA2 upregulation remain unclear. In this study, we investigated the role of EphA2 upregulation by active Src in cell adhesion. We utilized HeLa S3-derived HeLa S3/v-Src cells, which allow inducible v-Src expression upon doxycycline (Dox) treatment. Dox treatment induced v-Src expression, cell rounding, and a marked increase in global tyrosine phosphorylation. Consistent with previously reports, EphA2 expression was upregulated following v-Src induction. Time-course analysis revealed that EphA2 knockdown accelerated v-Src-induced cell rounding. Similarly, c-Src also upregulated EphA2 and induced cell rounding. Paxillin staining demonstrated that c-Src expression increased both the number and area of focal adhesions, as well as paxillin intensity at these sites. All of these effects were abolished by EphA2 knockdown. In conclusion, Src activity upregulates EphA2 expression, and increased EphA2 counteracts Src-induced cell detachment. However, as Src signaling intensifies, it overrides the counteracting effect of EphA2, resulting in cell rounding and detachment. The balance between Src and EphA2 may act as a key regulator of cellular adhesion dynamics.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 1","pages":"Article 114898"},"PeriodicalIF":3.5,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic mechanism of LncRNA KCNQ1OT1 in high-glucose-induced podocyte injury via m6A methylation modification","authors":"Yikai Hou ,&nbsp;Danli Wang ,&nbsp;Lijun Liu ,&nbsp;Jiakun Tian ,&nbsp;Min Zhi ,&nbsp;Yongbing Shi","doi":"10.1016/j.yexcr.2026.114897","DOIUrl":"10.1016/j.yexcr.2026.114897","url":null,"abstract":"<div><div>Podocyte injury is a hallmark of diabetic nephropathy associated with proteinuria and renal dysfunction. This study elucidated the role of long non-coding RNA KCNQ1 overlapping transcript 1 (LncRNA KCNQ1OT1) in high-glucose (HG)-induced podocyte injury. In HG-treated podocytes, KCNQ1OT1, WTAP, and MAPK6 were quantified. After KCNQ1OT1 interference, cell viability, apoptosis, inflammation, and oxidative stress were measured. Subcellular localization of KCNQ1OT1 was determined by nuclear-cytoplasmic fractionation and RNA FISH. Binding of MLL1 to KCNQ1OT1 was validated via RNA pull-down and RIP. MLL1/H3K4me3 enrichment on the WTAP promoter was detected by ChIP. m6A levels of MAPK6 were measured by MeRIP. Binding of IGF2BP1 to MAPK6 was confirmed via RIP. Rescue experiments explored the WTAP/MAPK6 axis in podocyte injury. HG treatment upregulated KCNQ1OT1, WTAP, and MAPK6 in podocytes. KCNQ1OT1 knockdown enhanced cell proliferation, reduced apoptosis, and attenuated inflammation and oxidative stress. Mechanistically, nuclear-localized KCNQ1OT1 recruited MLL1 to the WTAP promoter, enhancing H3K4me3 modification and WTAP activation. WTAP promoted m6A methylation of MAPK6 mRNA, which was stabilized by IGF2BP1. Overexpression of WTAP or MAPK6 abrogated the protective effects of KCNQ1OT1 knockdown on podocytes injury. In conclusions, KCNQ1OT1 exacerbates HG-induced podocyte injury by upregulating the WTAP/MAPK6 axis in an m6A-dependent manner.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 1","pages":"Article 114897"},"PeriodicalIF":3.5,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145988903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphofructokinase in glycolysis: Bridging enzymology and cell biology","authors":"Ashesh Sharma ,&nbsp;Songon An","doi":"10.1016/j.yexcr.2026.114887","DOIUrl":"10.1016/j.yexcr.2026.114887","url":null,"abstract":"<div><div>ATP-dependent phosphofructokinase (PFK) catalyzes a key committed step in glycolysis. Also called the “gatekeeper” of glycolysis, PFKs catalyze an irreversible phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. While eukaryotic PFKs are more than double the size of prokaryotic PFKs, the overall structure and mechanism of PFKs are largely conserved from prokaryotes to eukaryotes. Usually tetrameric to be active, PFKs are also found to form higher-order structures, such as octamers in yeasts and multimeric filaments in mammals. Due to their central role in glycolysis, the enzymatic activity of PFKs is highly regulated by a myriad of allosteric effectors, post-translational modifications, and various signaling pathways. Such complex regulatory networks of PFKs often result from and/or result in a variety of protein-protein interactions, thus providing the molecular basis of dynamic association and dissociation of PFKs into multienzyme metabolic assemblies (i.e., metabolons) in cells. The concept of metabolon has now become an organizational principle for a cell to regulate the function of PFKs and thus govern glycolysis. Therefore, this article aims to integrate current knowledge in PFK enzymology and cell biology to provide a molecular and cellular framework for repositioning this century-old drug target for innovative therapeutic applications.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 1","pages":"Article 114887"},"PeriodicalIF":3.5,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145951769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MiR-181c-5p-SIRT1 axis-driven Pink1/Parkin-mediated mitophagy prevents ferroptosis and vascular calcification in chronic kidney disease","authors":"Ruman Chen ,&nbsp;Jiqing He ,&nbsp;Na An,&nbsp;Mingzhi Xu,&nbsp;Liheng Wang,&nbsp;Yafei Bai","doi":"10.1016/j.yexcr.2025.114875","DOIUrl":"10.1016/j.yexcr.2025.114875","url":null,"abstract":"<div><h3>Background</h3><div>Vascular calcification (VC) is a severe cardiovascular complication of chronic kidney disease (CKD), driven by vascular smooth muscle cell (VSMC) osteogenic trans-differentiation and exacerbated by oxidative stress and cellular dysfunction. Despite its clinical relevance, the molecular mechanisms underlying CKD-associated VC remain incompletely understood. This study investigates the role of Sirtuin 1 (SIRT1) in modulating VC through ferroptosis inhibition and mitophagy activation and examines whether microRNA-181c-5p (miR-181c-5p) contributes to SIRT1 dysregulation in this context.</div></div><div><h3>Methods</h3><div>A CKD-associated VC model was induced in rats by 5/6 nephrectomy followed by high calcium/phosphate and calcitriol loading, and an <em>in vitro</em> calcification model was established in primary rat VSMCs. SIRT1 was manipulated using AAV9-mediated overexpression <em>in vivo</em> and plasmid overexpression or inhibition <em>in vitro</em>. Upstream regulation of SIRT1 by miR-181c-5p was predicted bioinformatically and validated by RNA pull-down and dual-luciferase assays. Ferroptosis was assessed by redox and Fe²⁺ indices, and mitophagy by Pink1/Parkin, LC3-II and p62 expression. Rescue experiments employed erastin, Mdivi-1 and Parkin knockdown.</div></div><div><h3>Results</h3><div>SIRT1 expression was markedly reduced in calcified aortic tissues and VSMCs. SIRT1 overexpression suppressed VC by reducing calcium deposition, downregulating osteogenic markers, and increasing fetuin-A levels. SIRT1 also suppressed ferroptosis by restoring the GSH/GPX4/SLC7A11 axis and limiting ROS and lipid peroxidation, whereas erastin abolished these effects. Mechanistically, miR-181c-5p was found to directly target SIRT1 and promote VSMC calcification by repressing SIRT1. Moreover, SIRT1 promoted mitophagy via the Pink1/Parkin pathway activation. Furthermore, inhibition of mitophagy reversed the anti-ferroptotic effects of SIRT1, confirming their functional interplay.</div></div><div><h3>Conclusions</h3><div>SIRT1, negatively regulated by miR-181c-5p, mitigates CKD-associated VC by suppressing ferroptosis and activating Pink1/Parkin-dependent mitophagy in VSMCs, highlighting a potential therapeutic axis for vascular protection in CKD.</div></div><div><h3>Clinical trial registration number</h3><div>Not applicable.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 1","pages":"Article 114875"},"PeriodicalIF":3.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"S-nitrosylated COX-2 is a microenvironment-regulated breast cancer cell biomarker of mesenchymal phenotypes","authors":"Reuben J. Hoffmann ,&nbsp;AeSoon Bensen ,&nbsp;Mark Dane,&nbsp;Jane Arterberry,&nbsp;Rebecca Smith,&nbsp;James Korkola,&nbsp;Pepper Schedin","doi":"10.1016/j.yexcr.2026.114888","DOIUrl":"10.1016/j.yexcr.2026.114888","url":null,"abstract":"<div><div>COX-2, an inducible enzyme key to production of inflammatory prostaglandins, has tumor cell-intrinsic oncogenic activity. Previously, we reported Cys-526-nitrosylated COX-2 (SNO-COX-2) associates with breast cancer progression and poor-prognostic young onset breast cancer. Here, using a 3D culture model of early-stage human breast cancer (MCF10DCIS cells), we report SNO-COX-2, but not non-nitrosylated COX-2, closely associated with mesenchymal cell phenotypes induced by fibrillar Col1. Inhibition of nitric oxide synthase (NOS) activity did not reduce SNO-COX-2 levels, suggesting alternative nitrosylation mechanisms. In 3D MCF10DCIS culture, mesenchymal phenotypes and SNO-COX-2 protein induced by Col1 did not associate with transcription of classic epithelial-to-mesenchymal transition (EMT) markers nor common cancer signaling pathways. Conversely, TGFβ-1 strongly induced EMT- and cancer signaling-related transcripts but was insufficient to increase SNO-COX-2 protein or mesenchymal phenotypes. These data suggest the mesenchymal phenotype and SNO-COX-2 expression in MCF10DCIS are driven by a non-transcriptional mechanism dependent on Col1. We tested 300 additional microenvironmental conditions and find SNO-COX-2 expression is driven by inflammatory, wound-resolving, and cancer-associated TME factors, including TNC, SPP1, decorin, Col1, Col3, INF-γ, and IL-4/13, with specific extracellular matrix-ligand combinations driving both high and low SNO-COX-2 expression. In sum, these observations show that in MCF10DCIS cells, SNO-COX-2 associates with mesenchymal phenotypes more strongly than non-nitrosylated COX-2; expression of classic EMT transcripts is neither sufficient nor necessary for acquisition of mesenchymal phenotypes; and expression of SNO-COX-2 is highly microenvironment-dependent. Future studies evaluating SNO-COX-2 as a biomarker for early-stage breast cancer with increased risk for progression, and its regulation, are warranted.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"456 1","pages":"Article 114888"},"PeriodicalIF":3.5,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145942969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}