Cell. Mol. Biol. Lett. [JOURNAL]
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200 papers
Discovery of a novel cannabidiol-derived transient receptor potential vanilloid 4 inhibitor to reduce pulmonary edema and lung vascular permeability in mice.
Arfath Y, Cham PS, Kotra T … +7 more , Akhter R, Ahmed S, Kour M, Abdullah ST, Singh PP, Rayees S, Ahmed Z
Cell Mol Biol Lett · 2026 May · PMID 42144577 · Full text
INTRODUCTION: Activation of TRPV4 ion channel during acute lung injury (ALI) exacerbates lung dysfunction by promoting edema and inflammation. Pharmacological inhibition of TRPV4 signaling in the lungs offers protective...
INTRODUCTION: Activation of TRPV4 ion channel during acute lung injury (ALI) exacerbates lung dysfunction by promoting edema and inflammation. Pharmacological inhibition of TRPV4 signaling in the lungs offers protective benefits, reducing vascular leakage, enhancing blood oxygenation, and alleviating edema. OBJECTIVES: We designed, synthesized, and preclinically evaluated cannabidiol-derived TRPV4 channel inhibitors for potential therapeutic application in ALI and future clinical translation. METHODS: We identified a lead cannabidiol-derived TRPV4 inhibitor through specific in vitro screening assays. The lead compound was then tested in a series of animal models of ALI. Initial evaluation employed the lipopolysaccharide (LPS) induced lung injury model, followed by models involving TRPV4 overexpression in alveolar macrophages, as well as models featuring TRPV4 hyperactivation. These models were strategically chosen to replicate key pathological features of clinical ALI. RESULTS: Our investigation revealed that administration of the lead derivative CS-85(4j) demonstrated significant protective effects in a mouse model of ALI. CS-85 effectively prevented lung edema and maintained the integrity of pulmonary vascular barrier. Notably, it inhibited neutrophil influx into the lung, reduced proinflammatory cytokine production, and mitigated associated pathological changes. In additional relevant preclinical in vivo models, we further investigated how TRPV4 hyperactivation via pharmacological stimulation and overexpression in alveolar macrophages through liposome-mediated gene delivery exacerbated key features of ALI. CS-85 effectively reduced this exaggerated lung inflammation and alleviated the ALI features. In exploring the downstream mechanisms of CS-85, we found that its pharmacological efficacy is mediated through modulation of the NLRP3-caspase-1, NFAT, and NF-ĸB signaling pathways, all of which are crucial inflammatory cascades. CONCLUSIONS: We identified CS-85 as a potent and promising TRPV4 inhibitor that demonstrates strong preclinical efficacy in mitigating ALI by preserving vascular integrity and modulating key inflammatory signaling pathways. Its dual mechanism of action highlights its therapeutic potential for ALI and supports further clinical evaluation.
QSOX1 confers ferroptosis resistance via redox modification of SLC7A11 in colorectal cancer.
Jia M, Chen H, Liu Y … +7 more , Guo J, Wang X, Liu Q, Liu Z, Meng Z, Wang C, Wang Y
Cell Mol Biol Lett · 2026 May · PMID 42141400 · Full text
BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for colorectal cancer (CRC). However, the precise mechanisms by which CR...
BACKGROUND: Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a promising therapeutic target for colorectal cancer (CRC). However, the precise mechanisms by which CRC cells evade ferroptosis remain incompletely understood. Cysteine redox modification, typically catalyzed by cysteine oxidases, is a key regulatory factor governing protein structure and function. Quiescin sulfhydryl oxidase 1 (QSOX1), a Golgi-localized sulfhydryl oxidase known to promote various physiological functions, has an uncharacterized role in ferroptosis. Therefore, this study investigated the effects of QSOX1 on ferroptosis sensitivity in colorectal cancer. METHODS: We utilized a comprehensive set of analytical techniques to elucidate the mechanisms of QSOX1 in CRC ferroptosis resistance. We assessed cell proliferation, colony formation, and sensitivity to ferroptosis inducers (Erastin and RSL3) in CRC cells. Levels of reactive oxygen species (ROS), intracellular Fe, and redox metabolites were measured by biochemical assays and flow cytometry. RNA sequencing (RNA-seq) and untargeted metabolomics were performed using QSOX1-deficient HT-29 cells. The interaction between QSOX1 and SLC7A11 was confirmed via coimmunoprecipitation, immunofluorescence, and nonreducing gel electrophoresis. Cystine uptake and glutamate release assays were used to assess SLC7A11 function. Tumor xenografts were generated to assess the in vivo sensitivity of colon cancer cells to ferroptosis inducers. RESULTS: QSOX1 was significantly upregulated in CRC tissues and promoted CRC cell proliferation in vitro and in vivo. Knockdown of QSOX1 sensitized CRC cells to ferroptosis inducers, whereas QSOX1 overexpression conferred resistance. Mechanistically, QSOX1 enhanced redox homeostasis and GSH metabolism in CRC cells. QSOX1 interacted with and facilitated redox modification of SLC7A11 at cysteine 158 via its thioredoxin motif (C449-C452) in the ERV/ALR domain. This oxidative regulation enhanced SLC7A11 membrane localization, cystine uptake, and glutamate release, thereby boosting intracellular GSH synthesis and suppressing ferroptosis. CONCLUSIONS: QSOX1 promotes ferroptosis resistance in CRC cells through redox-dependent post-translational modification of SLC7A11, enhancing its activity and promoting GSH synthesis. The QSOX1-SLC7A11 axis represents a potential therapeutic target to overcome ferroptosis resistance in CRC.
HS induces apoptosis of tumors with high IDO1 expression via NR4A1-BCL-2 and SOCS3 pathways.
He ZNT, Meng F, Qian X … +4 more , Liu Y, Fang X, Yang D, Yang Q
Cell Mol Biol Lett · 2026 May · PMID 42129631 · Full text
BACKGROUND: Hydrogen sulfide (HS) has been reported to exert both protumor and antitumor functions. It is worthy to clarify the condition under which HS exerts antitumor effects and its underlying mechanism. Our previous...
BACKGROUND: Hydrogen sulfide (HS) has been reported to exert both protumor and antitumor functions. It is worthy to clarify the condition under which HS exerts antitumor effects and its underlying mechanism. Our previous study connected the immune checkpoint indoleamine 2,3-dioxygenase 1 (IDO1) and HS by revealing that HS downregulates IDO1 expression, leading to our hypothesis that antitumor effect of HS is associated with IDO1 expression in tumor cells. METHODS: Apoptosis, cellular distribution of NR4A1, phosphorylation of IDO1, and the binding of phosphorylated IDO1 and SOCS3 are examined both in vitro and in vivo. RESULTS: In this study, we confirm our hypothesis by showing that HS significantly reduces proliferation and induces apoptosis of tumor cells with high IDO1 expression. In tumor cells with high IDO1 expression, HS promotes the translocation of NR4A1 out of nucleus and its binding with BCL-2, as well as the phosphorylation of IDO1 and the codegradation of phosphorylated IDO1 and SOCS3. Such mechanism by which HS induces apoptosis of tumors with high IDO1 expression is also elucidated in tumor-bearing mice, where HS shows great therapeutic effect against tumors with high IDO1 expression. CONCLUSIONS: HS induces apoptosis of tumor cells with high expression of IDO1 by promoting NR4A1-BCL-2 apoptotic pathway and the codegradation of phosphorylated IDO1 and SOCS3. Our study provides new theoretical and experimental evidence for a strategy for tumor therapy with HS.
Coming to light: the transcriptional regulatory roles of histone lysine crotonylation in health and disease.
Dai SK, Ren N, Liu CM … +1 more , Yang F
Cell Mol Biol Lett · 2026 May · PMID 42129630 · Full text
Research on histone lysine crotonylation has evolved from identifying its core regulatory factors and mapping its genome-wide landscape to dissecting its functions in physiological and pathological contexts. Since its di...
Research on histone lysine crotonylation has evolved from identifying its core regulatory factors and mapping its genome-wide landscape to dissecting its functions in physiological and pathological contexts. Since its discovery nearly 15 years ago, extensive biochemical, structural, and genetic studies have deepened our understanding of how this evolutionarily conserved modification is integrated into intricate epigenetic regulatory networks. In this review, we first summarize mechanistic insights into the molecular basis of transcriptional regulation mediated by histone crotonylation, and discuss competitive crosstalk between this modification and histone acetylation in local chromatin regions. We then present an updated integrative framework to systematically delineate the regulatory roles of histone crotonylation across genes with distinct transcriptional states, as well as its functional implications in health and disease. Finally, we propose a unifying context-dependent model for histone crotonylation-mediated transcriptional regulation, and outline key challenges and future directions in the field.
Implications of ferritinophagy in cardiovascular diseases and its pharmacological modulation: underlying mechanisms and clinical translation strategies.
Wu YL, Xiao L, Li HN … +1 more , Chen LX
Cell Mol Biol Lett · 2026 May · PMID 42129623 · Full text
Ferritinophagy is a crucial intracellular process mediated by the selective autophagy receptor nuclear receptor coactivator 4 (NCOA4), which plays a central role in maintaining iron homeostasis by regulating ferritin deg...
Ferritinophagy is a crucial intracellular process mediated by the selective autophagy receptor nuclear receptor coactivator 4 (NCOA4), which plays a central role in maintaining iron homeostasis by regulating ferritin degradation. In recent years, its function as a key interface between autophagy and iron metabolism has attracted considerable attention owing to its pathophysiological relevance in cardiovascular diseases (CVDs). This review systematically delineates the molecular mechanisms of ferritinophagy, including the formation of the NCOA4-ferritin complex, lysosomal degradation pathways, and the multilayered regulatory networks involved. Particular focus is given to the dual role of ferritinophagy in cardiovascular pathology, encompassing myocardial ischemia-reperfusion injury (MIRI), atherosclerosis (AS), and diabetic cardiomyopathy (DCM). While moderate ferritinophagy activity is essential for maintaining adequate cardiac iron supply, its excessive activation leads to labile iron accumulation, oxidative stress via the Fenton reaction, and ferroptosis, thereby exacerbating myocardial injury and pathological remodeling. Consequently, this article provides a comprehensive overview of pharmacological strategies targeting ferritinophagy, including direct inhibition approaches (e.g., NCOA4 small interfering RNA (siRNA) and lysosomal inhibitors) and indirect modulation strategies (e.g., ferroptosis inhibitors and natural compounds). Finally, challenges to clinical translation are addressed, particularly regarding tissue specificity, drug delivery efficiency, and long-term safety. Future research directions are proposed, including the development of organ-specific targeting strategies and the exploration of combination therapies, with the aim of offering novel insights and potential therapeutic avenues for the prevention and treatment of CVDs.
NAT10-mediated acC modification of TNFRSF1A promotes acute kidney injury by activating NF-κB pathway.
Zhang M, Li Y, Wu C … +3 more , Pan Q, Wang P, Liu HF
Cell Mol Biol Lett · 2026 May · PMID 42121010 · Full text
BACKGROUND: Acute kidney injury (AKI) is closely linked to inflammatory responses driven by the NF-κB pathway, yet the epigenetic mechanisms underlying this association remain poorly understood. This study investigates t...
BACKGROUND: Acute kidney injury (AKI) is closely linked to inflammatory responses driven by the NF-κB pathway, yet the epigenetic mechanisms underlying this association remain poorly understood. This study investigates the role of N-acetyltransferase 10 (NAT10)-mediated RNA N-acetylcytidine (acC) modification in regulating NF-κB signaling during AKI. METHODS: Clinical AKI specimens and experimental models (in vivo and in vitro) were analyzed to assess NAT10 expression in renal tubular epithelial cells (RTECs). Genetic knockdown and overexpression of NAT10 (including the catalytically inactive NAT10-G641E mutant) were performed in vitro to evaluate NF-κB pathway activity and hypoxia/reoxygenation (H/R)-induced inflammatory responses. In murine ischemia/reperfusion (I/R)-induced AKI models, genetic ablation of NAT10 in RTECs and pharmacological inhibition using Remodelin were employed to study renal inflammation and injury. Mechanistic insights were derived from integrated acC acetylated RNA immunoprecipitation sequencing (acRIP-seq) and RNA sequencing (RNA-seq) analyses to identify NAT10-mediated acC modification targets and their effects on RNA stability, translation efficiency, and signaling pathways. RESULTS: NAT10 was significantly upregulated in RTECs of clinical AKI specimens and experimental models. In vitro, NAT10 knockdown suppressed NF-κB activation, mitigating H/R-induced inflammation and cellular damage, while NAT10 overexpression (but not the G641E mutant) activated NF-κB, exacerbating RTECs injury. In murine I/R-AKI models, genetic or pharmacological inhibition of NAT10 attenuated NF-κB-mediated renal inflammation and tubular damage. Mechanistically, NAT10-mediated acC modification enhanced RNA stability and translation efficiency of tumor necrosis factor receptor superfamily member 1A (TNFRSF1A), leading to aberrant NF-κB activation and subsequent inflammatory cascades. CONCLUSIONS: This study identifies the NAT10-acC-TNFRSF1A axis as a novel epigenetic regulator of NF-κB-driven renal inflammation in AKI. NAT10 promotes inflammatory signaling and tubular damage by enhancing TNFRSF1A mRNA stability and translation efficiency, highlighting its potential as a therapeutic target. These findings provide a theoretical foundation for developing AKI treatments targeting NAT10-mediated acC modification to mitigate NF-κB-dependent pathology.
Rv1983 promotes mycobacterial dissemination by triggering ferroptosis through GPX4 ubiquitination.
Qu Z, Zhou Y, Cai Q … +4 more , Chen T, Xiang Y, Chen L, Yuan C
Cell Mol Biol Lett · 2026 May · PMID 42115929 · Full text
BACKGROUND: Ferroptosis, a unique form of regulated cell death induced by iron-dependent lipid peroxidation, has been implicated in the pathogenesis of Mycobacterium tuberculosis (Mtb). However, the role of Mtb proteins,...
BACKGROUND: Ferroptosis, a unique form of regulated cell death induced by iron-dependent lipid peroxidation, has been implicated in the pathogenesis of Mycobacterium tuberculosis (Mtb). However, the role of Mtb proteins, particularly those encoded by the genomic regions of deletion (RDs), involved in mediating macrophage ferroptosis has not been thoroughly investigated. This study aimed to screen for Mtb RD region-encoded proteins that induce macrophage ferroptosis and elucidate the underlying molecular mechanisms. METHODS: We identified the Rv1983 protein with cytotoxic activity against murine bone marrow-derived macrophages (BMDMs) through screening of prokaryotically expressed Mtb RDs proteins, and subsequently determined the specific cell death modality induced by Rv1983 in BMDMs through flow cytometry, western blotting, and cytotoxicity assays following Rv1983 stimulation. To investigate the role of Rv1983 in Mtb infection, we constructed an Rv1983-knockout Mtb H37Ra strain (H37RaΔRv1983) and compared its intracellular and extracellular bacterial loads with wild-type H37Ra strain in infected BMDMs. Using coimmunoprecipitation, immunofluorescence, and flow cytometry, we identified and validated the target protein of Rv1983 in macrophages and its functional role in Rv1983-mediated macrophage death. For in vivo validation, wild-type H37Ra and H37RaΔRv1983 strains were used to infect both wild-type and macrophage-specific Rv1983-binding protein knockout mice, and the role of Rv1983 during Mtb infection was assessed through bacterial colony counting, flow cytometry analysis, and histochemical staining. RESULTS: This study identifies Rv1983 (PE_PGRS35), an RD2-encoded secreted protein of Mtb that acts as a ferroptosis effector to promote mycobacterial dissemination. Mechanistically, Rv1983 binds to E3 ubiquitin ligase tripartite motif 25 (TRIM25) in macrophages through its PE domain, especially on the Y62 site. The Rv1983-TRIM25 complex interacts with glutathione peroxidase 4 (GPX4), and subsequently promotes K48-linked ubiquitination degradation of GPX4 at the K75 site, ultimately inducing ferroptosis to promote mycobacterial dissemination. An Rv1983-deficient Mtb strain (H37RaΔRv1983) displayed significant suppression of Mtb dissemination both in vitro and in vivo. CONCLUSIONS: These findings provide a new insight into the molecular mechanism of Mtb-induced ferroptosis, and suggest that targeting ferroptosis mediated by the Rv1983-TRIM25-GPX4 signaling axis is a potential strategy for therapeutic control of tuberculosis.
RING finger E3 ubiquitin ligases: novel therapeutic opportunities in melanoma.
Zhang JF, Li LT, Yang YY … +5 more , Zhang SC, Gao C, Zhu X, Xin H, Li XY
Cell Mol Biol Lett · 2026 May · PMID 42104227 · Full text
Melanoma is an aggressive type of cancer that is prone to developing resistance to targeted therapies and immunotherapies, so it is necessary to seek novel therapeutic opportunities. RING finger E3 ubiquitin ligases (RNF...
Melanoma is an aggressive type of cancer that is prone to developing resistance to targeted therapies and immunotherapies, so it is necessary to seek novel therapeutic opportunities. RING finger E3 ubiquitin ligases (RNFs) play a crucial role in the ubiquitin-proteasome system and are important in regulating the development of melanoma by orchestrating various pathways. In this review, we analyze the structural and functional characteristics of the RNF subfamily to clarify their mechanisms of action in melanoma and to compare the functional differences among various RNFs. Additionally, we systematically evaluate potential therapeutic strategies targeting RNFs, including small-molecule drugs, proteolysis-targeting chimeras (PROTACs), and molecular glues, and further propose new directions for drug design by using computer-aided technology. Furthermore, this review suggests that RNF-targeted therapy should be combined with existing therapies, providing a novel approach for the precise treatment of melanoma, and is significant for clinical application and drug development.
Endoplasmic reticulum and Golgi stress signaling-mediated regulation of protein secretion.
Bakambamba K, Nivet M, Martin S … +3 more , Lafont E, Chevet E, Avril T
Cell Mol Biol Lett · 2026 May · PMID 42098616 · Full text
The eukaryotic secretory pathway (SP) is essential to ensure cellular functions and multicellular communication. The early SP is constituted mostly of the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment...
The eukaryotic secretory pathway (SP) is essential to ensure cellular functions and multicellular communication. The early SP is constituted mostly of the endoplasmic reticulum (ER), the ER-Golgi intermediate compartment (ERGIC), and the Golgi apparatus. These intracellular organelles achieve proper folding and modification of newly synthesized transmembrane and secretory proteins, en route to their final destination, e.g., plasma membrane, endosomes, lysosomes, and the extracellular space. They also integrate quality control systems to ensure export of productively folded proteins and to trigger dysfunctional proteins to degradation. The ER as the first SP compartment is subjected to a precise control of its own homeostasis through signaling of the unfolded protein response. In this review, we provide an overview of the early SP and its regulatory mechanisms, focusing on the ER and Golgi stress-dependent signaling. We contextualize this information within physiological and pathological processes, and discuss how ER and Golgi stress responses might coordinate their regulatory effects across the entire SP.
Regulation of mitochondrial function during spermatogenesis and sperm maturation.
Meng K, Zhu Z, Jia H … +8 more , Feng Y, Feng J, Shen Y, Jiang W, Liu C, Qin Q, Gao F, Yuan J
Cell Mol Biol Lett · 2026 May · PMID 42098599 · Full text
With the recent increase in the incidence of male infertility, greater attention is being paid to male reproductive health. The causes of male infertility are complex, and damage occurring during any process from spermat...
With the recent increase in the incidence of male infertility, greater attention is being paid to male reproductive health. The causes of male infertility are complex, and damage occurring during any process from spermatogenesis to fertilization can affect sperm quantity and quality of the sperm. Mitochondria are the power sources of cells and help regulate cellular homeostasis and physiological function. Mitochondria play a crucial role in male reproduction. Mitochondria undergo dynamic changes during spermatogenesis, sperm maturation, and fertilization. Mitochondrial dynamics and mitophagy help regulate the structure and function of mitochondria by meeting the cellular energy requirements of sperm during reproduction and reducing levels of damaged mitochondrial DNA (mtDNA); the elimination of excess mtDNA during fertilization prevents the spread of genetic mutations. Stable mitochondrial function ensures the smooth occurrence and maturation of sperm, maintaining male fertility. Externally induced mitochondrial dysfunction can lead to an inadequate energy supply, oxidative stress, cellular apoptosis, and abnormal sperm structure formation, which can lead to male infertility. In this article, the mechanism through which mitochondrial dysfunction affects the entire process of male reproduction, from spermatogonial stem cell division to final fertilization, and leads to infertility is discussed in chronological order. This article explores potential therapeutic targets for improving male fertility through therapies targeting mitochondrial function to provide a reference for subsequent research and more precise treatment directions.
CRISPR and compound screens in a novel ex vivo tissue model identify DDR1 and ETA as regulators of cancer cell invasion.
Liu J, Jiang W, Wang X … +13 more , Azoitei A, Liu H, Najjar G, Liu K, Melzer MK, Stilgenbauer S, Elati M, Burkhalter MD, Philipp M, Wezel F, Zengerling F, Bolenz C, Günes C
Cell Mol Biol Lett · 2026 May · PMID 42092764 · Full text
BACKGROUND: Bladder cancer (BC) can be characterized clinically as either non-muscle-invasive (NMIBC) or muscle-invasive (MIBC). While NMIBC generally has a favorable prognosis, MIBC is characterized by high morbidity an...
BACKGROUND: Bladder cancer (BC) can be characterized clinically as either non-muscle-invasive (NMIBC) or muscle-invasive (MIBC). While NMIBC generally has a favorable prognosis, MIBC is characterized by high morbidity and mortality. Understanding the molecular determinants of tumor invasion is critical, yet research is hampered by the limitations of current experimental models. Standard assays such as the Boyden chamber lack physiological complexity, while porcine bladder models suffer from tissue contamination and genetic variability. There is an urgent need for reliable models that mimic the intact tissue architecture. METHODS: We established a unique ex vivo tissue invasion model (EXTIM) to evaluate the invasive capacity of BC cells within a largely intact tissue context, using freshly prepared bladders from mice. The invasiveness of human BC cells (RT4, T24, UMUC3) and the immortal urothelial cell strain (Y235T) was comparably evaluated using EXTIM, the Boyden chamber, and porcine models. Gene knockdown or ectopic expression of GJB3 or ORP3 indicated the suitability of EXTIM to investigate the impact of specific factors on tumor cell invasion. To identify novel genetic regulators of cell invasion, we combined EXTIM with a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout screen. Additionally, we utilized the EXTIM to perform a pharmacological screen of a small molecule library comprising 90 substances to identify compounds capable of suppressing BC cell dissemination. RESULTS: Importantly, by combining EXTIM with genomewide CRISPR-Cas9 screening, we identified several candidate genes involved in BC progression. Notably, discoidin domain receptor tyrosine kinase 1 (DDR1) was identified as a functional inhibitor of tumor cell invasion. Furthermore, the small-molecule screen revealed that PD-156707, a selective antagonist of the endothelin receptor A (ETA), significantly suppresses cancer cell invasion within the EXTIM environment. CONCLUSIONS: EXTIM serves as a robust and physiologically relevant tool for assessing tumor cell invasion and migration under ex vivo conditions. EXTIM can be used to identify factors involved in the progression of invasive BC by high-throughput genetic screenings in an ex vivo organ culture system, by culturing cells after transmigration through the bladder tissue. Moreover, the impact of specific genetic factors in the process of tumor cell dissemination can be assessed by placing bladders from genetically modified mice into the EXTIM.
DNASE1L3 functions as a significant metastatic suppressor by attenuating MYH9/β-catenin/c-Jun/LncRNA-KDM4A-induced E-cadherin ubiquitination degradation in nasopharyngeal carcinoma.
Tao X, Liu X, Zhao X … +12 more , Zhou B, Cheng C, Yan W, He J, Cao H, Su Y, Xin J, Gan X, Peng H, Lin W, Fang W, Liu Z
Cell Mol Biol Lett · 2026 May · PMID 42092754 · Full text
BACKGROUND: Deoxyribonuclease 1 Like 3 (DNASE1L3) is a member of the deoxyribonuclease I family that is associated with some diseases, including systemic lupus erythematosus and hypocomplementemic urticarial vasculitis....
BACKGROUND: Deoxyribonuclease 1 Like 3 (DNASE1L3) is a member of the deoxyribonuclease I family that is associated with some diseases, including systemic lupus erythematosus and hypocomplementemic urticarial vasculitis. Recently, abnormal DNASE1L3 was preliminarily shown to correlate with tumor pathogenesis. However, its role is still undetermined in nasopharyngeal carcinoma (NPC). METHODS: Multiple sets of Gene Expression Omnibus (GEO) high-throughput data were utilized to screen the differentially expressed genes. Signal pathway enrichment analysis analyzed the correlation between DNASE1L3 and epithelial-mesenchymal transition (EMT) and cytoskeleton reorganization. An immunohistochemistry assay for analysis of DNASE1L3 expression was used to detect the clinical samples. Woundhealing, migration, invasion assays, and mouse model of lung metastasis were used to assess the role of DNASE1L3 in NPC metastasis. The mechanism of DNASE1L3 inhibition of NPC metastasis by attenuating MYH9/β-catenin/c-Jun/LncRNA-KDM4A-induced E-cadherin ubiquitination degradation was demonstrated by protein stability evaluation, co-immunoprecipitation, immunofluorescence, chromatin immunoprecipitation, dual-luciferase reporter assay, and RNA immunoprecipitation. RESULTS: DNASE1L3 downregulation in patients with NPC was not only negatively related to lymph node metastasis and distant metastasis but was also positively associated with poor prognosis. Overexpression of DNASE1L3 in NPC cells suppresses migration, invasion, and metastasis in vitro and in vivo. Inversely, DNASE1L3 knockdown increased cell migration and invasion abilities. Mechanistically, DNASE1L3 recruited PARK2 to ubiquitinate and degrade MYH9 protein. MYH9 protein activated β-catenin/c-Jun signal and augmented c-Jun-induced LncRNA-KDM4A transcription. In the process of DNASE1L3-induced metastatic suppression, decreased LncRNA-KDM4A attenuated the recruitment of E3 ubiquitin ligase Hakai and thus impeded the degradation of E-cadherin, by which heightened E-cadherin protein stability and finally inactivated the EMT signal. CONCLUSIONS: Our data firstly elucidated that DNASE1L3 acts as a metastatic suppressor by attenuating E-cadherin ubiquitination degradation via the MYH9/β-catenin/c-Jun/LncRNA-KDM4A axis in NPC. DNASE1L3 is a potential marker for predicting NPC prognosis.
Beyond neurotransmission: the roles of serotonylation in physiological and pathological processes.
Wang JM, Zhang FH, Chen YR … +6 more , Chen DN, Wang X, Xie HY, Li JF, Luo JD, Xie LP
Cell Mol Biol Lett · 2026 May · PMID 42087096 · Full text
Serotonin, also known as 5-HT, is a classical neurotransmitter produced both in the nervous system and in non-nervous system. Its involvement in various fundamental physiological processes and pathogenic conditions is si...
Serotonin, also known as 5-HT, is a classical neurotransmitter produced both in the nervous system and in non-nervous system. Its involvement in various fundamental physiological processes and pathogenic conditions is significant, as it binds to a diverse array of functionally distinct receptors. Apart from binding to 5-HT receptors and activating downstream signaling cascades, recent studies have revealed a novel posttranslational modification named serotonylation, where serotonin is re-taken up by serotonin transporter and is covalently attached to target proteins ranging from histone proteins to nonhistone proteins. Transglutaminases (TGMs), especially TGM2, catalyze serotonylation through the transfer of serotonin to the glutamine residues of target proteins. This review aims to investigate recent progresses in understanding the involvement of serotonylation in physiological and pathological processes. In addition, this review emphasizes how to target serotonylation as a therapeutic strategy for disease management.
BRD2 upregulation as a pan-cancer adaptive resistance mechanism to BET inhibition.
Archasappawat S, Jacques J, Lee E … +1 more , Hwang CI
Cell Mol Biol Lett · 2026 May · PMID 42069518 · Full text
Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinica...
Bromodomain and extraterminal motif (BET) inhibitors, such as JQ1, are promising cancer therapeutics that target epigenetic regulators, particularly BRD4. However, resistance to BET inhibitors (BETi) limits their clinical utility, necessitating a better understanding of adaptive mechanisms. We identified BRD2 upregulation as a conserved response to BET inhibition across multiple cancer types and hypothesized that BRD2 compensates for BRD4 loss, sustaining essential transcriptional programs upon treatment. Consistent with this, BRD2 knockdown sensitized cancer cells to BETi in vitro, and combining BRD2 depletion and JQ1 treatment significantly impaired tumor growth in vivo. At the chromatin level, BRD2 and BRD4 ChIP-seq analysis of pancreatic cancer cells showed consistent BRD4 loss from chromatin after JQ1 treatment, while BRD2 displacement differed by sensitivity. Resistant cells maintained higher BRD2 occupancy than sensitive cells, suggesting a link between BRD2 retention and drug response. Mechanistically, NFYA mediates BRD2 upregulation as NFYA depletion attenuated BRD2 upregulation upon BETi treatment. Collectively, our findings establish BRD2 as a critical mediator of pan-cancer adaptive resistance to BETi and identify NFYA as a novel transcriptional regulator of this process. Co-targeting BRD2 or its regulatory network offers a rational strategy to enhance the durability and efficacy of BET-based therapies.
IRE1-XBP1driven induction of TMED9 stabilizes ATF6 during ER stress to promote cell survival.
Lenchisky C, Muhammad Majadly A, Bronshtein Berger I … +9 more , Biton D, Daoud Sarsour A, Arbeli N, Cohen T, Amos N, Kinstlinger S, Cohen O, Horwitz E, Dvela-Levitt M
Cell Mol Biol Lett · 2026 Apr · PMID 42062868 · Full text
BACKGROUND: The endoplasmic reticulum (ER) plays a central role in protein homeostasis by facilitating the folding, modification, and quality control of secretory and membrane proteins. Disruption of ER function results...
BACKGROUND: The endoplasmic reticulum (ER) plays a central role in protein homeostasis by facilitating the folding, modification, and quality control of secretory and membrane proteins. Disruption of ER function results in protein misfolding and ER stress, which activate the unfolded protein response (UPR). While the three canonical UPR branches, inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6), have been extensively studied, the mechanisms that coordinate their activities and ultimately dictate survival or death remain poorly understood. Transmembrane P24 trafficking protein 9 (TMED9), a cargo receptor that cycles between the ER and Golgi, has been implicated in protein quality control under pathological conditions, but its physiological role in ER proteostasis and UPR signaling is unclear. METHODS: The ER stress response was studied in cellular human models including normal epithelial cells and patient-derived pediatric glioma cultures. To define the regulatory mechanisms dictating TMED9 expression, quantitative Reverse Transcription polymerase chain reaction (qRT-PCR), luciferase reporter assay, and western blotting were employed. To elucidate TMED9 function, loss-of-function approaches, including clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-mediated knockout and small interfering RNA knockdown were used in combination with RNA-seq and live imaging. Protein stability was tested by pulse-chase experiments, ubiquitination, and degradation analyses. To study the implications of TMED9 activation, we screened curated gene expression datasets from the European Molecular Biology Laboratory- European Bioinformatics Institute (EMBL-EBI) Expression Atlas and employed live-cell imaging-based assays and functional assays (cell viability, apoptosis, migration, and self-renewal). RESULTS: Our study uncovers a physiological role for TMED9 in ER proteostasis and UPR signaling. We show that, under ER stress, TMED9 expression is transcriptionally induced by the IRE1-spliced X-box binding protein 1 (XBP1s) pathway via a conserved unfolded protein response element (UPRE)-like element in its promoter. Removal of TMED9 selectively impairs ATF6 activation without altering IRE1 or PERK signaling, resulting in increased sensitivity to ER stress-induced apoptosis. Mechanistically, we identify TMED9 as a stress-induced stabilizer of ATF6 that prevents its ubiquitin-dependent proteasomal degradation. Functionally, TMED9 regulation is exploited by tumor cells, which sustain IRE1-XBP1s activity to upregulate TMED9, thereby enhancing survival under ER stress conditions. CONCLUSIONS: Collectively, our findings establish TMED9 as a critical regulator of ER stress adaptation. TMED9 emerges as a molecular mediator that links IRE1-dependent transcriptional response to ATF6 stabilization, ultimately supporting increased secretory demand under stress conditions and in cancer development.
Differentiation state affects PD-L1 expression in cutaneous melanoma: a systematic review.
Sævarsson T, Vu HN, Steingrímsson E … +1 more , Einarsdóttir BÓ
Cell Mol Biol Lett · 2026 Apr · PMID 42056900 · Full text
BACKGROUND: Programmed death ligand-1 (PD-L1) is a widely used biomarker for immunotherapy in melanoma. The expression of PD-L1 in melanoma cells is known to vary considerably among and within patients' tumor samples. Re...
BACKGROUND: Programmed death ligand-1 (PD-L1) is a widely used biomarker for immunotherapy in melanoma. The expression of PD-L1 in melanoma cells is known to vary considerably among and within patients' tumor samples. Recent studies suggest that there may be a link between PD-L1 expression and the differentiation status of melanoma cells which is known to fluctuate in response to external stimuli and to be influenced by a multitude of regulators. Here, we systematically review which differentiation regulators affect PD-L1 expression in melanoma. METHODS: A systematic review was performed on studies collected through PubMed, Scopus, and Web of Knowledge up until February 13, 2026. Screening of abstracts and titles was performed independently by two reviewers. Screening of full-text articles, data extraction, and validity assessments were performed by one reviewer. Studies published in English reporting changes in PD-L1 expression associated with a known differentiation regulator in a melanocytic/melanoma model were included. Studies were assessed for risk of bias regarding imprecision in experimental reporting and model validity, using previously defined assessment tools. Synthesis of results was performed narratively. RESULTS: Out of 496 identified articles, 57 studies met the inclusion criteria. A total of 16 differentiation regulators were significantly associated with PD-L1 expression in melanoma cells. Most studies (45/57) reported a single regulator, while 12/57 reported multiple. STAT3 appeared in 20/57 studies; all other regulators were reported in eight or fewer. PD-L1 expression was positively associated with all dedifferentiation-linked regulators (9/9). Among differentiation-linked regulators, 3/4 (MITF, SOX10, IRF4) showed contrasting associations depending on the PD-L1 expression mode and study. In total, 120 human and 10 mouse melanoma cell lines were used. The A375, SK-MEL-28, and B16 cell lines were used in 20, 18, and 28 studies, respectively, suggesting lineage bias. Most studies had unclear risk of bias regarding imprecision (82%) and model validity (70%). CONCLUSIONS: PD-L1 expression is commonly affected by differentiation regulators in melanoma cells, linking high PD-L1 expression to dedifferentiated cell states. The various regulators and inducible pathways that affect PD-L1 may in turn explain the heterogeneity observed in PD-L1 expression between and within patients with melanoma. Owing to the clinical significance of PD-L1 expression as a predictive biomarker for immunotherapy response, it is crucial to better understand the impact of various regulators on its expression.
Chicoric acid targets PYGL to normalize glycogenolysis-driven glycolysis to suppress non-small cell lung cancer.
Huo X, Hou H, Zhang C … +5 more , Duan X, Lan H, Li Y, Zhou N, Zhang X
Cell Mol Biol Lett · 2026 Apr · PMID 42056865 · Full text
BACKGROUND: Chicoric acid (CA), a bioactive natural compound found in Chicory and Echinacea purpurea, exhibits antiinflammatory, antioxidant, and apoptosis-inducing properties. However, its therapeutic potential and unde...
BACKGROUND: Chicoric acid (CA), a bioactive natural compound found in Chicory and Echinacea purpurea, exhibits antiinflammatory, antioxidant, and apoptosis-inducing properties. However, its therapeutic potential and underlying mechanisms in non-small cell lung cancer (NSCLC) remain unclear. METHODS: We utilized bioinformatics analysis to identify potential hub genes targeted by CA. The clinical relevance of glycogen phosphorylase liver form (PYGL) was assessed via immunohistochemistry in NSCLC tissues. Functional assays, including Cell Counting Kit-8, flow cytometry, and xenograft models, were employed to evaluate the impact of PYGL on tumor growth. Glycogen metabolism and glycolytic flux were monitored using PAS staining and Seahorse assays. Direct binding between CA and PYGL was confirmed through virtual screening, molecular docking, cellular thermal shift assay, and surface plasmon resonance. Binding specificity was further validated using site-directed mutagenesis. RESULTS: Here, we demonstrate that CA restores glucose metabolic homeostasis and inhibits the proliferation of NSCLC cells. We identified PYGL as a key driver of NSCLC, where its upregulation enhances glycogenolysis to fuel glycolytic flux and promote tumor growth. Mechanistically, CA allosterically inhibits PYGL by binding to specific residues (Glu162, Arg247, Glu273) and inducing conformational changes, thereby suppressing glycogenolysis and reducing glycolysis. Furthermore, CA disrupts the interaction between PYGL and lactate dehydrogenase A (LDHA), accelerating the proteasomal degradation of LDHA and further reshaping glucose metabolic homeostasis. CONCLUSIONS: Our findings highlight PYGL as a metabolic vulnerability in NSCLC and establish CA as a promising lead compound that targets the PYGL-LDHA axis to reprogram glucose metabolism and inhibit tumor growth.
Placental exosomal miR-372-3p drives preeclampsia progression by inducing mitochondrial damage in RVLM neurons.
Zhang S, Wang L, Zhao B … +7 more , Dai T, Nie M, Tong L, Zeng Q, Guo W, Shen Y, Du D
Cell Mol Biol Lett · 2026 Apr · PMID 42032459 · Full text
BACKGROUND: Preeclampsia (PE) is a pregnancy-specific disorder rooted in placental dysfunction, characterized by new-onset hypertension with proteinuria and/or end-organ dysfunction, often linked to sympathetic overactiv...
BACKGROUND: Preeclampsia (PE) is a pregnancy-specific disorder rooted in placental dysfunction, characterized by new-onset hypertension with proteinuria and/or end-organ dysfunction, often linked to sympathetic overactivation. The rostral ventrolateral medulla (RVLM) serves as a crucial hub for sympathetic and blood pressure (BP) control. Placental exosomes are implicated in PE, but their role in placenta–RVLM communication is unclear. Investigating this could reveal the neurogenic pathogenesis underlying cardiovascular dysregulation in PE. METHODS: Placental exosomes derived from patients with PE (PE-exo) and normal pregnancies (N-exo) were isolated by ultracentrifugation. Their roles in regulating RVLM neuronal excitability, sympathetic tone, and BP, along with the underlying mechanisms, were evaluated using various experiments. RESULTS: Tail vein injection of PE-exo significantly enhanced RVLM neuronal excitability, sympathetic tone, and BP in pregnant rats. miR-372-3p levels were significantly elevated in PE-exo compared with N-exo and were upregulated in the RVLM of pregnant rats following PE-exo administration. miR-372-3p knockdown reversed the PE-exo-induced increases in RVLM neuronal excitability, sympathetic tone, and BP in pregnant rats. Mechanistically, miR-372-3p markedly reduced MPC1 expression, leading to RVLM neuronal mitochondrial damage. CONCLUSIONS: This study is the first to demonstrate that placental exosomes deliver miR-372-3p to the RVLM neurons, impairing neuronal mitochondrial function and thereby promoting neuronal hyperexcitability, sympathetic overactivity, and elevated BP in PE.
Upregulated CCN1 from pleural mesothelial cells alters collagen I conformation and drives fibrosis via ITGB1/MAPK signaling.
Cui XL, Song LJ, Li Q … +18 more , Jia ZH, Dai X, Wang M, Lv YP, Chen SJ, Zhang HD, Cheng PP, Ye SY, Hu SH, Lian CY, Liang LM, Yu F, He XL, Xiong L, Xiang F, Wang X, Ye H, Ma WL
Cell Mol Biol Lett · 2026 Apr · PMID 42021147 · Full text
BACKGROUND: Pleural mesothelial cells (PMCs) have been identified as key contributors to pleural fibrosis. Cellular communication network factor 1 (CCN1), a matricellular protein, regulates cell–matrix interactions and f...
BACKGROUND: Pleural mesothelial cells (PMCs) have been identified as key contributors to pleural fibrosis. Cellular communication network factor 1 (CCN1), a matricellular protein, regulates cell–matrix interactions and fibrotic signaling in multiple contexts. However, the specific role and mechanism of CCN1 in PMCs during pleural fibrosis remained unclear. METHODS: Expression of CCN1 was evaluated in human pleural fibrosis samples and bleomycin-induced mouse models. In vitro, PMCs were treated with recombinant CCN1 or fibrotic matrix. Mechanistic studies included gene knockdown, immunoprecipitation, mass spectrometry, and functional assays. RESULTS: CCN1 was significantly elevated in pleural fibrosis tissues. CCN1 expression was driven by YAP/TAZ activation and in turn promoted further YAP/TAZ activation, creating a feedback loop to produce more CCN1. Upregulated CCN1 directly altered conformation of type I collagen (collagen I) by binding vWC binding domain. Then, CCN1 with conformation-changed collagen I activated integrin β1 (ITGB1)/MAPK signaling, which induced remodeling of cytoskeleton as well as fibrosis. At last, it was confirmed that neutralization of CCN1 reduced pleural fibrosis in vitro and in vivo. CONCLUSIONS: Upregulated CCN1 contributes to pleural fibrosis via changing collagen I conformation and ITGB1/MAPK pathway activation. Targeting CCN1 is a potential therapeutic strategy.
DDX17-mediated raptor-dependent mTORC1 activation links autophagy inhibition and metabolic compensation in HCC development.
Lv C, Luo N, Wei C … +7 more , Zhang Q, Guo K, Jiang X, Cao X, Mazaher M, ElFar A, Fu J
Cell Mol Biol Lett · 2026 Apr · PMID 42021139 · Full text
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with an increasing global incidence and mortality. Dysregulated gene expression drives uncontrolled proliferation and metastasis, contributing to poor p...
Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with an increasing global incidence and mortality. Dysregulated gene expression drives uncontrolled proliferation and metastasis, contributing to poor patient survival despite therapeutic advances. The DEAD-box RNA helicase DDX17 has been implicated in tumorigenesis, but its functional role and underlying mechanisms in HCC remain incompletely defined. Here, we found that DDX17 drives HCC tumorigenesis via a novel mechanism involving direct binding to Raptor, a core component of the mTORC1 complex, thereby activating mTORC1 signaling and inhibiting autophagy, as evidenced by reduced autophagosome formation and a decreased LC3-II/LC3-I ratio. Moreover, DDX17 unwinds the RNA G-quadruplex (rG4) structure in the Raptor 3′ untranslated region (3′ UTR), enhancing its translation and establishing Raptor as an rG4-dependent oncogenic target. Combined DDX17 knockdown and rapamycin treatment synergistically suppressed proliferation and induced autophagy. Additionally, DDX17 inhibition reshaped tumor cell metabolism by decreasing extracellular acidification and promoting lipid droplet accumulation following autophagy induction, highlighting its role in metabolic adaptation. These findings suggest that DDX17 promotes HCC progression by unwinding the rG4 motif in Raptor mRNA to enhance translation, activating mTORC1 signaling, and suppressing autophagy. Hence, co-targeting DDX17 and mTORC1 produces strong synergistic antitumor effects, revealing a promising therapeutic strategy for HCC.
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