Cell. Mol. Biol. Lett. [JOURNAL]
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Abnormal cholesterol-cholesteryl ester metabolism impairs mouse oocyte quality during ovarian aging.
Zhang S, Guo B, Fang J … +10 more , Wang S, Liu Y, Wu D, Kang N, Zhang Y, Zhen X, Yan G, Ding L, Sun H, Liu C
Cell Mol Biol Lett · 2025 Nov · PMID 41286604 · Full text
BACKGROUND: Ovarian aging-induced decline in oocyte quality has been a main issue in women of advanced maternal age. However, the potential mechanism remains elusive, and there are no effective strategies to ameliorate a...
BACKGROUND: Ovarian aging-induced decline in oocyte quality has been a main issue in women of advanced maternal age. However, the potential mechanism remains elusive, and there are no effective strategies to ameliorate aged oocyte quality. The lipid metabolism of oocytes has drawn great attention, but the intrinsic regulation of oocyte quality by metabolites, metabolic enzymes, and intracellular mediators is less well-characterized. METHODS: Targeted lipidomics was employed to detect the neutral lipids in oocytes during maturation. We used 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503) and Filipin to stain cholesteryl ester and free cholesterol, respectively. The Cholesterol/Cholesteryl Ester Quantification Assay kit was used further to quantify cholesterol-related metabolites. Western blotting was performed to evaluate acyl-coenzyme A: cholesterol acyltransferase 1/2 (ACAT1/2) expression. Immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR) were conducted to validate the knockdown efficiency of ACAT1. Avasimibe treatment and ACAT1 small interfering RNA (siRNA) microinjection were performed to investigate the effect of impaired cholesterol-cholesteryl ester metabolism on oocyte quality. Single-oocyte RNA sequencing was conducted to explore the mechanism. Mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, reactive oxygen species (ROS), and mitochondrial autophagosomes were detected to evaluate mitochondrial function and mitophagy. RESULTS: There is a profound increase in the conversion of cholesterol to cholesteryl ester in oocytes during maturation, which depends on ACAT1. Conversely, disturbing the homeostasis of cholesterol-cholesteryl ester metabolism by manipulating ACAT1 impairs oocyte quality, primarily manifested as decreased polar body extrusion (PBE), increased meiotic defects, and abnormal early embryonic development. Mechanistically, the impaired conversion of cholesterol to cholesteryl ester reduces oocyte mitophagy, leading to mitochondrial dysfunction, including reduced MMP and ATP production, and excessive accumulation of ROS. Notably, we also reveal that this metabolic homeostasis is impaired in aged oocytes, accompanied by decreased ACAT1 levels. Moreover, cholesteryl ester supplementation via cholesterol conjugated to methyl-β-cyclodextrin (CCM) can effectively ameliorate aged oocyte quality by enhancing mitophagy. CONCLUSIONS: This study reveals the mechanism by which cholesterol-cholesteryl ester metabolism regulates oocyte quality and thus participates in the process of oocyte aging by influencing mitophagy and mitochondrial function.
Fusobacterium nucleatum-derived extracellular vesicles carrying virulence factor DNA trigger AIM2 inflammasome activation to facilitate UC progression.
Zhao Y, Wu R, Duan Y … +7 more , Kong X, Zhang Y, You Y, Zhang J, Wang Y, Zhou L, Duan L
Cell Mol Biol Lett · 2025 Nov · PMID 41249954 · Full text
BACKGROUND: Immune disorders and impaired intestinal barrier function resulting from dysbiosis of the intestinal flora play pivotal roles in the pathogenesis of ulcerative colitis (UC). Fusobacterium nucleatum (F. nuclea...
BACKGROUND: Immune disorders and impaired intestinal barrier function resulting from dysbiosis of the intestinal flora play pivotal roles in the pathogenesis of ulcerative colitis (UC). Fusobacterium nucleatum (F. nucleatum, Fn) can secrete extracellular vesicles (EVs) that surmount the mucus layer, thereby contributing to UC progression. However, the underlying mechanisms and their clinical significance remain elusive. METHODS: Bioinformatics and clinical sample analysis were employed to explore the relationship between F. nucleatum and the absent in melanoma 2 (AIM2) inflammasome. Both in vivo and in vitro studies were performed to analyze the regulatory effects of extracellular vesicles released by F. nucleatum (Fn-EVs), which carry harmful molecules to the AIM2 inflammasome, as well as their ultimate role and clinical significance in UC progression. RESULTS: Bioinformatics analysis showed upregulated expression of AIM2 and downstream pyroptosis-related genes in active UC, and that the AIM2 gene was linked to bacterial invasion and tight junctions. The clinical correlation between both F. nucleatum and its virulence proteins and the AIM2 inflammasome and downstream molecules was verified. Internalization of Fn-EVs by intestinal epithelial cells (IECs) triggered activation of the AIM2 inflammasome along with downstream pyroptosis molecules, resulting in damage to the intestinal barrier. Furthermore, we revealed that DNA components within Fn-EVs (Fn-EVs-DNA) play crucial roles in inducing these effects. Administration of DNase I, which targets Fn-EVs-DNA or A151 to block AIM2 inflammasome activation, effectively alleviated pyroptosis in IECs and restored gut barrier integrity, thereby mitigating UC progression. CONCLUSIONS: Fn-EVs carrying the virulence factor DNA (Fn-DNA) are internalized by IECs to trigger AIM2 inflammasome-dependent pyroptosis and intestinal barrier disruption, eventually aggravating colitis. Targeting the Fn-EVs-DNA–AIM2 cascade may represent a promising therapeutic strategy for UC.
Human umbilical cord mesenchymal stromal cell-derived exosomes alleviate antibiotic-induced intestinal barrier damage by regulating autophagy via the S100G/mTOR signaling pathway.
Guo Y, Li Y, Shi M … +10 more , Li Y, Qiang J, Li J, Gao H, Zhu G, Xie B, Guo X, He B, Zhang B, Liu B
Cell Mol Biol Lett · 2025 Nov · PMID 41249917 · Full text
BACKGROUND: Antibiotics are a double-edged sword. Long-term, broad-spectrum, and high-dose antibiotic use can lead to the occurrence of related diseases, particularly attracting attention in the context of intestinal bar...
BACKGROUND: Antibiotics are a double-edged sword. Long-term, broad-spectrum, and high-dose antibiotic use can lead to the occurrence of related diseases, particularly attracting attention in the context of intestinal barrier damage. However, current clinical treatments remain suboptimal. Human umbilical cord mesenchymal stromal/stem cell-derived exosomes (HucMSCs-Exo) have demonstrated therapeutic efficacy in tissue repair and inflammatory bowel diseases. However, studies on their role in antibiotic-induced intestinal barrier damage remain limited. OBJECTIVE: This study aims to investigate the therapeutic effects and underlying mechanisms of HucMSCs-Exo in treating antibiotic-induced intestinal mucosal barrier damage. METHODS: A mouse model of antibiotic-induced intestinal barrier damage was established by administering clindamycin hydrochloride via gavage for 28 consecutive days in C57BL/6 male mice. The therapeutic effects of HucMSCs-Exo were evaluated through intraperitoneal injections at low and high concentrations every other day. Transcriptomic sequencing and other techniques were used to identify target genes and mechanistic pathways involved in HucMSCs-Exo mediated repair of intestinal mucosal barrier damage. Finally, the findings were validated in vitro using human colonic epithelial NCM460 cells. RESULTS: The in vivo mouse experiments demonstrated that HucMSCs-Exo effectively alleviated antibiotic-induced intestinal barrier damage. Both low- and high-concentration exosome treatments improved the antibiotic-induced reduction in body weight gain, shortened colon length,disrupted intestinal epithelial continuity, increased permeability owing to microvilli structural damage, and decreased expression of tight junction proteins (ZO-1, Occludin, and Claudin-1). The in vitro cell experiments further showed that both low- and high-concentration exosome treatments restored antibiotic-induced reductions in cell proliferation and migration, as well as increased autophagy and apoptosis, with the high-concentration group showing significant differences (p < 0.05). Transcriptomic analysis of mouse colonic tissues revealed that differentially expressed genes were enriched in autophagy-related and apoptosis-related pathways, with S100G identified as a potential target gene of HucMSCs-Exo. Knockdown of the S100G gene in NCM460 cells yielded results consistent with the HucMSCs-Exo treatment group, indicating that HucMSCs-Exo exerts its effects by promoting mTOR phosphorylation, thereby inhibiting excessive autophagy. CONCLUSIONS: HucMSCs-Exo alleviates antibiotic-induced intestinal mucosal barrier damage by inhibiting excessive autophagy-mediated apoptosis via the S100G/mTOR signaling pathway. Our findings elucidate the role and mechanism of exosomes in antibiotic-induced intestinal mucosal barrier damage, providing new insights for the therapeutic potential of exosomes in related fields.
CDK5 regulates PPARγ/NF-κB signaling to exacerbate obesity-related osteoarthritis via modulating macrophage polarization and chondrocyte apoptosis.
Li Y, Li H, Chen X … +5 more , Li X, Su J, Yang S, Xiao W, Deng Z
Cell Mol Biol Lett · 2025 Nov · PMID 41233759 · Full text
BACKGROUND: Obesity is an important risk factor for osteoarthritis (OA), but the mechanisms associated with OA progression are still not fully understood. The aim of this study was to investigate the role of cyclin-depen...
BACKGROUND: Obesity is an important risk factor for osteoarthritis (OA), but the mechanisms associated with OA progression are still not fully understood. The aim of this study was to investigate the role of cyclin-dependent kinase 5 (CDK5) in regulating the peroxisome proliferator-activated receptor gamma (PPARγ)/nuclear factor-κB (NF-κB) signaling pathway and its effect on obesity-related OA. METHODS: By analyzing tissue samples from obese and nonobese patients with OA in conjunction with a high-fat diet (HFD)-induced obese mouse model of OA, we investigated the expression level of CDK5 and its effects on inflammation and apoptosis. The role of CDK5 in macrophage polarization and chondrocyte apoptosis was further explored by gene knockdown and pharmacological intervention. RESULTS: CDK5 levels were found to be significantly elevated in obese patients with OA, promoting M1 macrophage infiltration and chondrocyte apoptosis. In the model, CDK5 knockdown attenuated cartilage damage and inhibited PPARγ phosphorylation and NF-κB signaling. In vitro experiments showed that overexpression of CDK5 facilitated M1 macrophage polarization and chondrocyte apoptosis, and PPARγ agonists reversed these effects. Mechanically, CDK5 binds to PPARγ to regulate the NF-κB signaling pathway. CONCLUSION: CDK5 promotes the progression of obesity-associated OA through the PPARγ/NF-κB pathway and is a potential therapeutic target in OA, especially in obese patients.
E0703 targets ERβ to facilitate the upregulation of GLI3, thereby alleviating irradiation-induced DNA damage on lymphocytes.
Liao Z, Zhang L, Wu Z … +5 more , Hu C, Tang X, Xiao C, Qian L, Gao Y
Cell Mol Biol Lett · 2025 Nov · PMID 41233737 · Full text
BACKGROUND: Radiotherapy for malignant tumor treatment and irradiation (IR)-related diagnosis damage lymphocytes, which inevitably suppresses immunity and leads to unwanted clinical outcomes. However, a few agents have b...
BACKGROUND: Radiotherapy for malignant tumor treatment and irradiation (IR)-related diagnosis damage lymphocytes, which inevitably suppresses immunity and leads to unwanted clinical outcomes. However, a few agents have been approved by the Food and Drug Administration (FDA) to alleviate IR-induced injury. Here, the radioprotective effect and underlying mechanism of a new steroidal compound optimized from estradiol (E0703) were investigated. METHODS: Mice were exposed to γ-ray IR to establish an in vivo model of radiation injury, and human peripheral blood B lymphocytes (AHH-1) were employed to investigate injury in lymphocytes. Protein level changes in cell and tissue samples were detected by western blot and immunofluorescence. DNA damage was assessed by the comet assay and γH2AX staining. RNA sequencing was used to screen the critical genes mediating the radioprotective effect of E0703. To determine the direct target of E0703, cellular thermal shift (CETSA), drug affinity responsive target stability (DARTS), molecular docking, and surface plasmon resonance (SPR) assays were adopted. GLI3 transactivation by estrogen receptor β (ERβ) was determined by the chromatin immunoprecipitation (ChIP) assay, while protein interactions were detected by coimmunoprecipitation (Co-IP). IP products were subjected to label-free proteomics assay to screen GLI3 conjugates. RESULTS: E0703 significantly improved survival and tissue injury in mice exposed to IR damage. In lymphocytes, IR-induced DNA damage was ameliorated with E0703 in an ataxia-telangiectasia mutated protein (ATM)-checkpoint kinase 2 (CHK2)-dependent manner. ERβ but not ERα was a direct target of E0703, wherein ERβ enhancement on the promoter region of GLI3 triggered by E0703 could sustain its protein expression. The interaction between GLI3 and eIF4G1 favored by E0703 was critical for the formation of the eIF4F translation-initiation complex. eIF4F assembly was indispensable for the stimulation of ATM-CHK2 signaling involved in DNA damage repair. CONCLUSIONS: E0703 alleviated IR-induced DNA damage in lymphocytes by selectively targeting ERβ. The formation of the eIF4F complex in a GLI3-dependent manner was critical for ATM-CHK2 activation triggered by E0703. Our study provides an alternative countermeasure to alleviate IR-induced lymphopenia in individuals undergoing radiotherapy or IR-related diagnosis.
Cellular osmoregulation enhances porcine embryo development by restoring zygotic genome activation via metabolic-epigenetic crosstalk.
Zhao X, Liu L, Chu X … +6 more , Zhang Y, Tang Y, Shao J, Fan B, Yang Y, Xu B
Cell Mol Biol Lett · 2025 Nov · PMID 41233731 · Full text
INTRODUCTION: In vitro embryo culture is essential for human assisted reproduction and livestock breeding, yet its efficiency remains limited owing to developmental arrest triggered by suboptimal media composition and en...
INTRODUCTION: In vitro embryo culture is essential for human assisted reproduction and livestock breeding, yet its efficiency remains limited owing to developmental arrest triggered by suboptimal media composition and environmental stressors. Preimplantation embryos are highly sensitive to a minor increase in osmolarity under organic osmolyte deficiency, which disrupts cell volume homeostasis to cause developmental block. However, the osmosensing mechanisms and the causal link between volume dysregulation and developmental arrest remain undefined. Elucidating these mechanisms will identify targeted osmoregulatory interventions to enhance in vitro culture efficiency. METHODS: This study established a porcine two-cell embryo developmental arrest model under physiological-range hyperosmotic stress (330 mOsm) and organic osmolyte deficiency, which disrupts cell volume homeostasis. Through single-embryo RNA-seq, Real-time quantitative polymerase chain reaction (RT-qPCR), H3K4me3/H3K27ac/H3K9me3/mA/BrdU immunofluorescence, mitochondrial assays (MitoTracker Red and reactive oxygen species (ROS) staining), and metabolic analysis (pyruvate dehydrogenase (PDH) activity by Western blotting, fatty acid oxidation by FAOBlue staining), we identified hyperosmosis-induced developmental impairments. Rescue experiments via organic osmolyte supplementation, PDH modulation, and epigenetic interventions further defined the molecular basis of embryonic arrest. RESULTS: Here, we reveal that physiological-range hyperosmolarity in the absence of organic osmolytes disrupts cell volume homeostasis in porcine two-cell embryos, triggering developmental arrest at the S phase of the four-cell stage. This arrest coincides with aberrant maternal-to-zygotic transition, characterized by impaired maternal transcript degradation, compromised zygotic genome activation (ZGA), and coordinated dysregulation of nuclear and mitochondrial DNA transcription. Mechanistically, arrested embryos exhibit disrupted metabolic-epigenetic crosstalk, including PDH inactivation via S293 p-PDH accumulation that blocks pyruvate-to-acetyl-coenzyme A (CoA) conversion, fatty acid β-oxidation inhibition, alongside elevated mitochondrial membrane potential (MMP), increased ROS accumulation, and reduced H3K4me3 and H3K27ac modifications. Critically, while pharmacological modulation of H3K4me3/H3K27ac fails to rescue developmental defects, restoring volume homeostasis with organic osmolytes (e.g., glycine/betaine) or reactivating PDH via dichloroacetate (DCA) treatment completely reverses hyperosmotic stress-induced developmental arrest. CONCLUSIONS: These findings identify that mitochondria in porcine preimplantation embryos act as osmotic stress sensors. Under conditions of extracellular organic osmolyte deficiency and elevated osmolarity, they drive metabolic reprogramming and nuclear epigenetic dysregulation, ultimately disrupting mitochondrial-nuclear communication, compromising ZGA, and inducing developmental arrest. These findings provide mechanistic insights for optimizing in vitro culture systems in reproductive technologies.
Y-chromosome alteration and its impact on cancer progression and metastasis.
King SA, Jahan M, Prabhakaraalva P … +5 more , Zaman N, Chaudhary S, Kyprianou N, Tewari AK, Chakraborty G
Cell Mol Biol Lett · 2025 Nov · PMID 41214505 · Full text
The human Y chromosome (ChrY), which confers male sex determination, contains a relatively small number of protein-coding genes compared to other chromosomes; consequently, its functional impact on adult physiology was o...
The human Y chromosome (ChrY), which confers male sex determination, contains a relatively small number of protein-coding genes compared to other chromosomes; consequently, its functional impact on adult physiology was once severely unappreciated. While the repetitive structure of the ChrY once impeded sequencing, technological advances have now made it possible to identify its contents. Despite the historical view of ChrY as a virtual wasteland, we now know that it encodes a variety of genes which are hugely consequential to both human health and disease. The extreme downregulation of ChrY gene expression, resulting from partial or total loss of ChrY (LOY), is a common characteristic observed in various disease states in men, including cardiovascular, neurodegenerative, immunological health issues, and ,most notably, cancer. Additionally, mosaic LOY (mLOY) is sometimes found in primary cancerous tissues and is associated with poorer clinical outcome. Although, the reasons for these associations were once elusive, they are now understood to be linked to the activity of several ChrY genes, as well as the pleiotropic effects of their loss. In this review, we critically analyze contemporary and historic scientific literature which evaluate the clinical LOY trends seen in male exclusive/predominant cancers as well as explore the now identified mechanisms of ChrY alteration in cancer initiation, progression, and metastasis. Moreover, we discuss recent research studies which have uncovered novel mechanisms through which LOY may induce the physiological and molecular changes in the tumor microenvironment (TME) associated with malignant transformation and the evasion of innate immunity. Interestingly, the TME formed by malignant cells with LOY appears to contribute to early T cell exhaustion in infiltrating immune cells and consequent compromised tumor clearance; a phenomenon which has been profusely observed in patient samples. Furthermore, we describe the tumor-suppressive activities of the ChrY demonstrated in previous studies, as well as its newly identified roles in cancer immunology.
lncRNA IGFL2-AS1 mediates NSCLC chemoresistance via YBX1-induced HSPA1A/RAP1 activation.
Dong H, Xia Y, Qi J … +11 more , Liu C, Wang F, Cui B, Chen W, Lv W, Zhai N, Deng J, Yu Y, Ning F, Schmitt CA, Du J
Cell Mol Biol Lett · 2025 Nov · PMID 41204108 · Full text
BACKGROUND: The development of drug resistance in cancer is associated with multiple malignant properties, including proliferative progression, metastasis, and stemness. Long noncoding RNAs (lncRNAs) reportedly contribut...
BACKGROUND: The development of drug resistance in cancer is associated with multiple malignant properties, including proliferative progression, metastasis, and stemness. Long noncoding RNAs (lncRNAs) reportedly contribute to multidrug resistance in lung cancer. However, functional and mechanistic studies of key lncRNAs associated with lung cancer are lacking. METHODS: Candidate lncRNA IGFL2-AS1 and its downstream target, the HSPA1A and RAP1 cascade, were identified using RNA sequencing. In vitro functional assays, including proliferation, clonal formation, Transwell migration, sphere formation, and drug sensitivity test, were conducted to explore the function of the IGFL2-AS1/HSPA1A axis in lung cancer. For in vivo functional validation, subcutaneous implantation and tail vein injection of luciferase-tagged lung cancer cells were performed in mouse models. Moreover, RNA pulldown, RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), and point/truncated mutations were utilized to dissect the mechanisms underlying the activation of the YBX1-mediated IGFL2-AS1/HSPA1A axis. Pharmacological inhibition of HSPA1A was performed to restore chemotherapy sensitivity and attenuate lung cancer cell metastasis in vivo. Finally, tissue microarray staining was employed to evaluate the expression of the YBX1/IGFL2-AS1/HSPA1A/RAP1 axis in lung cancer specimens and its correlation with prognosis. RESULTS: IGFL2-AS1, stimulated by C/EBPβ, was aberrantly upregulated in chemoresistant cell lines and lung cancer specimens. IGFL2-AS1 promoted lung cancer proliferation, metastasis, drug resistance, and stemness by upregulating HSPA1A expression both in vitro and in vivo. Mechanistically, IGFL2-AS1 recruited YBX1 to the HSPA1A promoter, facilitating its transcription. Pharmacological inhibition of HSPA1A restored the sensitization of A549 cells resistant to cisplatin and 5-fluorouracil via the downstream RAP1 signaling cascade. Notably, the YBX1/IGFL2-AS1/HSPA1A axis was consistently activated in lung cancer specimens and correlated with poor patient prognosis. CONCLUSIONS: This study demonstrated that the YBX1-modulated IGFL2-AS1/HSPA1A/RAP1 axis is aberrantly activated in lung cancer cells and is associated with unfavorable prognosis, highlighting its potential as a novel therapeutic target in clinical settings.
The ISGylation tapestry in cancer: weaving phenotypic plasticity through multidimensional regulatory looms.
Wu R, Shao F, Koh SB … +9 more , Okoli UA, Li D, Wang J, Tuo Z, Zhang R, Wusiman D, Cheema U, Kong D, Feng D
Cell Mol Biol Lett · 2025 Nov · PMID 41193953 · Full text
Post-translational modification is an important mechanism for regulating protein function and cell signaling networks. Among these modifications, ISGylation is a ubiquitin-like modification regulated by ISG15. In this re...
Post-translational modification is an important mechanism for regulating protein function and cell signaling networks. Among these modifications, ISGylation is a ubiquitin-like modification regulated by ISG15. In this review, we explore the role of ISGylation in a variety of related phenotypes in the tumor context, including apoptosis regulation, autophagy regulation, immune escape, metabolic reprogramming, cancer stem cell maintenance, and DNA damage repair. ISGylation plays a dual role in apoptosis, promoting either pro-survival or pro-death pathways depending on contexts. It also regulates autophagy by promoting tumor adaptation or by regulating immune responses. Moreover, ISGylation contributes to the immune escape mechanism by regulating the stability of PD-L1 and immune cell infiltration. In addition, ISGylation is involved in metabolic reprogramming, supporting tumor growth and therapeutic resistance by regulating key metabolic pathways. It also plays a key role in maintaining the properties of cancer stem cells by stabilizing essential metabolic and signaling proteins. In sum, this review examines the functions and mechanisms of ISG15 and ISGylation in various tumor-associated phenotypes, enhancing our understanding of their role in tumorigenesis and disease progression.
Decoding epithelial regeneration in the cornea: multi-omic analysis reveals cellular plasticity as central mechanism.
Feret N, Megido AC, Kuony A … +13 more , Marangoni P, Fichter L, Garcia Llorens S, Attina A, Nhiri N, Jacquet E, Vialaret J, Daien V, David A, Hirtz C, Loulier K, Klein OD, Michon F
Cell Mol Biol Lett · 2025 Nov · PMID 41177882 · Full text
BACKGROUND: Rapid and efficient epithelial regeneration is fundamental for tissue homeostasis and proper function. As the outermost ocular structure, the cornea is transparent, multilayered, and vital for clear vision. D...
BACKGROUND: Rapid and efficient epithelial regeneration is fundamental for tissue homeostasis and proper function. As the outermost ocular structure, the cornea is transparent, multilayered, and vital for clear vision. Due to its exposed position, the cornea frequently undergoes various forms of injury affecting either the epithelium itself or its surrounding microenvironment, including corneal innervation and the tear film. Corneal abrasion, occurring commonly through trauma or as part of refractive surgical procedures, is typically viewed as a minor event since it usually resolves rapidly. Consequently, the cornea serves as an excellent model for studying epithelial wound healing. However, complications such as persistent epithelial defects or corneal opacity can develop, underscoring critical gaps in understanding the underlying molecular mechanisms. METHODS: Utilizing a unilateral corneal abrasion mouse model, we conducted a comprehensive multi-omics analysis, integrating transcriptomics, proteomics, and epitranscriptomics, to dissect the dynamic molecular responses post-injury in both wounded and contralateral tissues. To elucidate the role of the tear film, we performed additional studies involving lacrimal gland ablation combined with corneal injury. We applied RNA sequencing to profile transcriptomic changes in corneal and lacrimal gland tissues, and mass spectrometry to study tear proteomics and epitranscriptomic modifications. RESULTS: We revealed a major modulation of the cornea transcriptome after abrasion, suggesting a regulation of pathways including JAK-STAT, Wnt and TGF-β, and a reduction of nucleoside modifications. The lacrimal gland transcriptome and tears proteome were also significantly affected. Plus, we highlighted a bilateralization, both in the cornea transcriptome and tears proteome. In the tear-deficient conditions, the wound closure rate and molecular responses were altered, and the bilateralization was impacted, with an increased matrix remodeling and a modulation of keratins expression. CONCLUSIONS: Our multi-omics analyses revealed extensive epithelial cellular plasticity as a key mechanism driving rapid wound closure, characterized by profound remodeling of transcriptional networks and RNA modifications. Importantly, we uncovered a previously underappreciated role of the lacrimal gland and tear film in mediating bilateral molecular responses following unilateral injury, emphasizing their pivotal roles in tissue regeneration. Additionally, we identified novel regulatory roles for RNA methylation events and critical signaling pathways implicated in epithelial healing.
MicroRNA strand ratio disarray promotes temozolomide resistance in glioblastoma.
Shen F, Wu P, Li Z … +8 more , Yang M, Li Z, Nan Y, Yang Q, Wang Y, Li X, Ye Y, Wang J
Cell Mol Biol Lett · 2025 Oct · PMID 41174475 · Full text
BACKGROUND: Disarray in microRNA (miRNA) strand selection is associated with multiple tumors. However, the mechanisms underlying miRNA strand selection-driven temozolomide (TMZ) resistance in glioblastoma (GBM) remain un...
BACKGROUND: Disarray in microRNA (miRNA) strand selection is associated with multiple tumors. However, the mechanisms underlying miRNA strand selection-driven temozolomide (TMZ) resistance in glioblastoma (GBM) remain unexplored. APPROACH AND RESULTS: Here, we observed that the strand selection disarray of miR-92b contributes to enhancing TMZ resistance. The pattern of higher expression of miR-92b-3p and lower expression of miR-92b-5p is significantly correlated with TMZ resistance. In TMZ-resistant GBM cells, miR-92b-3p and miR-92b-5p increased the enrichment of H3K27ac in the COL7A1 promoter region by divergently targeting HDAC9 and FOXP3, thereby elevating COL7A1 expression and mediating collagen deposition. In addition, TUT4 regulated strand selection of pre-miR-92b through uridylation, promoting preference for the 3' strand (3p). The TUT4 inhibitor aurothioglucose hydrate (ATG-H) blocked the miR-92b strand selection disarray and restored TMZ sensitivity in TMZ-resistant GBM cells. CONCLUSIONS: Our study demonstrates that TUT4-mediated elevation of the miR-92b-3p/-5p ratio promotes COL7A1 transcription via silencing HDAC9 and alleviation of FOXP3 targeting, leading to collagen deposition and heightened TMZ resistance. Our results suggest that targeting miR-92b strand selection may serve as a potential therapeutic strategy for sensitizing GBM to TMZ.
DGKs in lipid signaling and disease intervention: structural basis, pathological mechanisms, and emerging therapeutic strategies.
Liu J, Ma J, Zhang Y … +6 more , Li J, Yang Y, Yin P, Wan X, Ma S, Shang D
Cell Mol Biol Lett · 2025 Oct · PMID 41162874 · Full text
Diacylglycerol kinases (DGKs) are crucial lipid-signaling enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA) through phosphorylation. This reaction modulates the DAG-PA axis, which is central to signal...
Diacylglycerol kinases (DGKs) are crucial lipid-signaling enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA) through phosphorylation. This reaction modulates the DAG-PA axis, which is central to signal transduction, metabolic homeostasis, and immune responses. Mammals express ten DGK isoforms, classified into five subtypes on the basis of their structural features. These isoforms exhibit subtype-specific characteristics and distinct subcellular localization patterns, underpinning their diverse physiological functions. Accumulating evidence implicates DGKs in the pathogenesis of metabolic disorders, cancer, and cardiovascular and neurological diseases, where they may play either pathogenic or protective roles depending on the cellular context. This isoform-specific functionality renders DGKs promising yet underexploited therapeutic targets. Notably, one DGKζ inhibitor (ASP1570) has entered clinical trials, while other candidates, such as DGKα inhibitors (e.g., CU-3), remain at the preclinical stage. This review systematically summarizes the structural classification, catalytic mechanisms, and pathological roles of DGKs, with a particular emphasis on therapeutic targeting strategies and the associated technical challenges.
FGF21 confers neuroprotection in Parkinson's disease by activating the FGFR1-sirt1 pathway.
Liu T, Wei J
Cell Mol Biol Lett · 2025 Oct · PMID 41152735 · Full text
BACKGROUND: Parkinson's disease (PD) lacks disease-modifying therapies. Fibroblast growth factor 21 (FGF21) is implicated in PD, but its neuroprotective mechanisms via fibroblast growth factor receptor 1 (FGFR1)-sirtuin...
BACKGROUND: Parkinson's disease (PD) lacks disease-modifying therapies. Fibroblast growth factor 21 (FGF21) is implicated in PD, but its neuroprotective mechanisms via fibroblast growth factor receptor 1 (FGFR1)-sirtuin 1 (Sirt1) remain unclear. METHODS: Using 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced PD mice and lipopolysaccharides (LPS)-stimulated BV2 microglia, this study employed recombinant adeno-associated virus (rAAV)-mediated FGF21 overexpression (OE). Multi-dimensional analyses (behavior, immunofluorescence, molecular docking, Western blot, PCR, transmission electron microscopy (TEM)) assessed FGF21's effects and mechanisms. RESULTS: FGF21 significantly improved motor deficits (gait, rotarod) and non-motor symptoms (depression/anxiety) in PD mice. It repaired the blood-brain barrier (BBB) by upregulating tight junction proteins (claudin, zonula occludens (ZO-1), occludin) and reducing astrocyte activation (glail fibrillary acidicprotein, GFAP). Mechanistically, FGF21 binding to FGFR1 activated Sirt1, enhancing mitochondrial fusion (optic atrophy 1 (OPA1), mitofusin 1 (Mfn1)) and inhibiting fission (dynamin-related protein 1 (Drp1), Fission 1 (Fis1)), improving membrane potential and ultrastructure. FGF21 also activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, boosting PINK1/Parkin-mediated mitophagy and inhibiting Casp3/Bax-dependent apoptosis. Furthermore, FGF21 reduced neuroinflammation by suppressing nuclear factor kappa-B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and shifting microglia from pro-inflammatory M1 to anti-inflammatory M2. Molecular docking and co-IP confirmed FGF21 enhances direct FGFR1-Sirt1 interaction, synergistically regulating these pathways. CONCLUSION: FGF21 exerts multi-faceted protection in PD via the FGFR1-Sirt1 axis, including BBB repair, mitochondrial homeostasis restoration, microglial polarization towards M2, balancing autophagy and apoptosis, and promoting neuronal survival.
Circular RNA circSLC39A10 promotes prostate cancer progression by activating Wnt signaling via the miR-936/PROX1/β-catenin axis.
Chen K, Pan X, Zhang S … +8 more , Xu M, Chen X, Pei F, Wu M, Meng F, Sun B, Zhang M, Luo Y
Cell Mol Biol Lett · 2025 Oct · PMID 41152723 · Full text
Circular RNAs (circRNAs) play a crucial role in the initiation and development of cancers. Understanding circRNAs' functions and molecular mechanisms in tumor development is expected to reveal new diagnostic indicators a...
Circular RNAs (circRNAs) play a crucial role in the initiation and development of cancers. Understanding circRNAs' functions and molecular mechanisms in tumor development is expected to reveal new diagnostic indicators and therapeutic targets of prostate cancer (PCa). In our study, we identified a new circRNA hsa-circ-0057553 (circSLC39A10) in PCa from a bioinformatic microarray analysis. The levels of circSLC39A10 were observed to be markedly elevated in both prostate cancer cells and tissues. This increased expression was associated with multiple clinicopathological features, suggesting its potential as a new diagnostic indicator for PCa. CircSLC39A10 exhibited oncogenic effects on the proliferation, migration, invasion, and metastasis of prostate cancer cells both in vivo and in vitro. CircSLC39A10 was identified as a factor that promoted the malignant progression of PCa cells through the miR-936/PROX1/β-catenin pathway, ultimately leading to the activation of Wnt signaling. Overall, circSLC39A10 is an oncogenic circRNA with potential as a biomarker for PCa. The identified circSLC39A10/miR-936/PROX1/β-catenin axis shows promise as an innovative therapeutic target for PCa.
PPARγ-Axl axis ameliorates intervertebral disc degeneration by activating PI3K/AKT-mediated autophagy to suppress ferroptosis.
Sun G, Xu D, Jiang Y … +3 more , Su K, Lu J, Zhou C
Cell Mol Biol Lett · 2025 Oct · PMID 41152705 · Full text
Peroxisome proliferator-activated receptors (PPARs) play a critical role in the development of intervertebral disc degeneration (IVDD), a major contributor to chronic low back pain (LBP). This condition is characterized...
Peroxisome proliferator-activated receptors (PPARs) play a critical role in the development of intervertebral disc degeneration (IVDD), a major contributor to chronic low back pain (LBP). This condition is characterized by excessive nucleus pulposus cell (NPC) death, which contributes to degradation of the extracellular matrix (ECM). Ferroptosis, an iron-dependent cell death mechanism, has emerged as a key player in IVDD. However, the underlying mechanism and pathogenesis remain incompletely understood. In this study, we aimed to assess the function of PPARγ in IVDD and its modulation of ferroptosis in vivo using rat models of IVDD and in vitro using NPC cultures treated with oxidative stress-inducing agents, such as tert-butyl hydroperoxide (TBHP) and interleukin (IL)-1β. NPC treatment with PPARγ agonist (pioglitazone) and inhibitor of ferroptosis (ferrostatin-1; Fer-1) maintained ECM homeostasis by downregulating matrix metalloproteinases and ferroptosis indicators and upregulating anabolic factors. Conversely, PPARγ knockdown exacerbated ferroptosis and ECM degradation, underscoring its protective effects against oxidative stress-induced ferroptosis in NPCs. PPARγ regulates ferroptosis and ECM homeostasis through autophagy. RNA-sequencing, chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR) and co-immunoprecipitation (Co-IP) assays confirmed Axl as a novel binding partner of PPARγ. Furthermore, using a Tet-on dual-inducible system, we demonstrated the involvement of the PPARγ-Axl axis in the alleviation of oxidative stress-induced ferroptosis by autophagy. In vivo, PPARγ overexpression in intervertebral disc (IVD) alleviated IVDD in rat models. In summary, these findings reveal a pivotal role for the PPARγ-Axl axis in mitigating ferroptosis and preserving ECM homeostasis in NPC via autophagy, providing a new therapeutic strategy for IVDD.
ID1 in hematopoiesis and hematologic disorders: novel potentials of a classic differentiation regulator.
Zhao Y, Xu J, You Y … +3 more , Qian H, Zhou J, Qian J
Cell Mol Biol Lett · 2025 Oct · PMID 41146039 · Full text
The basic helix-loop-helix (bHLH) transcription factor family plays a crucial role in regulating cellular differentiation and development. Inhibitor of DNA binding 1 (ID1), which lacks a DNA-binding motif, functions as a...
The basic helix-loop-helix (bHLH) transcription factor family plays a crucial role in regulating cellular differentiation and development. Inhibitor of DNA binding 1 (ID1), which lacks a DNA-binding motif, functions as a dominant-negative inhibitor of class I and II bHLH factors to antagonize their abilities to bind to DNA and transcriptionally regulate target genes. Given that hematopoiesis is a dynamic and intricate process involving the differentiation of hematopoietic stem and progenitor cells into mature lineage cell types, elucidating the regulatory role of ID1 as a differentiation inhibitor within the hematopoietic system is paramount. Physiologically, ID1 is indispensable for maintaining normal bone marrow function and cell fate determination. However, aberrant ID1 expression, driven by pathogenic mechanisms, such as gene mutations or oncogenic kinases, contributes to the initiation and progression of various blood disorders, particularly leukemia. In this review, we comprehensively summarize the expression patterns of ID1 in hematopoietic and stromal cells within the bone marrow niche, and delve into its modulation of blood lineage commitment and development. While some discrepancies in the literature may arise from differences in experimental models or detection methods, it is evident that precise ID1 regulation is crucial for myeloid-lymphoid fate decisions. Moreover, ID1 overexpression is a causal factor in hematologic malignancies. Encouragingly, significant strides have yielded promising antileukemic effects of ID1 inhibitors, both alone and in combination with targeted therapies against oncogenic signaling pathways. Nevertheless, further efforts are needed to develop innovative and practical strategies that modulate ID1 activity to restore and sustain hematopoietic homeostasis.
Cellular and molecular mechanisms underlying cardiovascular aging.
Zhang SY, Yang YH, Wen R … +3 more , Yang N, Feng SS, Zhang TN
Cell Mol Biol Lett · 2025 Oct · PMID 41146020 · Full text
Aging is a primary risk factor driving the increased prevalence of cardiovascular diseases, significantly contributing to global mortality and healthcare burdens. Aging-related alterations, including genomic instability,...
Aging is a primary risk factor driving the increased prevalence of cardiovascular diseases, significantly contributing to global mortality and healthcare burdens. Aging-related alterations, including genomic instability, telomere shortening, and loss of proteostasis, underpin the pathogenesis of numerous cardiovascular conditions such as heart failure, arrhythmia, cardiomyopathy, myocardial infarction, and atherosclerosis. Recent insights into molecular and cellular mechanisms highlight the roles of senescence, inflammation, mitochondrial dysfunction, and metabolic disturbances in cardiovascular aging. Cellular and vascular senescence further accelerates the development of aging-related cardiovascular diseases. Emerging therapeutic strategies targeting these pathways, such as metabolic regulators, senolytic agents, antioxidants, stem cell-derived exosomes, and natural bioactive compounds, offer promising avenues for mitigating aging-related cardiovascular pathology.
KIAA1429-mediated MA methylation inhibits osteoclast differentiation via stabilizing Lrp4 mRNA and protects against osteoporosis.
Liu J, Fu Q, Li M … +9 more , Chen J, Xu M, Zhai X, Li S, Li L, Wu X, Xu W, Wang K, Si H
Cell Mol Biol Lett · 2025 Oct · PMID 41146006 · Full text
N-methyladenosine (mA) is a novel epigenetic modification that has been reported to be involved in the progression of osteoporosis (OP), providing new insights into the pathogenesis of OP. The methyltransferases KIAA1429...
N-methyladenosine (mA) is a novel epigenetic modification that has been reported to be involved in the progression of osteoporosis (OP), providing new insights into the pathogenesis of OP. The methyltransferases KIAA1429 [also known as virus-like mA methyltransferase-associated protein (VIRMA)] participates in various essential biological processes by regulating target gene expression levels. However, the function of KIAA1429-mediated mA modification in OP progression remains unclear. This study aimed to investigate the biological roles and potential underlying mechanisms of KIAA1429 in OP and osteoclast differentiation. scRNA-seq combined with bulk RNA-seq screening for the differential gene KIAA1429. Analysis of clinical data confirmed KIAA1429 expression and its clinical significance in OP. KIAA1429 inhibited osteoclast differentiation in vitro and reduced bone resorption in ovariectomized (OVX) mice. Mechanistically, LRP4 was identified as a downstream target of KIAA1429. KIAA1429 mediated the mA modification of Lrp4 mRNA, and then YT521-B homology-domain-containing protein 1 (YTHDC1) increased Lrp4 stability and expression. In addition, LRP4 enhancement recruited TNFAIP3, which inactivated NF-κB signaling. This novel mechanism of NF-κB signaling pathway inhibition by enhanced KIAA1429/YTHDC1-coupled Lrp4 transcription during osteoclast differentiation highlights the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for OP progression.
Endothelial activation during the diapedesis of cancer cells: between the kiss of death and therapeutic breakthrough.
Piwowarczyk K, Madeja Z, Siedlar M … +1 more , Czyż J
Cell Mol Biol Lett · 2025 Oct · PMID 41120839 · Full text
Cancer development is a complex process, initiated by the combination of epigenetic and genetic changes in normal cells. Selective microenvironmental pressure within the primary tumors prompts the microevolution of invas...
Cancer development is a complex process, initiated by the combination of epigenetic and genetic changes in normal cells. Selective microenvironmental pressure within the primary tumors prompts the microevolution of invasive cell lineages that efficiently penetrate circulation and lymphatic systems and extravasate in distant organs, initiating the formation of metastases. Extravasation (diapedesis), i.e., the multistep penetration of the endothelial layer by circulating cancer cells, is regarded as the decisive step and one of the bottlenecks of the metastatic cascade. It limits malignant cancer dissemination, while initiating the formation of metastases. The efficiency of extravasation depends equally on the properties of circulating cancer cells and the local functional status of the endothelium, which remains sensitive to paracrine, adhesive, and juxtacrine stimuli generated by cancer and immune cells. Here, we review the current state of knowledge on the significance of endothelial activation for the diapedesis of circulating cancer cells, with the emphasis on the intercellular communication pathways that mediate this process. We also address the potential and limitations of endothelial activation as the target for novel strategies of cancer treatment.
Multi-omics analyses integration reveals a novel TRF2-miR-181a-5p-S100A10 regulatory axis in colon cancer.
Dinami R, Petti E, Ostano P … +16 more , Iachettini S, Rizzo A, Maresca C, Zizza P, Di Vito S, Porru M, D'Angelo C, Sibilio P, De Nicola F, Russo R, Di Benedetto A, Palange A, Fanciulli M, Chambery A, Gilson E, Biroccio A
Cell Mol Biol Lett · 2025 Oct · PMID 41116155 · Full text
BACKGROUND: The Telomeric repeat-binding factor 2 (TRF2) binds to TTAGGG repeats located at chromosomes ends and ensures telomere protection together with the other members of shelterin. In addition to its well-known rol...
BACKGROUND: The Telomeric repeat-binding factor 2 (TRF2) binds to TTAGGG repeats located at chromosomes ends and ensures telomere protection together with the other members of shelterin. In addition to its well-known role in telomere maintenance, TRF2 can also bind to interstitial telomeric sequences and regulate the expression of specific genes with a consequent impact on tumor formation and progression. However, a comprehensive analysis of the impact of TRF2 on global gene expression of human cancer cells and of the underlying mechanisms is still lacking. METHODS: The integration of omics technologies (RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP-seq), interactomics, and microRNA (miRNA) profiling) was used to deeply investigate the extra-telomeric role of TRF2. Differential gene expression and binding sites of TRF2 were confirmed by qRT-PCR while the interaction of TRF2 with TATA-box binding protein associated factor 15 (TAF15) was validated by immunoprecipitation and proximity ligation assay. Finally, target specificity was assessed by luciferase assay and western blotting while biological effects were investigated by cell migration analysis (unpaired t tests was used to calculate statistical significance). RESULTS: We found that TRF2 impinges on the expression of 717 genes involved in various cancer-related pathways. Unexpectedly, just a small portion of Differentially Regulated genes are directly bound by TRF2, suggesting the existence of alternative mechanisms of TRF2-mediated gene regulation. In particular, we found that TRF2 binds to various noncoding RNA regions and interacts with many RNA binding proteins, supporting TRF2's involvement in noncoding RNA-mediated mechanisms. Through the intersection of omics-analyses, we provided here experimental evidence of a multilayered mechanism of regulation where TRF2, interacting with TAF15, regulates miR-181A1 host gene and mature miR-181a-5p expression, which in turn targets S100A10, a known plasma membrane protein with oncogenic role. CONCLUSIONS: Our work shows, for the first time, a broad overview on the extra-telomeric role of TRF2 in human cancer, further revealing a new axis through which TRF2 contributes to cancer progression.
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