Cell. Mol. Biol. Lett. [JOURNAL]
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200 papers
Macrophage-derived legumain ameliorates excessive mechanical stress-induced ferroptosis of nucleus pulposus cells and intervertebral disc degeneration via integrin αvβ3-Hippo signaling.
Wang P, Xie Z, Deng L … +10 more , Zhou Y, Xu Z, Gao J, Sun R, Liu L, Wang Z, Wu X, Ren G, Zhang C, Wang Y
Cell Mol Biol Lett · 2026 Mar · PMID 41872751 · Full text
BACKGROUND: Excessive mechanical stress is a major cause of intervertebral disc degeneration (IVDD). Macrophages can sense physical signals, but their role in responding to mechanical stress within the disc to maintain h...
BACKGROUND: Excessive mechanical stress is a major cause of intervertebral disc degeneration (IVDD). Macrophages can sense physical signals, but their role in responding to mechanical stress within the disc to maintain homeostasis is unclear. This study investigates the function of macrophage-derived legumain (LGMN) in IVDD. METHODS: Single-cell RNA sequencing data of human disc samples were analyzed. Macrophage-specific Lgmn knockout (LgmnF/F;LysMCre) and nucleus pulposus cell (NPC)-specific Yap1 knockin (Yap1LSL/LSL; Col2a1Cre) mice were generated to study IVDD progression in vivo using a lumbar spine instability model. In vitro, NPCs and macrophages were cultured under mechanical compression. Molecular interactions were predicted with AlphaFold3 and validated by coimmunoprecipitation and mass spectrometry. Signaling pathways were analyzed via RNA sequencing, western blot, and chromatin immunoprecipitation. Engineered LGMN-overexpressing small extracellular vesicles (sEVs) were tested therapeutically in a rat compression model. RESULTS: LGMN was significantly upregulated in human and animal degenerate discs, primarily in macrophages. Conditional knockout in macrophages accelerated IVDD in mice. Mechanistically, macrophage-derived LGMN bound to integrin αvβ3 on NPCs, inhibiting RhoA activity and activating the Hippo pathway. This led to phosphorylation and cytoplasmic retention of YAP1, which suppressed mechanical stress-induced ferroptosis in NPCs. Mechanical stress promoted STAT3 nuclear translocation in macrophages, directly enhancing LGMN transcription. Intradiscal delivery of LGMN-enriched sEVs alleviated IVDD in rats. CONCLUSIONS: Macrophage-derived LGMN is a key mechanosensitive regulator that ameliorates IVDD by inhibiting NPC ferroptosis via the integrin αvβ3–Hippo pathway, revealing a novel endogenous protective mechanism and a potential therapeutic strategy.
Ash2l deficiency impairs adipose tissue thermogenesis and exacerbates obesity in mice.
Hu Y, Zhao J, Xiao C … +9 more , Liu J, Xu J, Xu S, Zhong W, Chen R, He M, Fan C, Chang J, Liu X
Cell Mol Biol Lett · 2026 Mar · PMID 41872744 · Full text
BACKGROUND: Epigenetic regulation plays a pivotal role in adipocyte development and thermogenesis. Ash2l, a key component of the COMPASS (Complex of Proteins Associated with Set1) histone methyltransferase, regulates gen...
BACKGROUND: Epigenetic regulation plays a pivotal role in adipocyte development and thermogenesis. Ash2l, a key component of the COMPASS (Complex of Proteins Associated with Set1) histone methyltransferase, regulates gene expression through epigenetic mechanisms. This study explored the role of Ash2l in adipose tissue thermogenesis and obesity-related metabolic dysfunction. METHODS: Ash2l was initially identified through transcriptomic analysis, and its expression was further validated in mouse models of high-fat diet (HFD), cold exposure, and CL316,243 stimulation. In vitro gain- and loss-of-function experiments were conducted to assess the role of Ash2l in adipogenesis and thermogenesis. To knockdown Ash2l in vivo, adeno-associated viruses carrying short hairpin RNA targeting Ash2l (AAV-shAsh2l) were injected into either the brown adipose tissue (BAT) or the inguinal white adipose tissue (iWAT). The functional consequences of Ash2l deficiency were evaluated in mice under room temperature, cold exposure, and HFD conditions. Finally, chromatin immunoprecipitation sequencing (ChIP-seq) was employed as an exploratory analysis to identify genomic regions associated with Ash2l during adipocyte development. RESULTS: Our findings demonstrate that Ash2l modulates the expression of both adipogenic and thermogenic genes in adipocytes. Mice with BAT- or iWAT-knockdown of Ash2l displayed defective cold-induced thermogenesis, aggravated diet-induced obesity, and systemic metabolic dysregulation. Moreover, Ash2l knockdown in BAT under cold exposure or HFD conditions also attenuated thermogenic activity in iWAT, an effect that may be mediated by reduced secretion of FABP4. CONCLUSIONS: These findings establish Ash2l as a critical regulator of adipogenesis and thermogenesis. This study provides important insights into the epigenetic role of Ash2l in maintaining metabolic homeostasis under conditions of nutritional excess.
Targeting dormant cancer cells: ferroptosis as a precision therapeutic strategy.
Hao S, Guo Y, Huang Q … +5 more , Gan L, Chen C, Li Q, Di C, Si J
Cell Mol Biol Lett · 2026 Mar · PMID 41862812 · Full text
Dormant cancer cells are a significant source of cancer recurrence and metastasis and exhibit robust resistance to conventional therapies. Therefore, the exploration of novel therapeutic strategies to eliminate these cel...
Dormant cancer cells are a significant source of cancer recurrence and metastasis and exhibit robust resistance to conventional therapies. Therefore, the exploration of novel therapeutic strategies to eliminate these cells has become a hot topic in cancer research. Ferroptosis, a newly identified form of regulated cell death, has garnered considerable attention in the field of cancer therapy in recent years. As a novel form of regulated cell death, the core mechanism of ferroptosis lies in the accumulation of intracellular iron and the induction of lipid peroxidation. Oxidative stress, the transforming growth factor-β (TGF-β) signaling pathway, autophagy, and lipid metabolism play dual roles in the survival of dormant cancer cells and the process of ferroptosis, influencing the response of dormant cancer cells to ferroptosis. These complex molecular mechanisms form a regulatory network between ferroptosis and dormant cancer cells, which holds significant implications for the development of future anti-tumor therapeutic strategies. This review synthesizes current evidence on targeting ferroptosis to eliminate dormant cancer cells, positions ferroptosis as a precision modality against dormant cancer cells, and discusses its therapeutic promise as a conceptual framework for developing next-generation anti-tumor strategies.
Intermittent fasting inhibits ferroptosis by modulating CD36 and its palmitoylation to alleviate diabetic dry eye.
Wang W, Xue J, Xiao B … +6 more , Qian X, Li J, Lin X, Chen Z, Wang W, Liang L
Cell Mol Biol Lett · 2026 Mar · PMID 41862802 · Full text
BACKGROUND: Excessive lipid accumulation in the lacrimal glands under diabetic conditions can lead to lacrimal gland dysfunction and reduced tear secretion, subsequently resulting in ocular surface inflammation, dry eye...
BACKGROUND: Excessive lipid accumulation in the lacrimal glands under diabetic conditions can lead to lacrimal gland dysfunction and reduced tear secretion, subsequently resulting in ocular surface inflammation, dry eye syndrome, and corneal vulnerability, ultimately compromising the patient’s quality of life. There are limited and easily implemented intervention strategies to reduce excessive lipid accumulation. While intermittent fasting (IF) has emerged as a promising metabolic intervention, its mechanistic underpinnings and therapeutic potential in diabetes-associated lacrimal gland disorders require systematic elucidation. METHODS: Diabetic mice were divided into three groups for an 8-week dietary intervention: ad libitum, meal feeding, and every-other-day feeding. After dietary intervention, we assessed the damage to lacrimal glands and ocular surface, and elucidated lipid accumulation, ferroptosis, and functional changes in the lacrimal glands. Transcriptomic analysis was used to examine gene expression. CD36 and its palmitoylation were examined around three groups. In addition, damage to the ocular surface and lacrimal glands was assessed in vivo, after the mice were injected with the ferroptosis inhibitor Fer-1 and CD36 shRNA. RESULTS: In this study, we found that compared with caloric restriction, IF more effectively reduced lipid accumulation in the lacrimal glands of diabetic db/db mice, decreased lipid peroxidation and ferroptosis, and improved function. IF downregulated CD36 expression and its palmitoylation, potentially mediated by ZDHHC20. CD36 shRNA and ferroptosis inhibition (Fer-1) comparably restored lacrimal secretory function, yet only CD36 knockdown concurrently resolved lipidostasis and ferroptosis. CONCLUSIONS: This analysis identifies CD36 as a key regulator bridging lipotoxic stress and ferroptotic execution in diabetic lacrimal gland dysfunction. Importantly, our findings suggest that ferroptosis may serve as the critical effector mechanism converting metabolic overload to glandular dysfunction, suggesting potential therapeutic value in dual targeting of lipidostasis and cell death pathways. SIGNIFICANCE: Intermittent fasting, which appears more effective than that of caloric restriction, may be associated with reduced lipid absorption resulting from decreased CD36 expression and its palmitoylation on lacrimal gland cell membranes. These findings uncover a potential novel treatment strategy for diabetic dry eye.
Combination of Tripterygium glycosides and Lactobacillus paracasei sensitises epithelial ovarian cancer to cisplatin via downregulating Keap1-Nrf2-GPX4 signalling pathway.
Tian M, Zeng X, Zhong Y … +7 more , Ma B, Feng Y, Wu X, Liao Y, Xu Y, Chen T, Tan B
Cell Mol Biol Lett · 2026 Mar · PMID 41862794 · Full text
BACKGROUND: Epithelial ovarian cancer (EOC) is a highly heterogeneous malignancy with significant morbidity and mortality, and cisplatin (DDP) resistance remains a major obstacle in its treatment. Previous studies sugges...
BACKGROUND: Epithelial ovarian cancer (EOC) is a highly heterogeneous malignancy with significant morbidity and mortality, and cisplatin (DDP) resistance remains a major obstacle in its treatment. Previous studies suggest that Tripterygium glycosides (TG), derived from Tripterygium wilfordii, may enhance EOC chemo-sensitivity to DDP, potentially involving gut microbiota, though the underlying mechanisms remain to be fully elucidated. PURPOSE: This study sought to determine how TG enhanced chemotherapy sensitivity in EOC and to examine the involvement of gut microbiota in this process. STUDY DESIGN: Experimental research in vivo models was conducted, including fecal microbiota transplantation (FMT) from healthy controls and validation assays with Lactobacillus paracasei. METHODS: TG were administered alone or combined with FMT to evaluate their impact on DDP sensitivity in EOC. Mechanistic studies focused on the Keap1-Nrf2-GPX4 signalling pathway and ferroptosis induction. L. paracasei was co-administered with TG to assess synergistic effects, while Nrf2 pathway activation was tested to confirm its regulatory role. RESULTS: TG significantly enhanced DDP sensitivity in EOC, either alone or synergistically with FMT. Mechanistically, TG inhibited the Keap1-Nrf2-GPX4 axis, inducing tumor ferroptosis. Gut microbiota, particularly the probiotic Lactobacillus, contributed to this effect: L. paracasei combined with TG amplified DDP cytotoxicity in EOC cells. Conversely, Nrf2 pathway activation attenuated the synergistic effect. CONCLUSION: TG sensitises EOC to DDP by suppressing the Keap1-Nrf2-GPX4 pathway to trigger ferroptosis, with gut microbiota (e.g., L. paracasei) playing a synergistic role. Combining TG and probiotics may offer a promising and innovative method to improve chemotherapy efficacy in EOC, offering a foundation for future therapeutic development.
NFAT1 microglia promote antiinflammatory polarization and angiogenesis via the HAS3-HA-LYVE1 axis to improve ischemic stroke outcomes.
Zhang Y, Cao X, Song Y … +5 more , Han X, Tian G, Tao D, Hou A, Han S
Cell Mol Biol Lett · 2026 Mar · PMID 41851636 · Full text
BACKGROUND: Neuroinflammation and angiogenesis are central to post-stroke repair. However, the cellular and molecular mechanisms regulating these events remain incompletely understood. The nuclear factor of activated T c...
BACKGROUND: Neuroinflammation and angiogenesis are central to post-stroke repair. However, the cellular and molecular mechanisms regulating these events remain incompletely understood. The nuclear factor of activated T cells-1 (NFAT1) is implicated in inflammation and vascular remodeling, yet its role in ischemic stroke is unclear. METHODS: We established Nfat1-deficient (Nfat1) and Nfat1 stroke mice to investigate the role of NFAT1 in post-stroke inflammation and repair. Neurological outcomes, infarct volume, neuronal injury, synaptic protein expression, neuroinflammation, angiogenesis, and cerebral blood flow were assessed by behavioral test, magnetic resonance imaging (MRI), Nissl staining, western blotting, ELISA, immunofluorescence, and laser speckle imaging, respectively. ChIP, dual-luciferase, and mechanistic assays identified NFAT1 downstream targets and signaling pathways. Conditioned medium experiments examined the impact of Nfat1 primary microglia on endothelial cell behavior. NFAT1-overexpressing microglia were transplanted to assess therapeutic efficacy in vivo. RESULTS: Nfat1 stroke mice showed worsened neurological function, increased neuronal damage, and reduced expression of antiinflammatory and proangiogenic factors (interleukin (IL)-10, tumor growth factor (TGF)-β, VEGFA, and FGF2). NFAT1 deficiency impaired microglial polarization (CD163 and CD206), angiogenesis, and blood perfusion. NFAT1 upregulated HAS3 and LYVE1, promoting HA-LYVE1 autocrine/paracrine signaling and activation of the Wnt/β-catenin pathway, which facilitated antiinflammatory polarization. Conditioned medium experiments confirmed that Nfat1 microglia enhanced endothelial cell proliferation, migration, and tube formation. NFAT1-overexpressing microglia therapy enhanced antiinflammatory responses and angiogenesis, improved neurological recovery (e.g. Garcia score at day 35 increased by 0.87 points versus control), and reduced infarct size (corrected infarct area decreased by 27.29 units) in stroke mice. CONCLUSIONS: Microglial NFAT1 drives antiinflammatory polarization and angiogenesis via the HAS3-HA-LYVE1-Wnt/β-catenin axis, ultimately improving stroke recovery. These findings reveal a previously unrecognized mechanism of neurovascular repair and highlight NFAT1 microglia as a promising therapeutic target for ischemic stroke.
STUB1 downregulates TOP2A through a dual mechanism of ubiquitination and FOXM1-mediated transcription repression, suppressing breast cancer growth and enhancing sensitivity to chemotherapy.
Yue B, Xiang Q, Qiu H … +5 more , Huang M, Qi M, Yi X, Zhou S, Xiong J
Cell Mol Biol Lett · 2026 Mar · PMID 41851614 · Full text
BACKGROUND: DNA topoisomerase IIɑ (TOP2A) is crucial for maintaining genomic stability and is an important target for genotoxic chemotherapeutic drugs. STIP1 homology and U-box-containing protein 1 (STUB1) is a U-box con...
BACKGROUND: DNA topoisomerase IIɑ (TOP2A) is crucial for maintaining genomic stability and is an important target for genotoxic chemotherapeutic drugs. STIP1 homology and U-box-containing protein 1 (STUB1) is a U-box containing E3 ubiquitin ligase that participates in the degradation of specific oncogenic proteins. This research examined the potential regulatory function of STUB1 in relation to TOP2A, and explored its functional implications. METHODS: To identify interactions between STUB1 and TOP2A, coimmunoprecipitation, Glutathione S-transferases (GST) pull-down, and immunofluorescence assays were performed. Cycloheximide (CHX) pulse-chase assay, in vivo and in vitro ubiquitination, quantitative RT-PCR, chromatin immunoprecipitation (CHIP), and luciferase assays were performed to determine how STUB1 interacts with TOP2A. In addition, TOP2A catalytic activity, colony formation, WST-1, and flow cytometry assays were performed and a xenograft model was further developed to explore whether STUB1 could downregulate the catalytic activity of TOP2A, reduce the growth of breast cancer, and increase its sensitivity to doxorubicin. Moreover, immunohistochemical staining was conducted to assess STUB1 and TOP2A expression levels, as well as their predictive roles in the efficacy of neoadjuvant chemotherapy in individuals diagnosed with breast cancer. RESULTS: STUB1 enhanced TOP2A translocation to the cytoplasm, downregulating its expression through increased ubiquitination and degradation. Forkhead box M1 (FOXM1), another substrate of STUB1, served as a transcription factor for TOP2A, playing a role in STUB1-mediated downregulation of TOP2A at the transcriptional level. STUB1 inhibited TOP2A’s activity, reduced cancer cell proliferation, increased doxorubicin-induced apoptosis, and promoted cell cycle arrest. In a breast cancer xenograft model, STUB1 suppressed tumor growth and improved doxorubicin sensitivity. A positive correlation between FOXM1 and TOP2A expression was found in patients with breast cancer undergoing EC-T chemotherapy, both negatively correlated with STUB1, whose higher expression levels were linked to increased pathologic complete response (pCR) rates. STUB1 was evaluated as an independent predictor of pCR through univariate and multivariate analyses. CONCLUSIONS: This study proposes a novel function of STUB1 in the downregulation of TOP2A, which directly enhances sensitivity to chemotherapy.
Dichotomous SMAD2/3 regulation and selective antihypertrophic activity of heparin during in vitro chondrogenesis of mesenchymal stromal cells.
Schmidt S, Chasan S, Dietmar HF … +6 more , Klampfleuthner FAM, Hesse E, Walker T, Freudenberg U, Richter W, Diederichs S
Cell Mol Biol Lett · 2026 Mar · PMID 41845215 · Full text
BACKGROUND: Endochondral instead of chondral differentiation hinders mesenchymal stromal cell (MSC) application for clinical cartilage regeneration. We previously showed that heparin-polyethylene glycol (PEG) hydrogels l...
BACKGROUND: Endochondral instead of chondral differentiation hinders mesenchymal stromal cell (MSC) application for clinical cartilage regeneration. We previously showed that heparin-polyethylene glycol (PEG) hydrogels loaded with transforming growth factor TGF-β instructed stable chondral MSC development in vivo. Here, we assessed this approach in vitro, utilizing heparin-PEG hydrogels or the pellet culture system with soluble heparin supplementation of chondrogenic medium. METHODS: Human MSCs were cultured in heparin-PEG hydrogels (22.4 mg/mL crosslinked heparin, 120 ng TGF-β1) or as pellet cultures treated with soluble heparin (0, 10, 100, 700 μg/mL) in TGF-β1-containing (10 ng/mL) chondrogenic medium. Chondral and endochondral signaling (1-3 h, 4 weeks) and cartilage matrix formation (4 weeks) were analyzed using western blot, histology, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and enzyme activity. RESULTS: Unlike in vivo, human MSCs differentiated in heparin-PEG hydrogels into type X collagen and alkaline phosphatase-positive hypertrophic chondrocytes in vitro. Interestingly, treating MSC pellets with soluble heparin (10-700 µg/mL) revealed reduced TGF-β-SMAD3 but not SMAD2 activation at unaffected type II collagen and proteoglycan/DNA levels. We propose that the stimulation of the insulin-AKT pathway by heparin aided in maintaining SMAD2 activation, which apparently plays a more prominent role than SMAD3 for MSC chondrogenesis. Heparin treatment inhibited the pro-hypertrophic WNT/β-catenin pathway in vitro but insufficiently silenced TGF-β-SMAD1/5/9 activation and unfortunately reduced antihypertrophic prostaglandin PGE2 levels. Ultimately, treatment with 10 µg/mL heparin reduced the upregulation of several hypertrophy markers (MEF2C, IHH, IBSP messenger RNAs [mRNAs], alkaline phosphatase activity) below control levels, but type X collagen remained unresponsive. Thus, soluble heparin treatment was similarly selective and effective as previous antihypertrophic interventions (PTHrP pulses, WNT inhibition), while offering technical simplicity, reduced cost, and solvent-free formulation. CONCLUSIONS: Taken together, heparin-TGF-β showed a novel dichotomous SMAD2/3 inhibition at maintained chondrogenic differentiation and context-dependent lineage-instructive properties-permitting endochondral commitment in vitro but chondral development in vivo. Thus, environmental contributions are mandatory to allow heparin-PEG-guided chondral versus endochondral lineage commitment of MSCs in vivo, potentially involving SMAD1/5/9 suppressors and PGE2 sources.
Persistent PI3K-AKT signaling fortifies cellular defense against oxidative stress and ferroptosis through augmented mitochondrial fitness.
Xie X, Wang S, Zeng W … +5 more , Long X, Zheng D, Ye J, Rezgui R, Liu PS
Cell Mol Biol Lett · 2026 Mar · PMID 41832434 · Full text
BACKGROUND: Chronic oxidative stress is recognized as a hallmark of cancer and represents a potentially targetable vulnerability in malignant cells. Oncogenic mutations in phosphatidylinositol 3-kinase (PI3K) are frequen...
BACKGROUND: Chronic oxidative stress is recognized as a hallmark of cancer and represents a potentially targetable vulnerability in malignant cells. Oncogenic mutations in phosphatidylinositol 3-kinase (PI3K) are frequently observed across diverse malignancies, playing a crucial role in cancer progression. However, the relationship between PI3K–AKT signaling, mitochondrial fitness, and ferroptosis resistance remains poorly understood. METHODS: We compared the sensitivity of MCF-7 cells (harboring oncogenic PI3K activation) and MDA-MB-231 cells with oxidative stress and ferroptosis inducers using high-content imaging analysis and flow cytometry. RNA-sequencing was performed to identify transcriptomic changes following PI3K inhibition. Mitochondrial fitness was assessed by measuring mitochondrial mass, membrane potential, ATP production, and glutathione levels. Functional validation was conducted through pharmacological manipulation using PI3K–AKT–mTOR pathway inhibitors and AKT activators, as well as genetic approaches involving ectopic expression of oncogenic PIK3CA-E542K in HeLa cells. RESULTS: Cancer cells with constitutive PI3K activation exhibited high resistance to oxidative stress and ferroptosis compared with cells without oncogenic PI3K mutations. Mechanistically, PI3K–AKT signaling orchestrated an augmented mitochondrial gene program, enhancing mitochondrial fitness and antioxidant capacity. Inhibition of the PI3K–AKT–mTOR pathway selectively increased reactive oxygen species levels, compromised mitochondrial fitness, induced mitophagy, and sensitized cells with oncogenic PI3K activation to ferroptosis. Conversely, ectopic expression of oncogenic PIK3CA or pharmacological activation of AKT conferred resistance to oxidative stress and ferroptosis in a mitochondria-dependent manner, as evidenced by the abrogation of protective effects upon mitochondrial uncoupling. CONCLUSIONS: Our findings establish a novel link between enhanced mitochondrial fitness and ferroptosis resistance in cancer cells with hyperactive PI3K signaling. These results suggest that combining ferroptosis induction with PI3K inhibition and mitochondrial fitness impairment may offer a promising therapeutic strategy for cancers harboring oncogenic PI3K mutations. This approach provides new insights into potential treatment modalities that exploit the interplay between oncogenic signaling pathways and cellular redox homeostasis in cancer cells.
Post-translational modifications of selective autophagy receptors: orchestrating cellular homeostasis, disease pathogenesis, and therapeutic opportunities.
Zhu W, Wang X, Li Q … +2 more , Jiang X, Xu G
Cell Mol Biol Lett · 2026 Mar · PMID 41832417 · Full text
Selective autophagy, an evolutionarily conserved quality control process, preserves cellular homeostasis by degrading specific substrates or organelles. Autophagy receptors, which precisely recognize and target substrate...
Selective autophagy, an evolutionarily conserved quality control process, preserves cellular homeostasis by degrading specific substrates or organelles. Autophagy receptors, which precisely recognize and target substrates through sophisticated molecular mechanisms, are central to this pathway. These receptors orchestrate diverse biological functions ranging from DNA damage response, protein degradation, proteostasis, neuronal health, to immune modulation. Increasing evidence suggests that posttranslational modifications (PTMs) critically regulate the biological functions of autophagy receptors, forming a complex regulatory network that remains incompletely characterized in disease pathogenesis. This review first summarizes current knowledge of mammalian autophagy, including the principal molecular machinery across diverse pathways. We then categorize autophagy receptors on the basis of cargo specificity, and highlight PTM-mediated regulatory mechanisms. Furthermore, we explore their pathophysiological roles and assess their therapeutic potential by integrating recent advances. Finally, we discuss emerging perspectives in the autophagy research field, especially for the discovery of pathology-associated PTMs that modulate the functions of autophagy receptors. A deeper understanding of autophagic regulation and its pathophysiological significance will advance innovative therapeutic strategies targeting diseases associated with autophagy dysfunction.
Endothelial Ffar4 protects against diabetic kidney disease by potentiating endogenous retinoic acid metabolism.
Li J, Cui S, Wang W … +5 more , Zhang T, Wang Z, Ye X, Chen YQ, Zhu S
Cell Mol Biol Lett · 2026 Mar · PMID 41832416 · Full text
BACKGROUND: Diabetic kidney disease (DKD) occurs in up to 40% of individuals with diabetes and remains the primary cause of kidney failure worldwide, and a complex interaction of genetic and environmental dietary factors...
BACKGROUND: Diabetic kidney disease (DKD) occurs in up to 40% of individuals with diabetes and remains the primary cause of kidney failure worldwide, and a complex interaction of genetic and environmental dietary factors may be involved. Free fatty acid receptor 4 (Ffar4) may serve as a link between the genetic and dietary aspects of DKD progression; however, its role in DKD remains unclear. METHODS: Ffar4-mediated DKD protection was evaluated using comprehensive genetic models. In addition, the effects of Ffar4 on glomerular inflammation and endothelial injury in mice were evaluated in vivo and in vitro, and the regulation of the Aldh1a1 gene by Ffar4 to maintain endogenous retinoic acid (RA) metabolic balance and related signaling pathways in the glomeruli was investigated. RESULTS: We found that Ffar4 expression was decreased in diabetes and was associated with renal complications. Conventional and endothelial-specific Ffar4 knockout exacerbated DKD, whereas endothelial-specific Ffar4 overexpression improved renal function. Mechanistically, Ffar4 regulated endogenous RA metabolism in the glomeruli through the Atf4–Aldh1a1 pathway. RA supplementation partially reversed DKD progression in endothelial-specific Ffar4 knockout mice. CONCLUSIONS: Taken together, these findings revealed a novel role of Ffar4 in potentiating endogenous RA production and delaying the progression of DKD-related multi-dysfunction.
G-quadruplex stabilization via small molecules as a potential anti-cancer strategy.
Li C, Liu J, Wang R
Cell Mol Biol Lett · 2026 Mar · PMID 41826810 · Full text
G-quadruplexes (G4s) are noncanonical nucleic acid secondary structures formed by guanine-rich DNA or RNA sequences, predominantly located at telomeric ends and within the promoter regions of oncogenes. These structures...
G-quadruplexes (G4s) are noncanonical nucleic acid secondary structures formed by guanine-rich DNA or RNA sequences, predominantly located at telomeric ends and within the promoter regions of oncogenes. These structures play essential roles in maintaining telomere stability, regulating DNA replication, and modulating gene transcription and translation. Stabilization of G4 structures can induce cellular senescence and apoptosis while suppressing oncogene expression, positioning them as highly promising therapeutic targets in anticancer research. In recent years, a variety of small-molecule G4 ligands have been developed, many of which exhibit potent antitumor activity by selectively stabilizing G4s. Targeting G4s has thus emerged as a cutting-edge strategy in cancer therapy, offering new avenues for precision medicine. This review provides a comprehensive overview of G4 structure and function, highlights recent progress in the development of G4-targeting ligands, and discusses their therapeutic potential in oncology. Our goal is to offer insights into the design and application of G4-targeted agents for future anticancer drug development.
mTORC1 as a metabolic rheostat coordinates hormonal signals and cellular proliferation to sustain endometrial competence.
Sun Y, Wan S, Zhao M … +8 more , Chen K, Wu Y, Huang Y, He J, Liu F, Shuai H, Yan J, Yang M
Cell Mol Biol Lett · 2026 Mar · PMID 41826809 · Full text
BACKGROUND: Optimal endometrial thickness and receptivity, precisely regulated by steroid hormones, are critical determinants for successful embryo implantation. Thin endometrium is a major cause of female infertility, y...
BACKGROUND: Optimal endometrial thickness and receptivity, precisely regulated by steroid hormones, are critical determinants for successful embryo implantation. Thin endometrium is a major cause of female infertility, yet its pathogenesis requires further exploration. Cellular proliferation and differentiation are highly dependent on the activation status of intracellular metabolic signaling pathways, among which the mammalian target of rapamycin (mTOR) signaling pathway serves as a central metabolic integrator. However, the mechanistic links between mTOR dysregulation, metabolic reprogramming, and endometrial regenerative failure remain poorly understood, representing a critical knowledge gap in reproductive medicine. METHODS: Uterine-specific Raptor knockout mice (Rptorfl/flPgrcre/+) were generated using the Cre-LoxP system. Endometrial pathology was assessed through multi-dimensional analyses: (1) hematoxylin–eosin staining, immunofluorescence, and T2-weighted magnetic resonance imaging were used to quantify endometrial dimensions, glandular development, and vascularization; (2) Functional competence was evaluated via the Pollard experiment and artificial decidualization models to assess receptivity and decidualization; (3) Molecular mechanisms were dissected using high-throughput RNA sequencing and flow cytometry to profile mTORC1-mediated cholesterol synthesis signaling, endometrial renewal, and cell cycle progression. RESULTS: Rptorfl/flPgrcre/+ mice recapitulated key features of thin endometrium syndrome, exhibiting significantly reduced endometrial thickness, impaired glandular development, and defective vascularization. Despite having comparable estrogen and progesterone levels, these mice displayed profound endometrial receptivity defects and impaired decidual response. Raptor deficiency attenuated cell proliferation by disrupting lipid metabolism pathways, consequently impairing estrogen responsiveness and diminishing uterine regenerative capacity. CONCLUSIONS: Our study establishes that mTORC1 signaling orchestrates hormone-responsive endometrial proliferation through metabolic regulation, fundamentally underpinning endometrial receptivity and decidualization. These findings provide mechanistic insights into the pathogenesis of thin endometrium and highlight potential therapeutic targets for infertility treatment.
LncRNA MEG3 regulates the development of porcine skeletal muscle satellite cells by enhancing HMGA1 stability.
Liu Q, Zhou H, Fu C … +3 more , Xie S, Li M, Li C
Cell Mol Biol Lett · 2026 Mar · PMID 41820853 · Full text
BACKGROUND: Porcine skeletal muscle satellite cells (PSCs) are the core stem cell population for the development of porcine skeletal muscle. In postnatal piglets, PSCs can differentiate into myoblasts and fuse with exist...
BACKGROUND: Porcine skeletal muscle satellite cells (PSCs) are the core stem cell population for the development of porcine skeletal muscle. In postnatal piglets, PSCs can differentiate into myoblasts and fuse with existing muscle fibers, increasing muscle fiber volume. While the long noncoding RNA MEG3 (MEG3) has been shown to modulate PSC development, its mechanisms remain nebulous. Here, we aim to explore the mechanism whereby MEG3 modulates PSC development. METHODS: Core interaction regions between MEG3 and CDC23 were detected using truncated constructs combined with RNA pull-down and RNA immunoprecipitation (RIP). Potential CDC23 target proteins were analyzed using coimmunoprecipitation (Co-IP) and bimolecular fluorescence complementation (BiFC). The potential mechanism of MEG3 modulation was then further explored by employing MG-132 and cycloheximide (CHX) treatment and ubiquitination assays. Finally, downstream signaling pathways associated with MEG3 were detected by transcriptome sequencing (RNA-seq) and western blot analysis. RESULTS: The 787–839 nt region of MEG3 and the 464–594aa region of CDC23 are necessary for binding, with MEG3 (Δ787–839 nt) showing a reduced inhibitory effect on proliferation and promoting effect on differentiation. Furthermore, CDC23 promotes HMGA1 ubiquitination via a K48 linkage at the K7 site, significantly shortening its half-life. MEG3 competitively binds CDC23, enhancing HMGA1 stability and protecting it from proteasome degradation. Functional detection and transcriptome sequencing further clarified that MEG3 acts through HMGA1-mediate inhibition of proliferation and promotion of differentiation. Furthermore, MEG3 knockdown, and subsequent HMGA1 downregulation, mediates the activation of ERK signaling, thereby promoting PSC proliferation and inhibiting differentiation. CONCLUSIONS: This study demonstrates a novel mechanism of MEG3 regulation in PSC development, implicates potential genetic targets, and provides a theoretical basis for accelerated porcine skeletal muscle development.
miR-223-3p improves macrophage polarization balance and mitochondrial metabolism to ameliorate uveitis by orchestrating P65 acetylation through RBPJ/HDAC1 axis.
Peng Y, Liu B, Xu S … +10 more , Qu R, Zhang R, Wang C, Liu Y, Wei H, Tian Q, Zhang M, Bi H, Yin X, Guo D
Cell Mol Biol Lett · 2026 Mar · PMID 41808024 · Full text
BACKGROUND: Uveitis is an autoimmune disease characterized by iris, ciliary muscle, and choroid inflammation. miR-223-3p, an anti-inflammatory microRNA, can regulate the expression of inflammatory genes involved in the d...
BACKGROUND: Uveitis is an autoimmune disease characterized by iris, ciliary muscle, and choroid inflammation. miR-223-3p, an anti-inflammatory microRNA, can regulate the expression of inflammatory genes involved in the disease process. However, the role and potential mechanism of miR-223-3p against uveitis remain unclear. METHODS: STRING website prediction, molecular docking, and co-IP experiments were performed to verify whether there was an interaction between RBPJ-HDAC1, HDAC1-P65, and P65-ARG1. Based on ex vivo and in vivo experiments, we detected NF-κB P65lys310 acetylation, P65 nuclear translocation, and the level of M1/M2 macrophage polarization. In addition, we also determined the levels of mitochondrial pressure and calcium flux under different conditions. Regulation of NF-κB P65lys310 acetylation via the RBPJ/HDAC1 axis affects macrophage polarization and mitochondrial function. RESULTS: We first found reduced miR-223-3p expression, elevated RBPJ and total acetylation levels, and an imbalance in macrophage polarization in peripheral blood monocyte-derived macrophages from patients with uveitis. Co-IP experiments supported the interaction between RBPJ and HDAC1, and HDAC1, as a key deacetylase, could inhibit NF-κB P65lys310 acetylation. Notably, overactivation of NF-κB P65lys310 acetylation levels in uveitis leads to elevated polarization of M1 macrophages and mitochondrial dysfunction. miR-223-3p can attenuate NF-κB P65lys310 acetylation and P65 nuclear translocation levels through the RBPJ/HDAC1 axis in uveitis, effectively reducing pro-inflammatory macrophage levels and mitigating mitochondrial damage, thereby reducing ocular inflammation and positively regulating the intraocular microenvironment in uveitis. CONCLUSION: miR-223-3p can inhibit P65lys310 acetylation and enhance mitochondrial function to improve M1/M2 macrophage polarization balance to ameliorate uveitis through RBPJ/HDAC1 axis.
GPA33 forms a distinct diagnostic target class to Claudin 18.2 in oesophageal adenocarcinoma enabling the development of a novel GPA33 antibody-based detection platform.
Brydon J, Krejcir R, Zavadil-Kokas F … +15 more , Singh A, Henek T, Hernychova L, Coleman S, Al Shboul S, Hrabal V, Kuncova Z, Mayordomo MY, Arcimowicz Ł, Ball KL, Padariya M, Kalathiya U, Vojtesek B, Hupp T, O'Neill JR
Cell Mol Biol Lett · 2026 Mar · PMID 41808009 · Full text
BACKGROUND: Oesophageal adenocarcinoma (OAC) is a cancer of high unmet clinical need. Because of tumour heterogeneity, it is likely that OAC will be stratified into several subtypes. Claudin 18.2 antibodies form emerging...
BACKGROUND: Oesophageal adenocarcinoma (OAC) is a cancer of high unmet clinical need. Because of tumour heterogeneity, it is likely that OAC will be stratified into several subtypes. Claudin 18.2 antibodies form emerging novel therapeutics in patients with a subtype of OAC. A large-scale proteogenomics screen in OAC identified glycoprotein A33 (GPA33) protein as a dominating cancer-specific target. We set out to determine whether GPA33 is distinct from or overlaps with Claudin 18.2 as a theranostic target in OAC. METHODS: A microarray from n = 106 patients, composed of cancer, normal squamous tissue, normal gastric tissue, and metastatic lymph nodes, was used to compare the expression of GPA33 and Claudin 18.2. A single-chain variable fragment (scFv)-phage display library was screened against recombinant GPA33 protein to isolate novel monoclonal antibodies. Next-generation complementarity-determining region 3 (CDR3) DNA sequencing (NGS) and enzyme-linked immunosorbent assay (ELISA) were both used to measure efficacy of antibody enrichment during biopanning. RESULTS: GPA33 exhibits superior tumour-specific expression compared with Claudin 18.2, the latter of which is expressed in normal gastric tissue. GPA33 and Claudin 18.2 exhibit statistically significant mutually exclusive expression in cancer tissue cores; 36% of cancers are GPA33/Claudin 18.2, whilst 22% are GPA33/Claudin 18.2. GPA33 therefore forms a novel target for theranostics in a significant number of patients. A monoclonal antibody (RSE-05) targeting GPA33 was isolated from a scFV-phage display library. The antibody required a di-sulphide bridge to maintain its epitope on the antigen. Epitope mapping was performed using di-sulphide bridge mutagenesis, peptide-phage display, and XL-MS. The dominant epitope resides in the V-type IgG domain of GPA33 at residues 27-29 and structural amino acids S17 and K65. This di-sulphide bridge-constrained epitope defines a novel monoclonal antibody binding interface. The RSE-05 monoclonal antibody can be adapted and used as a capture-sensor tool to measure GPA33 protein in liquid phase using a two-site sandwich ELISA format. CONCLUSIONS: GPA33 exhibits elevated cancer-specific expression relative to Claudin 18.2, indicating that GPA33 can also form the basis for a cancer diagnostic. Claudin 18.2 and GPA33 generally exhibit mutually exclusive expression suggestive of two different OAC development pathways. Thus, GPA33 forms a novel target that captures the Claudin 18.2-negative patient class, and the monoclonal antibody we describe forms the basis for novel diagnostic and therapeutic tools for development in OAC.
ZmWAKL21 is a maize wall-associated kinase-like protein that interacts with AvrRppC and contributes to southern corn rust resistance.
Sun J, Xu Q, Lv M … +17 more , Li X, Yang J, Nguyen T, Tian Z, Li Z, Liao X, Hu M, Li H, Bo J, Jia F, Geng C, Kang X, Chen Z, Hao J, Tang J, Zheng T, Ding J
Cell Mol Biol Lett · 2026 Mar · PMID 41807998 · Full text
UNLABELLED: Southern corn rust (SCR), caused by the fungal pathogen (), is a major threat to maize production worldwide. To date, two major nucleotide-binding leucine-rich repeat (NLR) resistance genes, and , have been...
UNLABELLED: Southern corn rust (SCR), caused by the fungal pathogen (), is a major threat to maize production worldwide. To date, two major nucleotide-binding leucine-rich repeat (NLR) resistance genes, and , have been identified that confer protection against . However, their durability is frequently undermined by the rapid evolution of the pathogen. While key components of NLR-mediated resistance have been characterized, the molecular interface between maize and —particularly the roles of fungal effectors such as AvrRppC—remains largely unexplored. In particular, the early immune signaling events at the plasma membrane are still poorly defined in this pathosystem. In this study, an MBP-tagged AvrRppC pull-down MS (Mass spectrometry) screening system within the maize– pathosystem was first established. Using this approach, we identified , which encodes a wall-associated receptor kinase-like protein. Molecular, biochemical, and cellular assays show that AvrRppC can bind ZmWAKL21 on the plasma membrane. During infection, positively increases the expression of and , resulting in elevated production of reactive oxygen species (ROS). Kinase assays further revealed that ZmWAKL21 possesses intrinsic serine/threonine kinase activity, which is directly suppressed by AvrRppC, highlighting an arm race between host and pathogen. Despite this antagonistic interaction, transgenic maize plants overexpressing exhibited significantly enhanced resistance to compared with wild-type controls, whereas CRISPR-Cas9-generated knockout mutants were more susceptible. Together, our findings uncover an immune interface in the maize– pathosystem, in which the fungal effector AvrRppC suppresses the kinase activity of ZmWAKL21, yet overexpression of still enhances ROS-associated defense responses. This study provides new mechanistic insights into fungal effector–kinase interactions and the regulation of immune signaling in monocot plants. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11658-026-00868-1.
Reduced eccDNA content in idiopathic asthenozoospermia sperm is associated with compromised DNA repair capacity and elevated DNA damage.
Wang Z, Song C, Hong X … +28 more , Yu J, Xu Z, Han P, He C, Mao S, Li Z, Yuan H, Wang X, Zhai J, Tan S, Fan W, Xu Y, Zhang T, Yang Z, Lin S, Zhu W, Huang L, Chen C, Zou G, Chen W, Lv W, Bolund L, Lin L, Luo Y, Zhang F, Mao F, Li J, Xiang X
Cell Mol Biol Lett · 2026 Mar · PMID 41807995 · Full text
BACKGROUND: Despite representing approximately 30% of male infertility cases, idiopathic asthenozoospermia (iAZS) remains etiologically uncharacterized. Extrachromosomal circular DNA (eccDNA) is mobile and circular DNA o...
BACKGROUND: Despite representing approximately 30% of male infertility cases, idiopathic asthenozoospermia (iAZS) remains etiologically uncharacterized. Extrachromosomal circular DNA (eccDNA) is mobile and circular DNA outside of linear chromosomes. Although eccDNA has been identified in human sperm, its biogenesis and potential role in iAZS pathogenesis requires further study. METHODS: We enrolled 31 patients with idiopathic asthenozoospermia (iAZS) and 31 healthy controls (normozoospermia, NZS), collecting sperm samples with progressive motility (PR) ranging from 0.3% to 90.9%. Sperm eccDNAs were purified and characterized using Circle-seq. Outward PCR, Sanger sequencing, and Nanopore long-read sequencing were employed to investigate eccDNA biogenesis and its potential genomic effects. In addition, spermatozoa RNA sequencing (RNA-seq) and immunofluorescence staining were conducted to identify DNA repair-related candidate genes. A CRISPR/Cas9-mediated APLF knockout model was established to explore DNA repair mechanisms in eccDNA formation in vitro. RESULTS: Comprehensive analysis of eccDNAs derived from the sperm samples revealed a significant positive correlation between sperm motility and eccDNA abundance. Larger eccDNAs (≥ 3 kb) showed inverse associations with meiotic recombination rates and coding gene density, while smaller eccDNAs lacked these trends. Although eccDNA formation broadly aligned with transposable element (TE) densities, larger eccDNAs (≥ 3 kb) were negatively correlated with short interspersed nuclear elements (SINEs) (mainly Alu elements). Microhomology-mediated end joining (MMEJ) likely drove eccDNA biogenesis, as 58% of eccDNAs harbored 3 bp direct repeat (DR) pairs. Nanopore and variant analyses suggested eccDNAs may arise from genomic deletions and later reintegrate. Importantly, sperm motility and eccDNA abundance correlated positively with DNA repair capacity but negatively with DNA damage. Finally, we identified APLF, a downregulated DNA repair protein in low-motility sperm, as a key regulator of eccDNA formation in vitro. CONCLUSIONS: These findings emphasize the potential interplay between genomic elements and sperm eccDNA formation, highlight that impaired DNA repair and elevated DNA damage level may be major causes of reduced sperm motility and pathogenesis of iAZS, and offer new insights into strategies for improving male fertility.
The miR-8/miR-200 family: from functional diversification to translational applications.
Yuan X, He Y, Wang C … +1 more , Fu Y
Cell Mol Biol Lett · 2026 Mar · PMID 41807937 · Full text
The miR-8/miR-200 family is a phylogenetically ancient microRNA regulator conserved across bilaterian animals, originating as a single miR-8 isoform in invertebrates and expanding to miR-200a/b/c, miR-141, and miR-429 in...
The miR-8/miR-200 family is a phylogenetically ancient microRNA regulator conserved across bilaterian animals, originating as a single miR-8 isoform in invertebrates and expanding to miR-200a/b/c, miR-141, and miR-429 in vertebrates through gene duplication. This review summarizes the biogenesis, genealogical details, and regulatory roles of the miR-8/miR-200 family. Furthermore, it presents the first comprehensive analysis of its evolutionary trajectory from invertebrates to vertebrates, thereby establishing a foundational understanding that underscores its significant potential for translational applications. Phylogenetic analyses confirm its sequence conservation and lineage-specific distribution, indicating that miR-8 originated in Platyhelminthes, with subsequent isoforms emerging in chordates. Functionally, this family plays pleiotropic roles: in invertebrates, miR-8 regulates immune defense, reproduction, and biosynthesis; in vertebrates, miR-200 subtypes modulate stress responses, epithelial-mesenchymal transition (EMT), tumor suppression, and neurodevelopment via conserved pathways (e.g., Wnt, Notch, PI3K). Cross-species conservation underlies core functions in cell differentiation, apoptosis, and growth, while vertebrate-specific adaptations drive roles in cancer (e.g., targeting ZEB1 in metastasis) and metabolic diseases (e.g., diabetes via β-cell apoptosis). This work explores the translational potential of this family, including nucleic acid pesticides in agriculture (targeting insect miR-8) and diagnostic/therapeutic tools in medicine (miR-200 as cancer biomarkers). Key challenges remain in delivery specificity and addressing functional pleiotropy. Future research should elucidate regulatory networks in non-model species and refine targeted delivery systems for clinical and agricultural applications.
HK2-driven histone H3K18 lactylation promotes stromal cell senescence and decidualization deficiency in URSA via CUX1-mediated SASP factor transcription.
Zhao X, Zhao Y, Jiang Y … +4 more , Ma Y, Ma J, Zhao H, Feng X
Cell Mol Biol Lett · 2026 Mar · PMID 41803676 · Full text
BACKGROUND: Unexplained recurrent spontaneous abortion (URSA) is characterized by defective endometrial stromal cell decidualization, with cellular senescence emerging as a key contributor. However, the metabolic-epigene...
BACKGROUND: Unexplained recurrent spontaneous abortion (URSA) is characterized by defective endometrial stromal cell decidualization, with cellular senescence emerging as a key contributor. However, the metabolic-epigenetic mechanisms linking glycolysis to senescence-driven decidualization failure remain unclear. This study elucidates how hexokinase 2 (HK2)-mediated glycolytic reprogramming promotes histone lactylation-dependent stromal senescence and decidualization impairment in URSA. METHODS: We employed multi-omics profiling (RNA-seq, metabolomics, and CUT&Tag) of primary stromal cells from patients with URSA and controls to map the histone H3K18 lactylation (H3K18la)-cut-like homeobox 1 (CUX1)-senescence-associated secretory phenotype (SASP) axis. Subsequently, this axis was validated both in vitro decidualization models and URSA murine models. RESULTS: Decidual tissues from patients with URSA exhibited stromal cell senescence and impaired decidualization. Mechanistically, HK2-driven glycolysis elevated lactate production, which in turn promoted H3K18la at the CUX1 promoter. CUX1 then directly activated the transcription of key SASP factors, thereby propagating the senescence state. Critically, CUX1 depletion or glycolysis inhibition rescued these senescence and decidualization deficiency in vitro. Furthermore, CUX1 knockdown in the URSA murine model reduced stromal senescence and improved decidualization. CONCLUSIONS: Our findings define a novel HK2-H3K18la-CUX1-SASP signaling axis that drives URSA pathogenesis by linking metabolic reprogramming with epigenetic regulation. This work highlights CUX1 as a potential therapeutic target for correcting decidualization deficiency in URSA.
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