International Journal Of Biological Sciences[JOURNAL]
Sun
200 papers
Sanggenol L Induces Endoplasmic Reticulum Stress and Triggers Cell Apoptosis in Glioblastoma by Binding to BiP.
Xu J, Chang H, Du Y … +8 more , Tang Z, Qin Z, Wang Y, Wei F, Hu X, Hou J, Xu M, Cui H
Int J Biol Sci · 2026 · PMID 42157950 · Full text
(white mulberry) is a medicinal plant whose extracts possess significant anti-tumor potential. Through screening 59 commercially available mulberry-derived compounds, we identified a small molecule, Sanggenol L (SL), whi...
(white mulberry) is a medicinal plant whose extracts possess significant anti-tumor potential. Through screening 59 commercially available mulberry-derived compounds, we identified a small molecule, Sanggenol L (SL), which exhibited potent inhibitory effects on glioblastoma while showing minimal toxicity toward normal cells. This study aimed to elucidate the anti-cancer function and underlying mechanism of SL in glioblastoma cells. Experimental results demonstrated that SL induced cytotoxic endoplasmic reticulum (ER) stress, suppressed cell viability, and triggered apoptosis. Mechanistically, LC-MS/MS and CETSA analyses revealed that SL specifically binds to BiP, creating a steric hindrance that blocks its interaction with IRE1α. This leads to excessive dimerization of IRE1α and hyper-activation of the IRE1/CHOP/XBP1s/Bcl-2 pathway, thereby amplifying cytotoxic ER stress and ultimately promoting apoptosis. Furthermore, we found that SL promotes ubiquitination and degradation of MGMT, consequently enhancing the chemosensitivity of glioblastoma to temozolomide.
HDAC7-Induced Epigenetic Repression Modulates ATF3 Functional Plasticity in Colorectal Cancer Pathogenesis.
Wang Q, Ji D, Jia Y … +10 more , Li S, Gao W, Liang T, Liang Y, Zeng C, Wang C, Cheung KL, Wang Q, Zhou MM, Zeng L
Int J Biol Sci · 2026 · PMID 42157949 · Full text
Class IIa histone deacetylase 7 (HDAC7) regulates transcription primarily through scaffolding functions, but its molecular mechanisms in cancer pathogenesis remain incompletely understood. Here, we establish HDAC7 as a k...
Class IIa histone deacetylase 7 (HDAC7) regulates transcription primarily through scaffolding functions, but its molecular mechanisms in cancer pathogenesis remain incompletely understood. Here, we establish HDAC7 as a key epigenetic regulator in colorectal cancer (CRC). HDAC7 is overexpressed in CRC tumors and correlates with advanced disease stages, lymph node metastasis, and poor patient survival. Mechanistically, HDAC7 scaffolds a repressive complex with HDAC3 and the stress-responsive transcription factor ATF3. This reduces H3K27ac/H3K18ac occupancy and blocks BRD4/RNA polymerase II (Pol II) recruitment at regulatory regions to epigenetically silence its transcription. Consequently, this repression inactivates ATF3's tumor-suppressive functions, activating oncogenic PI3K-Akt signaling while suppressing the Hippo pathway. Genetic depletion or pharmacological inhibition of HDAC7 disrupts this repressive complex, triggering a functional switch in ATF3. This promotes BRD4/Pol II recruitment and H3K27ac enrichment at the ATF3 locus, enabling ATF3 to undergo transcriptional self-activation. Reactivated ATF3 suppresses CRC proliferation and survival by downregulating Bcl-2, upregulating p21 () to induce cell cycle arrest, promoting caspase-3-mediated apoptosis, and inhibiting PI3K-Akt signaling. Xenograft studies confirm that HDAC7 depletion suppresses tumorigenicity . Our work identifies HDAC7 as a molecular mediator that governs ATF3's functional plasticity through competitive cofactor recruitment, positioning HDAC7 inhibition as a therapeutic strategy to reactivate ATF3-mediated tumor suppression in CRC.
Piezo1 in hypertrophic chondrocytes regulates osteoclastogenesis in endochondral ossification.
Tschaffon-Müller MEA, Schoppa A, Eckl F … +8 more , Brylka LJ, Haffner-Luntzer M, Yorgan TA, Dieterich S, Kölbl C, Amling M, Schinke T, Ignatius A
Int J Biol Sci · 2026 · PMID 42157948 · Full text
Ion channels of the Piezo family are key mechanosensors in diverse tissues, including bone. Recent studies have demonstrated that Piezo1 in differentiating chondrocytes is critical for endochondral ossification during bo...
Ion channels of the Piezo family are key mechanosensors in diverse tissues, including bone. Recent studies have demonstrated that Piezo1 in differentiating chondrocytes is critical for endochondral ossification during bone development and regeneration. During endochondral ossification, chondrocytes undergo hypertrophy prior to apoptosis or transdifferentiation into bone-forming osteoblasts, thereby significantly contributing to new bone formation. Here, we investigated the specific role of Piezo1 in hypertrophic chondrocytes using a mouse model with conditional deficiency under control of the collagen X promoter ( ). These mice exhibited a pronounced osteopenic bone phenotype and impaired callus maturation. Notably, hypertrophic chondrocyte apoptosis and chondrocyte-to-osteoblast transdifferentiation remained unaffected during endochondral ossification in mice. Instead, these mice displayed markedly increased osteoclast numbers in the primary spongiosa beneath the growth plates and within the fracture callus. Further and analysis revealed that Piezo1 regulates osteoclastogenesis by repressing receptor activator of NF-κB ligand and inducing osteoprotegerin expression in hypertrophic chondrocytes. Collectively, our findings identify Piezo1 as an important regulator of hypertrophic chondrocyte-osteoclast communication during endochondral bone formation.
NOP56 Drives Colorectal Cancer Progression by Modulating p53 Acetylation through SIRT1/p300.
Park JE, Ahn CH, Sim DY … +5 more , Park SY, Cha HJ, Shim BS, Kim B, Kim SH
Int J Biol Sci · 2026 · PMID 42157947 · Full text
Nucleolar protein 56 (NOP56), a core component of small nucleolar ribonucleoprotein complexes, has been implicated in oncogenesis through the regulation of reactive oxygen species (ROS) homeostasis; however, its role in...
Nucleolar protein 56 (NOP56), a core component of small nucleolar ribonucleoprotein complexes, has been implicated in oncogenesis through the regulation of reactive oxygen species (ROS) homeostasis; however, its role in colorectal cancer (CRC) remains unclear. Here, we investigated the clinical relevance and biological function of NOP56 in CRC using TCGA datasets, tissue microarrays, next-generation sequencing, and and models. NOP56 expression was markedly elevated in CRC tissues compared with adjacent normal tissues and was correlated with poor patient survival. Silencing of NOP56 suppressed cell viability, colony formation, and migration, particularly in p53 wild-type HCT116 cells, and altered gene expression programs related to DNA damage response and apoptosis. Mechanistically, NOP56 depletion induced cell cycle arrest and apoptosis, accompanied by increased p53 and p21 levels and reduced expression of pro-caspase-3, c-Myc, Cyclin E, CDK2, CDK4, MDM2, and SIRT1. Conversely, NOP56 overexpression promoted p53 degradation, whereas its knockdown enhanced p53 stability and acetylation through suppression of SIRT1 and activation of p300, as supported by evidence of direct interaction and colocalization. Furthermore, NOP56 silencing synergistically enhanced the cytotoxic effect of 5-fluorouracil (5-FU). In a xenograft model, NOP56 knockdown markedly reduced tumor growth as well as PCNA and SIRT1 expression, while increasing p53 and cleaved caspase-3 levels. Collectively, these findings identify NOP56 as an oncogenic driver that promotes CRC progression by inducing p53 degradation, whereas its inhibition triggers apoptosis via p53 acetylation regulated by the SIRT1/p300 axis, highlighting NOP56 as a promising therapeutic target for p53 wild-type CRC.
ABHD11-AS1 Suppresses Colorectal Cancer Progression by Disrupting EIF4E-mediated POU2F1 Ubiquitination.
Li S, Jiang X, Oyang L … +7 more , Xia L, Tan S, Ren Z, Peng Q, Lin J, Liao Q, Zhou Y
Int J Biol Sci · 2026 · PMID 42157946 · Full text
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, yet the underlying mechanisms driving its progression are not fully elucidated. Long non-coding RNAs (lncRNAs) have recentl...
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, yet the underlying mechanisms driving its progression are not fully elucidated. Long non-coding RNAs (lncRNAs) have recently emerged as key regulatory molecules in tumor biology. In this study, we identified ABHD11-AS1 as a tumor-suppressive lncRNA that is significantly downregulated in CRC tissues, its low expression is correlated with poor patient prognosis. Functional assays demonstrated that ABHD11-AS1 inhibits CRC cell proliferation, migration, and invasion, and enhances sensitivity to oxaliplatin. Mechanistically, ABHD11-AS1 directly binds to EIF4E and disrupts its phase separation, thereby suppressing the translation of USP18, a deubiquitinating enzyme that stabilises the oncogenic protein POU2F1. Reduced USP18 expression leads to increased ubiquitination and proteasomal degradation of POU2F1, ultimately inhibiting malignant progression and enhancing chemotherapy sensitivity. Collectively, our findings uncover a previously unrecognised mechanism by which ABHD11-AS1 modulates EIF4E-mediated phase separation to regulate protein homeostasis, highlighting its potential as a therapeutic target in CRC.
Bone Marrow-Derived Macrophage NLRP3 Mediates Renal Fibrosis by triggering TGF-β/Smad3-mediated Macrophage-Myofibroblast Transition.
Wang W, Li J, Zhong Y … +7 more , Chen J, Wu L, Wan L, Huang XR, Ye Z, Yu X, Lan HY
Int J Biol Sci · 2026 · PMID 42157945 · Full text
NLRP3 is a well-recognized pro-inflammatory mediator in renal inflammation. Here, we report a new role for NLRP3 in the pathogenesis of renal fibrosis. Using a large-scale single-cell RNA sequencing, we found that NLRP3...
NLRP3 is a well-recognized pro-inflammatory mediator in renal inflammation. Here, we report a new role for NLRP3 in the pathogenesis of renal fibrosis. Using a large-scale single-cell RNA sequencing, we found that NLRP3 is mainly expressed by macrophages, but not by tubular cells. Functionally, we unexpectedly found that NLRP3 is profibrotic, as mice lacking NLRP3 or macrophage-specific deletion of NLRP3 were protected from UUO and ischemia reperfusion injury (IRI)-induced renal fibrosis. Mechanistically, we uncovered that NLRP3 directly bound TGF-β receptors II and I to trigger the activation of TGF-β/Smad3 signaling and progressive renal fibrosis via the macrophage-myofibroblast transition (MMT) process. This was further confirmed by pharmacological inhibition in a mouse model of UUO in which blockade of NLRP3 inhibited TGF-β/Smad3 signaling, MMT, and progressive renal fibrosis. In conclusion, macrophage NLRP3 is profibrotic and mediates renal fibrosis via the TGF-β/Smad3-MMT mechanism. Targeting macrophage NLRP3 may be a promising therapeutic approach for CKD.
Surfactant Protein B Precursor Inhibit the Progression of Resectable Non-small Cell Lung Cancer by Suppressing eIF4F-mediated Immune Evasion and Cancer Stemness.
Wen Y, Luo H, Ji X … +9 more , Zheng Y, Zhang L, Jian D, Chen J, Zhang H, Zhao NN, Jin H, Xu CX, Wang RT
Int J Biol Sci · 2026 · PMID 42157944 · Full text
Postoperative progression remains a major challenge in resectable non-small cell lung cancer (rNSCLC), but its factors and mechanisms are not fully understood. Here, we found that 34%-43% of rNSCLC patients have lower su...
Postoperative progression remains a major challenge in resectable non-small cell lung cancer (rNSCLC), but its factors and mechanisms are not fully understood. Here, we found that 34%-43% of rNSCLC patients have lower surfactant protein B precursor (pro-SFTPB) expression in tumor compared to adjacent tissues, and this low expression of pro-SFTPB is associated with low major pathological response to neoadjuvant chemoimmunotherapy and recurrence in rNSCLC. and animal experiments have shown that pro-SFTPB inhibits cancer stemness and immune evasion in NSCLC, and promotes the efficacy of PD-1 inhibitors. Targeting eIF4F improves the sensitivity of NSCLC with pro-SFTPB low expression to PD-1 inhibitors. Mechanistically, eIF4F promotes pro-SFTPB expression, while pro-SFTPB inhibits the formation of eIF4F complex by binding to eIF4A1, thereby suppressing the translation c-myc and PD-L1 that promote cancer stemness and immune evasion. Finally, we demonstrated that the reduction of SFTPB mRNA in NSCLC disrupts the negative regulation of pro-SFTPB on eIF4F complex formation, leading to activation of the eIF4F translation pathway and ultimately promoting tumor stemness and immune escape. In conclusion, the downregulation of pro-SFTPB in rNSCLC is an important factor in activating eIF4F-mediated cancer stemness and immune evasion to induce resistance to immunotherapy and promote disease progression.
A Novel PROTAC Confers a Dual Benefit Against Amyloid and Tau Pathology in Alzheimer's Disease via DAPK1 Degradation.
Li R, Yao J, Peng W … +13 more , Zheng L, Wu X, Shui X, Zheng X, Tian W, Wang L, Zhou Y, Ruan X, Pan X, Zhang T, Liu Y, Lee TH, Chen D
Int J Biol Sci · 2026 · PMID 42157943 · Full text
Alzheimer's disease (AD) is a neurodegenerative disorder that is caused by multiple factors, characterized by a progressive decline in cognitive ability, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibri...
Alzheimer's disease (AD) is a neurodegenerative disorder that is caused by multiple factors, characterized by a progressive decline in cognitive ability, extracellular amyloid-β (Aβ) plaques, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Current treatment strategies can provide only symptomatic treatment or limited efficacy, highlighting the need to intervene in the upstream regulatory factors that drive both amyloid and tau pathologies. Death-associated protein kinase 1 (DAPK1) is a key driver upstream of both amyloid precursor protein processing and tau phosphorylation, simultaneously promoting amyloidogenesis and tau-mediated pathology in AD. In this study, we developed CP1, a bifunctional proteolysis-targeting chimera (PROTAC), to recruit E3 ubiquitin ligase to DAPK1, thereby inducing the ubiquitination and proteasomal degradation of DAPK1. CP1 efficiently eliminated the DAPK1 protein in primary cortical neurons without affecting its mRNA level, resulting in reduced Aβ generation and tau hyperphosphorylation. , upon systemic administration, CP1 effectively crossed the blood-brain barrier, degraded DAPK1, and consequently reduced the Aβ plaque burden and mitigated neuroinflammation in female 5xFAD mice. In a AAV-hTau-P301L tauopathy model, CP1 treatment suppressed tau hyperphosphorylation, preserved NeuN- and MAP2-positive neurons, attenuated astrocytic and microglial activation, and ultimately restored learning and memory abilities in both male and female mice. In summary, these findings demonstrate that degrading DAPK1 via a PROTAC strategy simultaneously mitigates both amyloid and tau pathology, indicating that CP1 is an effective candidate for disease-modifying therapy.
The Role of NADPH Oxidase 4 in Neutrophil-Mediated Immune Escape in Gastric Cancer.
Jiang J, Xi W, Zheng Y … +9 more , Ji J, Zhou C, Shi M, Wu J, Jin Y, Zhang B, Zhao L, Cai Q, Zhang J
Int J Biol Sci · 2026 · PMID 42157942 · Full text
NADPH oxidase 4 (NOX4) transmits electrons for various redox reactions by generating reactive oxygen species (ROS), which are present at high levels in a variety of malignant tumors, including gastric cancer (GC). Nevert...
NADPH oxidase 4 (NOX4) transmits electrons for various redox reactions by generating reactive oxygen species (ROS), which are present at high levels in a variety of malignant tumors, including gastric cancer (GC). Nevertheless, the role of NOX4 in inducing immune escape in GC remains unknown. We analyzed the correlation between NOX4 expression and infiltrating neutrophils in human GC tissue. NOX4 overexpression correlated with poor prognosis and enhanced neutrophil infiltration in GC patients and mouse models. Tumor-derived NOX4 promoted secretion of GM-CSF, which was established through functional assays as the key factor responsible for neutrophil recruitment. Recruited neutrophils inhibited GC cell apoptosis and fostered an immunosuppressive microenvironment. NOX4/GM-CSF signaling further enhanced PHGDH and ASNS-mediated metabolic adaptation in neutrophils. Elevated NOX4 and neutrophil infiltration were observed in GC patients unresponsive to neoadjuvant anti-PD-1 therapy. Tumor-derived NOX4 drives GM-CSF-dependent neutrophil recruitment, leading to metabolic reprogramming and immunosuppression in GC. Targeting the GM-CSF/neutrophil axis may overcome resistance to immune checkpoint inhibitors.
Competitive Binding of UBA52 and HOPX Modulates β-catenin Stability in Colorectal Cancer in the Context of High-Iron Intake.
Liu X, Tang T, Wang X … +17 more , Feng J, Yang X, Luo Y, Huang Y, Xu L, Liu B, Wang N, Luo Y, Tian H, Wang S, Huang L, Xu Z, Hu H, Liu C, Lei X, Lang J, Liu D
Int J Biol Sci · 2026 · PMID 42157941 · Full text
Over-intake of dietary iron and hereditary iron overload are implicated in colorectal cancer (CRC) carcinogenesis, yet the mechanistic basis of how iron-mediated signaling leads to oncogenesis remains enigmatic. Here we...
Over-intake of dietary iron and hereditary iron overload are implicated in colorectal cancer (CRC) carcinogenesis, yet the mechanistic basis of how iron-mediated signaling leads to oncogenesis remains enigmatic. Here we demonstrate that high iron diet augments the regenerative capacity of Hopx intestinal stem cells (ISCs) rather than Lgr5 ISCs to functionally contribute to colon tumor formation. Mechanistically, high iron activates a robust Wnt/β-catenin signaling in ISCs to enhance the proliferation of colonic cells in a Hopx-dependent manner. Furthermore, Wnt/β-catenin induction is attributed to Hopx stabilizing β-catenin protein by directly inhibiting the interaction of β-catenin with UBA52, which targets ubiquitination degradation of β-catenin. This study thus identifies an iron-triggered pathway regulating intestinal tumorigenesis and indicates that iron interventions may complement current prevention and treatment strategies for CRC, and Hopx is a previously unrecognized regulator of β-catenin and a therapeutic target of CRC.
Immunologic Combinations in Multiple Myeloma: Synergistic Stimulation with T cells and NK cells.
Liu Z, Lai J, Yang C … +4 more , Liu H, Ding K, Song J, Fu R
Int J Biol Sci · 2026 · PMID 42157940 · Full text
Bone marrow plasma cells proliferate malignantly in multiple myeloma (MM), a hematological cancer. MM is now the second most common hematologic illness, followed by non-Hodgkin's lymphoma. The tumor microenvironment (TME...
Bone marrow plasma cells proliferate malignantly in multiple myeloma (MM), a hematological cancer. MM is now the second most common hematologic illness, followed by non-Hodgkin's lymphoma. The tumor microenvironment (TME) is a crucial factor in MM development. T cells, natural killer (NK) cells, and natural killer T (NKT) cells are the key anti-MM immune cells in the bone marrow microenvironment (BMME). By direct contact or cytokine production, these cells prevent MM cells from proliferation and survival. However, a major factor contributing to the insufficiency of anti-tumor immune responses is the inhibition of T cells and NK cells functions. We aimed to summarize the mechanisms of T cells and NK cells suppression in MM and discuss emerging immunotherapies that target both cell types.
Canagliflozin and Brusatol Synergize against LKB1-KEAP1 Co-Mutant NSCLC through AKT Suppression.
Chen Y, Gao XZ, Rong D … +5 more , Gao L, Tang M, Lu G, Ling ZQ, Shen HM
Int J Biol Sci · 2026 · PMID 42157939 · Full text
Liver kinase B1 (LKB1, encoded by ) is an important tumour suppressor, with approximately 30% of non-small cell lung cancer (NSCLC) patients harbouring LKB1 mutations. Our previous work showed that LKB1-mutant NSCLC cell...
Liver kinase B1 (LKB1, encoded by ) is an important tumour suppressor, with approximately 30% of non-small cell lung cancer (NSCLC) patients harbouring LKB1 mutations. Our previous work showed that LKB1-mutant NSCLC cells are sensitive to glucose starvation, suggesting that suppression of glucose metabolism may serve as a potential therapeutic strategy for NSCLC patients with LKB1 mutation. In this study, we found LKB1 mutations frequently co-occur with mutations in Kelch-like ECH-associated-protein 1 (KEAP1), another key tumour suppressor regulating the NRF2-mediated antioxidant response. To target LKB1-KEAP1 co-mutant NSCLC, we utilized Canagliflozin, an FDA-approved sodium-glucose co-transporter 2 (SGLT2) inhibitor that mimics glucose starvation via inhibiting glucose uptake, in combination with Brusatol, an inhibitor of NRF2 signalling. Our results demonstrate that the combined treatment of Canagliflozin and Brusatol exerts potent anti-tumour effects in LKB1-KEAP1 co-mutant NSCLC cells both and . Mechanistically, the combination suppresses AKT activity and promotes AKT degradation, ultimately leading to apoptotic cell death. Taken together, these findings support the potential of combined Canagliflozin and Brusatol treatment as an effective therapeutic approach for LKB1-KEAP1 co-mutant NSCLCs.
Circulating cytokines as triggers of endothelial dysfunction and sex-specific interstitial cell response in fibrocalcific aortic valve disease.
Valerio V, Bertolini F, Rusconi V … +12 more , Chiesa M, Massaiu I, Gripari P, Mantegazza V, Gatto C, Ciccarelli M, Galotta A, Bonomi A, Zanobini M, Agrifoglio M, Myasoedova VA, Poggio P
Int J Biol Sci · 2026 · PMID 42157938 · Full text
BACKGROUND: Fibrocalcific aortic valve disease (FCAVD) is a progressive and multifactorial pathology that remains asymptomatic in its early stages and lacks effective pharmacological therapies. Aortic valve sclerosis (AV...
BACKGROUND: Fibrocalcific aortic valve disease (FCAVD) is a progressive and multifactorial pathology that remains asymptomatic in its early stages and lacks effective pharmacological therapies. Aortic valve sclerosis (AVSc), the initial phase of FCAVD, is marked by leaflet thickening and early calcium deposition without significant hemodynamic changes. While local inflammation is known to drive valvular remodeling, recent studies suggest that systemic inflammation may also play a critical role, potentially interacting with endothelial (VEC) and interstitial cells (VIC) and thus promoting disease progression. Notably, sex differences in fibrocalcific processes have been identified, yet their mechanistic basis remains understudied. Thus, we hypothesize that systemic inflammation exacerbates endothelial dysfunction and accelerates fibrocalcific remodeling, with distinct processes in men and women, and aim to investigate how these mechanisms contribute to disease progression. METHODS: A total of 238 individuals were enrolled across three groups: controls (CTRL n = 80), AVSc (n = 78), and severe aortic stenosis (AS n = 80). A broad panel of circulating cytokines was measured and analyzed with respect to sex and disease stage. To assess the functional impact of key cytokines, experiments were conducted using human VECs and VICs treated with interleukin-1β (IL-1β) and interferon-β (IFNβ). Cellular responses were evaluated morphological analyses, gene and protein expression assays, and calcification potential under normal and pro-osteogenic conditions. RESULTS: Cytokine profiling revealed that AVSc patients exhibited significantly elevated levels of IL-1β compared to both CTRL and AS, with IL-1β being consistently higher in males across all stages. , IL-1β triggered endothelial-to-mesenchymal transition in VECs, promoting a pro-fibrotic and inflammatory phenotype. Sex-stratified analysis of VICs showed that IFNβ enhanced RUNX2 expression and calcification in a dose-dependent manner, with female-derived VICs being more responsive. Conversely, IFNβ exerted anti-fibrotic effects by reducing and expression, more markedly in female cells, particularly at the protein level. CONCLUSION: Our findings reveal a previously overlooked role of systemic inflammation, primarily driven by IL-1β and IFNβ, in promoting early endothelial activation and sex-specific fibrocalcific remodeling in FCAVD. These cytokines not only serve as markers of disease but also actively influence cell-specific responses, shaping the distinct aortic valve fibrocalcific patterns observed in men and women. Unraveling these mechanisms could open new avenues for developing early monitoring of circulating IL-1β and IFNβ, while informing sex-specific therapeutic strategies to modulate cytokine signaling to slow or prevent FCAVD progression.
Loss of BATF3 impairs adipose-liver homeostasis and accelerates the transition from steatosis to fibrosis in high-fat diet-fed mice.
Dong H, Hao L, Guo W … +2 more , Sun X, Zhou Z
Int J Biol Sci · 2026 · PMID 42157937 · Full text
BATF3 is a transcription factor critical for dendritic cell differentiation and immune regulation. Although recent studies suggest that BATF3 is involved in metabolic disorders, the mechanism by which BATF3 deficiency co...
BATF3 is a transcription factor critical for dendritic cell differentiation and immune regulation. Although recent studies suggest that BATF3 is involved in metabolic disorders, the mechanism by which BATF3 deficiency contributes to the development of metabolic dysfunction-associated fatty liver disease (MASLD) remains unclear. Here, we examined the impact of BATF3 deficiency in mice fed a high-fat diet (HFD). We discovered that BATF3 is essential for maintaining metabolic homeostasis in adipose tissue and liver. Batf3⁻/⁻ mice developed aggravated hepatic steatosis, inflammation, and fibrosis, accompanied by enhanced adipose lipolysis, increased hepatic fatty acid uptake, and impaired insulin-AKT signaling. Our investigations into gene expression affected by BATF3 deficiency showed that angiopoietin-like protein 8 (ANGPTL8), a hepatokine abundantly expressed in the liver and adipose tissue, was specifically downregulated, identifying ANGPTL8 as a key mediator of BATF3-regulated hepatic and adipose tissue homeostasis. Importantly, we found that in addition to directly inhibiting inflammation-induced hepatic stellate cell activation, ANGPTL8 also has tissue-specific effects on lipid metabolism, alleviating hepatic lipid deposition and suppressing adipose tissue lipolysis. Collectively, our findings provide mechanistic insights into how BATF3 regulates hepatic and adipose homeostasis, contributing to fibrosis development, and highlight the BATF3-ANGPTL8 axis as a potential therapeutic target in fatty liver disease.
METTL3-IGF2BP3 as a glucose sensor in hyperglycemic microenvironment promotes tumorigenesis and glycolysis.
Liu L, Zhang Y, Shao Z … +9 more , Zhao X, Huang Y, Wang Q, Liu X, Zheng X, Zhou B, Zhang F, Gao Z, Yan S
Int J Biol Sci · 2026 · PMID 42157936 · Full text
Glycemic disorders, especially diabetes characterized by elevated blood glucose, significantly increase the risk of various cancers, including increasing the risk of hepatocellular carcinoma (HCC) by 239%. Diabetes melli...
Glycemic disorders, especially diabetes characterized by elevated blood glucose, significantly increase the risk of various cancers, including increasing the risk of hepatocellular carcinoma (HCC) by 239%. Diabetes mellitus has now been confirmed as an independent risk factor for the development of HCC, with T2DM increasing the risk by 4.59 times. However, little is known about mechanisms regulate glucose signal transduction in HCC. We investigated the relationship between high glucose levels and methylation-related gene expression in HCC. The effects of METTL3-IGF2BP3 on transcriptome profiles were used to identify downstream molecules. Proliferation, glucose uptake, lactate production, ATP levels, extracellular acidification rate, and oxygen consumption rate were examined in HCC cells. The mechanism by which METTL3-IGF2BP3 activates the PI3K-AKT pathway was explored. The results showed that mA modification levels were significantly elevated in HCC cells under a hyperglycemic microenvironment, primarily due to transcriptional activation of c-MYC-initiated METTL3. Additionally, glucose could directly bind to IGF2BP3 and promote its function in recognizing mA sites. SLC39A10 as a downstream molecule of METTL3-IGF2BP3, promoting the uptake of Zn in HCC. METTL3, IGF2BP3, or SLC39A10 silencing inhibited proliferation, colony formation, glycolysis in HCC cells. Mechanistically, silencing METTL3-IGF2BP3 significantly reduced the methylation level and function of SLC39A10, decreased intracellular Zn²⁺ levels, inhibited ADAM17 activity, and thus attenuated EGFR phosphorylation-induced PI3K-AKT pathway activation. Concurrently, alterations in intracellular Zn²⁺ levels are associated with altered immune cell infiltration in the HCC tumor microenvironment. In conclusion, the METTL3-IGF2BP3 axis promotes HCC tumorigenesis by enhancing glycolytic reprogramming and remodeling the immunosuppressive tumor microenvironment.
System L Amino Acid Transporter LAT1 is required for Mouse Intestinal Epithelial Homeostasis.
Bao L, Peng Z, Shi B … +1 more , Shi YB
Int J Biol Sci · 2026 · PMID 42157935 · Full text
The adult mammalian intestinal epithelium is constantly self-renewed via cell proliferation in the crypt. Earlier studies have revealed many genes and pathways important for regulating intestinal epithelial cell prolifer...
The adult mammalian intestinal epithelium is constantly self-renewed via cell proliferation in the crypt. Earlier studies have revealed many genes and pathways important for regulating intestinal epithelial cell proliferation and differentiation to maintain adult epithelial homeostasis. Of interest among them is system L amino acid transporter 1 (), also known as slc7a5. Slc7a5 can transport thyroid hormone and large, neutral amino acids such as leucine and tryptophan. It can activate mTORC1 to increase cell proliferation by transporting amino acid. We have previously shown that slc7a5 is highly expressed in adult mouse intestinal crypt and that intestinal epithelial cell-specific knockout () of slc7a5 ( ) reduces mTORC1 signaling. Unexpectedly, intestinal crypts have increased cell proliferation in the small intestine. There is also a drastic reduction in mature Paneth cells, suggesting a possible indirect effect of slc7a5 on cell proliferation by regulating secretory cell differentiation. Here, we have generated a tamoxifen-inducible intestinal epithelial-specific slc7a5 knockout line (slc7a5 ). We show that inducible knockout of slc7a5 in adult mice also leads to reduced mature Paneth cells and increased cell proliferation in the crypt, revealing that slc7a5 is important for adult intestinal epithelial homeostasis. Kinetically, the reduction of mature Paneth cells occurs before the increase in cell proliferation. Furthermore, in stable intestinal epithelial cell-specific knockout ( ) animals, a reduction in mature Paneth cells occurs soon after mature Paneth cells are first formed during post-natal development while an increase in crypt cell proliferation occurs later by postnatal day 28 after intestinal maturation is complete. These findings support a mechanism where slc7a5 affects cell proliferation indirectly by regulating Paneth cell differentiation to maintain adult intestinal epithelial homeostasis.
Mitochondria and polycystic ovary syndrome: The role of ferroptosis, inflammasomes, and endoplasmic reticulum stress.
Zhang X, Sun T, Wang X … +3 more , Ma Y, Cao L, Tan J
Int J Biol Sci · 2026 · PMID 42157934 · Full text
Polycystic ovary syndrome (PCOS) poses a major threat to women of reproductive age and is strongly associated with metabolic and inflammatory abnormalities. Over the past decade, tremendous progress has been made in our...
Polycystic ovary syndrome (PCOS) poses a major threat to women of reproductive age and is strongly associated with metabolic and inflammatory abnormalities. Over the past decade, tremendous progress has been made in our understanding of signaling events regulated by mitochondria. Emerging evidence underscores mitochondrial dysfunction as a central pathophysiological hub in PCOS. The intricate crosstalk among mitochondrial dysfunction, ferroptosis, inflammasomes, and endoplasmic reticulum (ER) stress creates a pathological network that underpins ovarian dysfunction, metabolic abnormalities, and chronic inflammation in PCOS, highlighting promising novel targets for diagnosis and therapeutic intervention in this complex disorder.
Nuclear Galectin-1 Drives Cancer Progression through -GlcNAcylation-Dependent Regulation of SOX2.
Kim W, Yim YS, Baek JH … +6 more , Park YS, Song JJ, Chung JY, Gim J, Kim SJ, Chun KH
Int J Biol Sci · 2026 · PMID 42157933 · Full text
Galectin-1 is frequently upregulated in tumors and contributes to cancer progression. Here, we identify galectin-1 as a critical regulator of cancer stem-like properties. Silencing galectin-1 suppressed proliferation, mo...
Galectin-1 is frequently upregulated in tumors and contributes to cancer progression. Here, we identify galectin-1 as a critical regulator of cancer stem-like properties. Silencing galectin-1 suppressed proliferation, motility, side population fraction, and tumorsphere formation , and impaired tumor initiation and growth , whereas overexpression enhanced these malignant phenotypes. Transcriptomic profiling revealed stemness-associated transcription factors as major downstream targets, with SOX2 emerging as a key effector. Galectin-1 knockdown reduced SOX2 expression, whereas overexpression increased SOX2 nuclear abundance and transcriptional activity. Rescue experiments demonstrated that SOX2 is functionally required for galectin-1-mediated stemness and tumorigenesis. Mechanistically, galectin-1 associates with SOX2 in an -GlcNAcylation-dependent manner. Inhibition of -GlcNAcylation or mutation of SOX2 -GlcNAc sites disrupted this interaction, reduced SOX2 transcriptional activity, and impaired tumorsphere formation, supporting an intracellular lectin-like function. Structural modeling predicted that residues E71 and R73 within the carbohydrate recognition domain are critical for carbohydrate-mediated recognition of -GlcNAc-modified SOX2, which was validated by mutagenesis. Clinically, galectin-1 was highly expressed in gastric tumors, correlated with advanced stage, and predicted poor prognosis. Notably, high co-expression of galectin-1 and SOX2 was significantly associated with unfavorable survival outcomes. These findings establish galectin-1 as a reader-like protein that functionally engages -GlcNAcylated SOX2 and highlight the galectin-1/SOX2 axis as a potential therapeutic target in gastric cancer.
Synonymous editing alters ion channel function, favoring prime editing for retinal disease correction.
Kabra M, Moosajee M, Navarrete A … +13 more , Newby GA, Rawding P, Xie R, Mechoulam H, Rivera A, Hung A, Tiwari S, Waxman AJ, Molugu K, Saha K, Gong S, Liu DR, Pattnaik BR
Int J Biol Sci · 2026 · PMID 42157932 · Full text
Point mutations in the gene cause autosomal recessive childhood blindness, Leber congenital amaurosis (LCA16), by disrupting Kir7.1 channel function. We describe the etiology of the LCA16 retinopathy phenotype in three...
Point mutations in the gene cause autosomal recessive childhood blindness, Leber congenital amaurosis (LCA16), by disrupting Kir7.1 channel function. We describe the etiology of the LCA16 retinopathy phenotype in three patients from two unrelated families harboring a homozygous missense mutation (c.431T>C, p.Leu144Pro). Our prediction and validation using a human iPSC-derived retinal pigmented epithelium (RPE) model created via lipid nanoparticle-mediated delivery of the adenine base editor (ABE8e) demonstrated that the L144P mutation impairs Kir7.1 channel function and confirmed that non-viral biologic delivery is clinically translatable. We used two cytosine base editors (CBEs, BE4max-WTCas9 and evoCDA-SpCas9-NG) to correct this mutation in an L144P HEK293 stable cell model, achieving high on-target editing efficiency. However, our electrophysiological measurements showed minimal functional rescue of the channel in CBE-edited cells due to bystander nucleotide editing. Editing with evoCDA introduced a bystander missense mutation (L143F), whereas BE4max primarily generated silent mutations. Extended characterization of BE4max-edited cells revealed a distorted mRNA structure, altered half-life, and reduced abundance of cognate tRNA, all associated with these silent changes. In contrast, prime editing successfully restored channel function. Prime editors targeting the L144P locus achieved approximately 20% on-target editing without introducing bystander nucleotide editing or synonymous changes. Functional assessment demonstrated a strong genotype-phenotype correlation, with restored Kir7.1 channel activity observed in 28% of edited cells (12/43). Overall, these results highlight the importance of comprehensive functional validation of genome editing outcomes and emphasize the need for rigorous preclinical studies to translate therapeutic genome editing into first-in-human trials for genetically diverse diseases.
PRDM16 Drives Thyroid Cancer Differentiation via a TRIM58-MVP Axis to Suppress MAPK and PI3K/AKT Signaling.
Yu J, Luo W, Niu Z … +13 more , Zhang M, Gao Y, Tian M, Wang Z, Wan X, Gui H, Su Q, Chen W, Hu L, Hou X, Dong Q, Ruan X, Zheng X
Int J Biol Sci · 2026 · PMID 42157931 · Full text
Thyroid cancer frequently undergoes dedifferentiation, progressing into poorly differentiated or anaplastic carcinoma, which is characterized by therapeutic resistance and a poor prognosis. Epigenetic dysregulation, part...
Thyroid cancer frequently undergoes dedifferentiation, progressing into poorly differentiated or anaplastic carcinoma, which is characterized by therapeutic resistance and a poor prognosis. Epigenetic dysregulation, particularly histone methylation, plays a critical role in this process. In this study, we identify PRDM16 as an essential regulator of thyroid cancer differentiation. Mechanistically, we demonstrate that PRDM16 catalyzes H3K9 monomethylation at the TRIM58 promoter region, thereby enhancing TRIM58 transcription. Upregulated TRIM58 subsequently promotes ubiquitination and degradation of MVP, leading to suppression of both the MAPK and PI3K/AKT signaling pathways and maintenance of cellular differentiation. This PRDM16-TRIM58-MVP axis modulates proliferation, epithelial-mesenchymal transition, and radioiodine uptake in thyroid cancer cells. Moreover, PRDM16 overexpression enhances the efficacy of MAPK inhibitor-induced redifferentiation therapy. Collectively, these findings establish PRDM16 as a novel tumor suppressor and potential therapeutic target, offering a promising redifferentiation-based strategy for the treatment of advanced thyroid cancer.
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