International Journal Of Biological Sciences[JOURNAL]
Sun
200 papers
Gut microbial-derived metabolites: key players in kidney disease and renal fibrosis.
Zhang WY, Zhang YL, Yu QQ … +4 more , Zhou JT, Miao H, Liu LM, Zhao YY
Int J Biol Sci · 2026 · PMID 42212329 · Full text
Kidney disease is a major global public health problem that affects 15-20% of adults globally. Increasing evidence shows that kidney injury results in intestinal barrier dysfunction, microbial dysbiosis, and microbial-de...
Kidney disease is a major global public health problem that affects 15-20% of adults globally. Increasing evidence shows that kidney injury results in intestinal barrier dysfunction, microbial dysbiosis, and microbial-derived metabolite disorder. Microbial-derived metabolites are recognized as multi-kingdom intermediates. The alterations of the gut microbiota lead to the reductions of short-chain fatty acids including acetate, butyrate, and propionate, while excessive accumulation of uremic toxins, including indoxyl sulfate, indole-3-acetic acid, trimethylamine-N-oxide, and p-cresyl sulphate that involved in renal disease. Various effects are moderated by regulating aryl hydrocarbon receptor, G-protein-coupled receptor 43, Toll-like receptor 4, domain-like receptor family protein 3, phosphatidylinositol-3 kinase, inhibitor of kappa B /nuclear factor kappa B and kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathways via gut microbiota-derived metabolites. Among them, tryptophan metabolites are considered pivotal in the communication between gut microbiota and kidneys. This review summarizes current understanding of the role of gut microbial-derived metabolites in acute kidney injury and chronic kidney disease including diabetic kidney disease, immunoglobulin A nephropathy and membranous nephropathy, explain the underlying pathophysiology of these associations and pinpoint potential targets for the future precision-based modulation of therapies. This review also explores therapeutic options, such as natural products, prebiotics, probiotics, and renal replacement therapy, for targeting gut microbiota dysbiosis and their metabolites in patients with kidney diseases to provide a more concept-driven and precise therapy strategy.
E3 ligase UHRF2 hijacks nuclear TBK1 to epigenetically repress type I interferons expression.
Huang W, Song R, Shen Q … +5 more , Shi Y, Wang X, Li N, Zhang Q, Cao X
Int J Biol Sci · 2026 · PMID 42212328 · Full text
The rapid induction of type I interferons (IFN-I) by innate signaling is indispensable for host defense; however, its uncontrolled expression invariably leads to autoimmune diseases. Here, we reveal that the E3 ubiquitin...
The rapid induction of type I interferons (IFN-I) by innate signaling is indispensable for host defense; however, its uncontrolled expression invariably leads to autoimmune diseases. Here, we reveal that the E3 ubiquitin ligase UHRF2 functions as a highly specific epigenetic repressor of IFN-I gene transcription. During viral infection, activated TBK1 undergoes nuclear translocation, where it is hijacked by UHRF2 to achieve gene-specific targeting at IFN-I loci. Upon recruitment to IFN-I loci, UHRF2 physically interacts with histone deacetylase 1 (HDAC1), catalyzes atypical K29-linked polyubiquitination and prevents HDAC1 from degradation. This stabilized UHRF2-HDAC1 complex actively erases the lactylation of histone H4 at lysine 12 (H4K12la), thereby silencing IFN-I transcription. To mount an effective initial antiviral response, IFN-I signaling feedback transiently downregulates UHRF2 expression. Consequently, -deficient mice exhibit profound resistance to lethal virus infection in vivo due to IFN-I overproduction. These findings uncover a highly coordinated mechanism wherein nuclear TBK1, UHRF2, and HDAC1 converge to epigenetically regulate immune homeostasis through histone delactylation, identifying UHRF2 as a potential therapeutic target for virus infection or autoimmune diseases.
Impaired Neuregulin 1 Processing is Associated with Synaptic and Behavioral Abnormalities in a Prenatal Valproic Acid Model of Autism.
Kim YJ, Kim HB, Lim HM … +2 more , Choi Y, Woo RS
Int J Biol Sci · 2026 · PMID 42212327 · Full text
Autism spectrum disorder (ASD) is characterized by deficits in social communication and restricted/repetitive behaviors, yet the molecular mechanisms by which prenatal environmental insults lead to circuit dysfunction re...
Autism spectrum disorder (ASD) is characterized by deficits in social communication and restricted/repetitive behaviors, yet the molecular mechanisms by which prenatal environmental insults lead to circuit dysfunction remain incompletely understood. Neuregulin 1 (NRG1)-ErbB4 signaling is a key regulator of synaptic development and excitation-inhibition (E/I) balance, but whether altered NRG1 processing contributes to ASD-related phenotypes remains unclear. Here, using a prenatal valproic acid (VPA) rat model, we examined the relationship between NRG1 processing, synaptic integrity, and behavioral outcomes. Prenatal VPA exposure reduced cleaved NRG1 protein without altering transcript levels and was accompanied by decreased expression of the NRG1 sheddases ADAM10, ADAM17, and BACE1. These alterations were accompanied by attenuated ErbB4-AKT/ERK1/2 signaling, reduced synaptic scaffolding proteins, and impaired dendritic spine maturation in the hippocampus. Behaviorally, VPA-exposed offspring exhibited abnormalities across multiple ASD-relevant domains. Recombinant NRG1β1 administration during adolescence improved repetitive behaviors in both sexes, whereas deficits and rescue effects in social and sensorimotor domains were primarily observed in males. As robust social deficits were not evident in females, subsequent molecular and synaptic analyses were conducted in male hippocampus, where NRG1 restored ErbB4 signaling, synaptic organization, and spine maturity without affecting locomotor activity. Collectively, these findings indicate that altered NRG1 processing is associated with synaptic and behavioral abnormalities in the VPA model. Enhancement of NRG1-ErbB4 signaling modulates these phenotypes, supporting a functionally relevant role of this pathway in ASD-related neurodevelopmental alterations.
YY1 Lactylation Elicits CARD9 Deficiency in Dendritic Cells Promoting Pancreatic Cancer Immune Escape.
Ding L, Tian C, Feng Y … +6 more , Xu R, Li S, Zheng M, Wang X, Xu Q, Xiang M
Int J Biol Sci · 2026 · PMID 42212326 · Full text
Pancreatic cancer (PC) cells suppress dendritic cell (DC) maturation and function through multiple pathways, further impairing antitumor activity of CD8 T cells. Our previous study revealed that caspase-recruitment domai...
Pancreatic cancer (PC) cells suppress dendritic cell (DC) maturation and function through multiple pathways, further impairing antitumor activity of CD8 T cells. Our previous study revealed that caspase-recruitment domain-containing protein 9 (CARD9) deficiency led to DC dysfunction and exacerbated PC progression, yet the precise mechanism underlying CARD9 downregulation in DCs remains elusive. In this study, we observed that CARD9 expression was progressively downregulated in PC tumors and associated with advanced clinicopathological stages and DC dysfunction. Functionally, PC cells reduced CARD9 expression, impaired DC maturation and weakened CD8 T cell activation, with these suppressive effects attenuated in CARD9-deficient DCs and reversed when CARD9 was restored. Then, we identified YY1 as a critical upstream transcription factor that bound to the promoter of CARD9 and repressed it, accompanied with DC dysfunction and tumor growth. Mechanistically, tumor-derived lactate induced YY1 lactylation at lysine 183, facilitating YY1 nuclear entry and strengthening its combination with CARD9 promoter. Furthermore, we identified p300 as the "writer" catalyzing YY1-K183 lactylation, and HDAC2 as its enzymatic "eraser". Lactylation enhanced YY1 stability by limiting ubiquitination, sustaining YY1 activation and reinforcing CARD9 suppression. Overall, our findings define a lactate-p300/HDAC2-YY1 lactylation-CARD9 regulatory axis that restricts DC function and promotes immune escape in PC.
PSMC5 Orchestrates an Immunosuppressive Niche and Metastasis in Colorectal Cancer via SMURF1-Mediated K11-Linked Ubiquitination of METTL14.
Zhang Y, Yang X, Zhong H … +9 more , Ding C, Xu X, Shao Y, Sun B, Zhang W, Ma J, Feng B, Zheng M, He Z
Int J Biol Sci · 2026 · PMID 42212325 · Full text
Colorectal cancer (CRC) metastasis requires coordination between tumor-intrinsic programs and the surrounding microenvironment, yet how proteasomal regulation intersects with the epitranscriptome in this process remains...
Colorectal cancer (CRC) metastasis requires coordination between tumor-intrinsic programs and the surrounding microenvironment, yet how proteasomal regulation intersects with the epitranscriptome in this process remains unclear. Here, analyses of TCGA, GEO, and an institutional cohort of 146 CRC patients identified PSMC5 upregulation as associated with metastatic progression and poor prognosis. Mechanistically, PSMC5 promoted SMURF1-dependent K11-linked ubiquitination of METTL14 at K263, leading to METTL14 destabilization, global m⁶A remodeling, and activation of EMT-associated malignant phenotypes. Rescue experiments further supported METTL14 as a functional downstream effector of PSMC5. Integrative single-cell, spatial transcriptomic, and multiplex immunofluorescence analyses showed that PSMC5-high epithelial states were associated with spatially organized "regulatory islands," defined here as PSMC5-high epithelial nests with peripheral Treg and M2 enrichment together with relative CD8⁺ T-cell exclusion. , SMURF1 silencing restored METTL14 expression and attenuated PSMC5-driven tumor growth and lung metastasis. Collectively, these findings define a PSMC5/SMURF1/METTL14 axis that links proteasomal regulation to epitranscriptomic remodeling and metastatic progression in CRC, and identify this pathway as a candidate therapeutically actionable axis.
A context-dependent METTL1-m7G-SLC7A11 axis links metabolic stress to epithelial fate in ulcerative colitis.
Yang L, Sun Q, Jiang Z … +4 more , Yao B, Yang C, Liu G, Yuan L
Int J Biol Sci · 2026 · PMID 42212324 · Full text
Ulcerative colitis (UC) is characterized by chronic intestinal inflammation accompanied by epithelial barrier dysfunction and profound metabolic stress; however, how metabolic cues are integrated to determine epithelial...
Ulcerative colitis (UC) is characterized by chronic intestinal inflammation accompanied by epithelial barrier dysfunction and profound metabolic stress; however, how metabolic cues are integrated to determine epithelial cell fate remains incompletely understood. Here, we identify a context-dependent METTL1-m7G-SLC7A11 regulatory axis that links metabolic stress to intestinal epithelial outcomes during UC progression. By integrating analyses of human UC tissues, DSS-induced acute and chronic colitis mouse models, and mechanistic experiments, we demonstrate that METTL1 enhances N7-methylguanosine (m7G) modification of SLC7A11 mRNA, thereby stabilizing the transcript and sustaining SLC7A11 expression in inflammatory settings. Functionally, SLC7A11 exhibits glucose-dependent dual effects. Under glucose-replete conditions, SLC7A11 supports cystine uptake, glutathione synthesis, and redox homeostasis, protecting epithelial integrity and limiting inflammation. In contrast, under glucose deprivation-a characteristic feature of inflamed UC mucosa-persistent SLC7A11 activation induces disulfide stress, cytoskeletal collapse, and disulfidptosis-associated epithelial injury. , inhibition of the METTL1/m7G/SLC7A11 axis exacerbates chronic DSS-induced colitis but alleviates acute DSS-induced colitis, revealing a switch from adaptive to maladaptive signaling with escalating metabolic stress. Collectively, these findings establish the METTL1-m7G-SLC7A11 axis as a metabolic rheostat that integrates inflammatory cues and nutrient availability to determine epithelial cell fate in UC, highlighting the importance of stage- and context-specific therapeutic strategies.
SQSTM1/p62 UFMylation Enhances Autophagic Clearance of Pathogenic Mutant Huntingtin.
Wang X, Lv X, Jiang H … +9 more , Zhu W, Cao L, Zhou L, Lin F, Deng R, Hu LF, Ma J, Li JB, Xu G
Int J Biol Sci · 2026 · PMID 42212323 · Full text
Ubiquitin-fold modifier 1 (UFM1) covalently modifies protein substrates (UFMylation) and alters their biological functions. Genetic screening disclosed that enzymes in the UFMylation system play critical roles in regulat...
Ubiquitin-fold modifier 1 (UFM1) covalently modifies protein substrates (UFMylation) and alters their biological functions. Genetic screening disclosed that enzymes in the UFMylation system play critical roles in regulating autophagy. However, it is still elusive which protein is UFMylated and how this modification modulates autophagy. Here, our quantitative proteomics and biochemical experiments identify SQSTM1/p62 as a UFMylation substrate and discover its two major UFMylation sites, K420 and K435. Mutating them to Arg (p62) completely abolishes the effect of p62 on autophagic activity. Fusion of UFM1 to p62 (p62-UFM1) restores the p62-mediated pathogenic autophagic degradation in primary cortical neurons and Huntington's disease mouse striatum. Mechanistically, p62 UFMylation enhances its interaction with LC3, augments autophagic flux, and eliminates pathogenic mutant huntingtin. Collectively, this work discovers a new post-translational modification, UFMylation, on p62 and establishes this modification as a key regulator of autophagy that promotes the clearance of mutant huntingtin, offering a potential target for therapeutic intervention.
SPARC Drives Tubulointerstitial Fibrosis through Regulating the CBP-DOT1L Pathway.
Jiang H, Yang Q, Wang K … +11 more , Tan Q, Xiong C, Zhou X, Gan C, Xiao H, Qiu L, Chen Y, Wang M, Yang H, Jiang W, Li Q
Int J Biol Sci · 2026 · PMID 42212322 · Full text
Renal tubulointerstitial fibrosis (TIF) is a central pathological feature driving the progression of chronic kidney disease (CKD) toward end-stage renal failure. Despite advances in understanding fibrotic mechanisms, eff...
Renal tubulointerstitial fibrosis (TIF) is a central pathological feature driving the progression of chronic kidney disease (CKD) toward end-stage renal failure. Despite advances in understanding fibrotic mechanisms, effective anti-fibrotic therapies remain limited. Here, we identify SPARC, a matricellular protein expressed in proximal tubular epithelial cells (PTECs), as a key mediator of TIF. SPARC expression strongly correlates with fibrosis severity in both human CKD biopsies and murine models of unilateral ureteral obstruction (UUO) and ischemia-reperfusion injury (IRI). Genetic ablation of Sparc markedly attenuates renal fibrosis in these models. Mechanistically, SPARC stabilizes DOT1L protein, enhancing H3K79 di-methylation (H3K79me2) and promoting fibrotic changes in PTECs. This process is orchestrated by the acetyltransferase CBP, whose regulation of DOT1L stability depends on MEK-ERK signaling. The SPARC-CBP-DOT1L axis thus defines a previously unrecognized epigenetic pathway driving renal fibrosis. Our findings establish SPARC as a critical driver of TIF and highlight the SPARC-CBP-DOT1L signaling cascade as a promising therapeutic target for halting fibrotic progression in CKD.
PIP5K1A-PIP2-RhoA Signaling Orchestrates Membrane Remodeling during Early Porcine Embryo Development.
Zhan CL, Lee SH, Nie ZW … +1 more , Cui XS
Int J Biol Sci · 2026 · PMID 42212321 · Full text
Dynamic plasma membrane remodeling is fundamental for cleavage, signal transduction, and cytoskeletal organization during mammalian embryogenesis. Although oocyte activation triggers membrane remodeling and elevates phos...
Dynamic plasma membrane remodeling is fundamental for cleavage, signal transduction, and cytoskeletal organization during mammalian embryogenesis. Although oocyte activation triggers membrane remodeling and elevates phosphatidylinositol (4,5)-bisphosphate (PIP2), the underlying regulatory mechanisms remain elusive. Here, we identify phosphatidylinositol-4-phosphate 5-kinase type I alpha (PIP5K1A), an enzyme responsible for generating PIP2, as a key regulator of membrane remodeling in porcine embryos. Maternal depletion of PIP5K1A impaired oocyte activation, disrupted actin organization and vesicle trafficking, and blocked early development. Conversely, excessive expression of PIP5K1A caused accumulation of PIP2-enriched vesicles that trapped filamentous actin and reduced membrane contractility, resulting in cleavage failure. Structure-function analysis revealed that residue Q169 mediates PIP5K1A interaction with RhoA, the PIPB motif anchors it to the plasma membrane, and the activation loop drives catalytic activity and is required for proper RhoA membrane localization and is associated with endocytic abnormalities when mutated. PIP5K1A also sustains phospholipase C-inositol trisphosphate-Ca signaling, coordinating vesicle fusion and cytoskeletal remodeling. During cytokinesis, PIP5K1A-enriched membrane clusters serve as hubs for RhoA recruitment. These findings suggest PIP5K1A as a central organizer of lipid signaling, actin dynamics, and membrane contractility to drive successful early embryonic development in mammals.
Fangchinoline Activates cGAS-STING to Promote Antitumor Immunity without Pathological Inflammation.
Zhao Y, Chen X, Xie Y … +10 more , Liu T, Luo Y, Liu Z, Zhu Y, Chen L, Ren Y, Liu H, Zhao P, Wang Q, You F
Int J Biol Sci · 2026 · PMID 42212320 · Full text
Effective cancer immunotherapy requires strengthening tumor-directed immunity while avoiding pathological inflammation, highlighting an urgent need for single agents that can achieve this balance. Here, we identified fan...
Effective cancer immunotherapy requires strengthening tumor-directed immunity while avoiding pathological inflammation, highlighting an urgent need for single agents that can achieve this balance. Here, we identified fangchinoline (Fan) as a dual immunomodulator that activated antitumor immune responses and restrained hyperinflammation. Fan induced robust type I interferon production across multiple human and murine cell types and in mice, and these responses were largely abolished by genetic deletion of cGAS or STING. Mechanistically, Fan directly bound and sensitized human cGAS and enhanced 2',3'-cGAMP synthesis, including detectable activity in the absence of exogenous DNA, and this effect required an intact catalytic center. In vivo, Fan suppressed tumor growth in B16F10 melanoma and Pan02 pancreatic cancer models, increased intratumoral immune activation, and improved the efficacy of PD-1 blockade. Single-cell and multi-omics analyses further revealed coordinated transcriptional, chromatin-accessibility, and intercellular communication changes that supported enhanced CD8⁺ T cell effector programs within the tumor microenvironment. In parallel, Fan attenuated LPS-driven inflammatory responses in macrophages, reversed LPS-associated transcriptional and chromatin-opening programs, and improved survival in an endotoxemia model. Together, these findings established Fan as a cGAS-targeting immunomodulator that coupled antitumor immunity with control of inflammatory toxicity, providing a potential strategy to broaden the therapeutic window of immune activation.
Heparanase 2 (Hpa2) protects the exocrine pancreas from damages of Western diet and pancreatic cancer.
Kayal Y, Farhoud M, Odeh M … +7 more , Barash U, Naroditsky I, Bassal R, Nishioka Y, Sanderson RD, Ilan N, Vlodavsky I
Int J Biol Sci · 2026 · PMID 42212319 · Full text
Fatty pancreas and pancreatitis are increasingly linked to Western dietary patterns and pancreatic cancer risk, yet intrinsic molecular mechanisms that preserve pancreatic identity under metabolic stress remain insuffici...
Fatty pancreas and pancreatitis are increasingly linked to Western dietary patterns and pancreatic cancer risk, yet intrinsic molecular mechanisms that preserve pancreatic identity under metabolic stress remain insufficiently defined. Heparanase-2 (Hpa2), a homolog of heparanase that lacks heparan sulfate-degrading activity, is clinically associated with favorable cancer outcomes, but its role in pancreatic homeostasis remains poorly defined. We fed wild-type (WT) and conditional Hpa2 knockout (Hpa2-KO) mice with a high-fat diet (HFD) and integrated histopathologic, transcriptomic, and proteomic analyses to define diet-dependent pancreatic responses. HFD elicited profound pancreatic remodeling selectively in Hpa2-KO mice, marked by massive fatty infiltration (fatty pancreas), extensive acinar-to-ductal metaplasia, β-islet hyperplasia, fibrosis, and pancreatic intraepithelial neoplasia (PanIN). These changes coincided with a decrease in acinar lineage identity, as reflected by marked suppression of GATA4, GATA6, MIST1, and PDX1. Systems-level analyses identified mTORC1 as a dominant signaling hub linking Hpa2 deficiency to metabolic reprogramming, with unanticipated effects on mitochondrial oxidative phosphorylation and ribosomal function. The results strongly imply that Hpa2 functions critically in preserving exocrine pancreatic identity and suppressing Western diet-driven pancreatic injury and neoplastic progression. Loss of Hpa2 advances diet-induced pancreatic disease, positioning Hpa2 as a key regulator of fatty pancreas, pancreatitis, and pancreatic cancer risk.
Reprogramming Transcriptional Networks via CREB1 Lactylation at K122 Activates HMGB1-Mediated NETosis and Chemoresistance.
Wang JM, Zhao FY, Zhang Q … +6 more , Yuan Y, Li BQ, Liu N, Li JJ, Liu C, Wang HQ
Int J Biol Sci · 2026 · PMID 42212318 · Full text
Cisplatin resistance remains a major obstacle in ovarian cancer treatment. While lactate-rich tumor microenvironments promote chemoresistance, the role of lysine lactylation (Kla) in this process remains poorly understoo...
Cisplatin resistance remains a major obstacle in ovarian cancer treatment. While lactate-rich tumor microenvironments promote chemoresistance, the role of lysine lactylation (Kla) in this process remains poorly understood. Here, we identify CREB1 lactylation at K122 as a pivotal epigenetic driver of cisplatin resistance. Through quantitative lactyl-proteomics, we found CREB1 K122 as a hyperlactylated site specifically enriched in cisplatin-resistant ovarian cancer cells and patient tissues. This modification is dynamically regulated by the opposing activities of p300 (writer) and SIRT1 (eraser). Functionally, a lactylation-mimetic CREB1 mutant (K122Q) conferred robust resistance, enhancing cell survival and tumor growth, whereas a lactylation-deficient mutant (K122R) sensitized cells to cisplatin. Mechanistically, CUT&Tag analysis revealed that K122la remodels chromatin architecture, redistributing CREB1 binding from promoters to distal enhancers and substantially expanding its target repertoire. This transcriptional rewiring specifically activated neutrophil extracellular trap (NETosis) programs, with high mobility group box 1 (HMGB1) emerging as a key downstream effector. Lactylated CREB1 promotes HMGB1 transcription and subsequent exosomal secretion into the tumor microenvironment. Secreted HMGB1 then engages Toll-like receptor 4 (TLR4) on neutrophils to trigger NETosis, establishing a chemoprotective niche. Clinically, cisplatin-resistant patients exhibited elevated tumor K122 lactylation and serum exosomal HMGB1 levels. Most importantly, we developed a tumor-targeted lipid nanoparticle (LNP) system delivering a lactylation-deficient CREB1 K122R competitive peptide. This nanotherapeutic approach, particularly when combined with cisplatin, potently suppressed tumor growth and reduced serum exosomal HMGB1 levels, effectively reversing chemoresistance. Our work unveils the lactate-CREB1 K122la-HMGB1-NETs axis as a metabolic-epigenetic-immune driver of cisplatin resistance and provides a promising nanomedicine strategy for overcoming treatment resistance in ovarian cancer.
B3GNT6-Linked Multimodal Signatures Integrate Tissue Morphology and PTM-Related Transcriptomics to Stratify Tumor.
Mei K, Xu Y, Gu R … +9 more , Chen Z, Tan F, Shao Z, Zhu J, Wang X, Liu X, Huang Y, Yu X, Liu H
Int J Biol Sci · 2026 · PMID 42212317 · Full text
Colon adenocarcinoma (COAD) exhibits substantial molecular and microenvironmental heterogeneity, limiting the reliability and clinical application of single-omics biomarkers. Post-translational modifications (PTMs) play...
Colon adenocarcinoma (COAD) exhibits substantial molecular and microenvironmental heterogeneity, limiting the reliability and clinical application of single-omics biomarkers. Post-translational modifications (PTMs) play a pivotal role in connecting genotype to phenotype, yet prognostic models informed by PTMs seldom incorporate tissue architecture alongside transcriptomic states. This study developed a PTM-based multimodal framework for prognostic stratification and mechanistic analysis in COAD. Additionally, bulk RNA-seq data, clinicopathological information, and whole-slide H&E images from TCGA-COAD were integrated with single-cell RNA-seq (GSE132465) and spatial transcriptomics (GSE225857). Differentially expressed genes related to PTMs were identified, and pathomic features derived from H&E slides were fused with transcriptomic data via an autoencoder-based latent space. Prognosis-related latent features were then selected to establish a patient-level PTM-related multimodal risk score (PTMLS). A total of 102 PTM-related differentially expressed genes were enriched in glycan biosynthesis and ubiquitin-mediated pathways. The PTMLS effectively stratified patients into high- and low-risk groups, with significant differences in overall survival in both training (HR = 3.54, 95% CI 2.67-4.70, P = 0.001) and validation cohorts (HR = 2.68, 95% CI 1.49-4.82, P = 0.006). Low-risk tumors displayed higher immune and ESTIMATE scores, lower TIDE scores, distinct immunotherapy responder profiles, and differential predicted drug sensitivity. Cross-modal interpretation identified B3GNT6 as a key contributor linked to histopathological features. Single-cell and spatial analyses localized B3GNT6-associated epithelial states and their interactions with vascular and stromal compartments. Functional experiments further revealed that B3GNT6 expression was downregulated in tumors and inhibited colorectal cancer proliferation, migration, tumor growth, and metastasis. This PTM-informed multimodal framework integrates routine pathology and transcriptomic data, providing robust prognostic stratification, clinically relevant immune and therapeutic phenotyping, and mechanistic insight supporting B3GNT6 as a potential therapeutic target in COAD.
CXCL6 exacerbates metabolic dysfunction-associated steatohepatitis by suppressing LPIN1-mediated fatty acid oxidation in hepatocytes.
Cho YE, Kim MJ, Kim Y … +12 more , Lim H, Park Y, Kim S, Kim SJ, Yoo JW, Ryu S, Song P, Hong C, He Y, Lee H, Cho JY, Hwang S
Int J Biol Sci · 2026 · PMID 42212316 · Full text
Progression of hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH) is driven by impaired fatty acid (FA) oxidation and subsequent hepatocyte lipotoxicity. While MASH is characterized by upregulat...
Progression of hepatic steatosis to metabolic dysfunction-associated steatohepatitis (MASH) is driven by impaired fatty acid (FA) oxidation and subsequent hepatocyte lipotoxicity. While MASH is characterized by upregulation of the neutrophil chemoattractant CXCL6, which functions through CXCR2, the direct impact of this pathway on hepatocyte FA metabolism during MASH progression remains unclear. Here, we demonstrate that hepatic overexpression of (the murine homolog of ) inhibits hepatocyte FA oxidation and promotes MASH progression in mice. In contrast, deficiency conferred protection against diet-induced MASH by reducing hepatic FA levels and restoring the expression of LPIN1, a transcriptional coactivator of PPARα, thereby normalizing FA metabolic gene expression. Mechanistically, CXCL6 activated JNK, leading to the inhibitory phosphorylation of the glucocorticoid receptor (GR). This blockade prevented GR-dependent activation of the LPIN1 promoter, thereby suppressing the LPIN1-PPARα axis in hepatocytes. knockdown reversed the protective phenotype in -deficient mice, confirming that LPIN1 suppression is the essential driver of CXCL6-mediated MASH progression. Consistently, human MASH samples exhibited reduced LPIN1 expression, which inversely correlated with CXCL6 expression. In conclusion, beyond its canonical role in neutrophil recruitment, CXCL6 promotes MASH progression by inhibiting the GR-LPIN1-PPARα axis in hepatocytes, resulting in impaired FA oxidation and lipotoxicity.
SIRT3 activation by oroxylin A phosphate diethyl ester triggers mitochondrial dysfunction and apoptosis in non-small cell lung cancer.
Lee CW, Lin YF, Lee KH … +7 more , Sun YS, Chang TM, Chi MC, Lin ZC, Yamamoto A, Peng KT, Liu JF
Int J Biol Sci · 2026 · PMID 42212315 · Full text
Lung cancer remains the leading cause of cancer mortality worldwide, and outcomes for advanced non-small cell lung cancer (NSCLC) are limited by resistance and toxicity. Sirtuin 3 (SIRT3), a mitochondrial NAD-dependent d...
Lung cancer remains the leading cause of cancer mortality worldwide, and outcomes for advanced non-small cell lung cancer (NSCLC) are limited by resistance and toxicity. Sirtuin 3 (SIRT3), a mitochondrial NAD-dependent deacetylase, regulates mitochondrial homeostasis and redox balance, but its therapeutic potential in NSCLC is incompletely defined. Here, bioinformatic analyses, structure-based virtual screening, and and validation were used to evaluate SIRT3 modulation in NSCLC. Although SIRT3 mRNA expression varied across lung cancer cohorts, higher SIRT3 expression was associated with better overall survival in lung adenocarcinoma (LUAD), and protein-level analyses demonstrated reduced SIRT3 expression in lung cancer specimens. Immunohistochemical analysis of clinical specimens and western blotting of NSCLC cell lines further confirmed reduced SIRT3 expression in lung cancer. To identify a SIRT3-targeting compound, we performed structure-based virtual screening using the SIRT3 crystal structure and prioritized oroxylin A phosphate diethyl ester (OA-OEt), a derivative of oroxylin A. OA-OEt markedly enhanced SIRT3 activity and exhibited stronger antiproliferative effects than oroxylin A in H1299 and A549 cells. Mechanistically, OA-OEt suppressed cell growth, induced G2/M arrest, and increased apoptosis. OA-OEt disrupted mitochondrial homeostasis, including elevated mitochondrial superoxide, reduced SOD2, altered mitochondrial dynamics markers, and impaired mitochondrial respiration; mitochondrial ROS scavenging partially rescued apoptosis. In an H1299 xenograft model, OA-OEt reduced tumor growth without overt body-weight loss and increased tumor SIRT3 and cleaved caspase-3 with consistent mitochondrial marker changes. Collectively, these findings support SIRT3 as a functionally tumor-suppressive mitochondrial regulator in NSCLC and suggest that OA-OEt may represent a promising SIRT3-activating lead compound.
The MCU-MECOM Axis Orchestrates Glioblastoma Progression by Remodeling Mitochondrial Dynamics and Quality Control via MAMs.
Li X, Wang Y, Wu F … +16 more , Huang X, Ni Z, Xu G, Wang W, Tie J, Huang Y, Sun Y, Wang Z, Li S, Zheng Q, Liu Y, Wu Y, Gong C, Guo Q, Yang Y, Wang Y
Int J Biol Sci · 2026 · PMID 42212314 · Full text
Glioblastoma (GBM) exhibits metabolic plasticity, relying on mitochondrial oxidative phosphorylation (OXPHOS) to support migration and therapy resistance. Although mitochondrial calcium overload typically induces apoptos...
Glioblastoma (GBM) exhibits metabolic plasticity, relying on mitochondrial oxidative phosphorylation (OXPHOS) to support migration and therapy resistance. Although mitochondrial calcium overload typically induces apoptosis, GBM cells maintain viability under high calcium conditions. The structural and metabolic coupling mechanisms underlying this adaptation remain incompletely understood. Here, we identify a mitochondria-associated membranes (MAMs) regulatory axis driven by a positive feedback loop between the mitochondrial calcium uniporter (MCU) and the transcription factor MECOM. Using multi-omics profiling, time-resolved functional assays, and mitochondrial transfer experiments, we show that MCU-mediated calcium influx expands MAMs without triggering cell death. This influx initiates adaptive mitochondrial cristae remodeling via the Mic10/Mic60 complex and activates selective mitophagy. Pharmacological blockade and autophagy-rescue experiments (using si-ATG5 and chloroquine) indicate that this mitophagy-dependent quality control promotes tumor migration and buffers reactive oxygen species (ROS) to sustain OXPHOS capacity. Targeting the MCU-MECOM axis induces metabolic suppression and reduces glioma cell viability. To translate these findings into a diagnostic application, we developed MAMs-Net, a deep-learning framework for the automated quantification of MAMs ultrastructure from transmission electron microscope (TEM) images. In an independent external validation cohort, MAMs-Net achieved an AUC of 0.95 for glioma pathological stratification. This study characterizes an MCU-MECOM structural-metabolic circuit that supports GBM survival under calcium overload, identifying a potential therapeutic target and providing a pathophysiologically interpretable, AI-driven tool for glioma evaluation.
Redirecting Cholesterol Metabolism During Biomanufacturing Enhances the Metabolic Fitness and Antitumor Efficacy of CAR-T Cells.
Zhu Y, Tu J, Li S … +9 more , Li S, Xiao B, Zhou X, Zhang G, Li X, He Y, Wu N, Lu Z, Zhang C
Int J Biol Sci · 2026 · PMID 42212313 · Full text
Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies; however, its efficacy in solid tumors remains limited, partly due to T cell exhaustion during manufacturing....
Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies; however, its efficacy in solid tumors remains limited, partly due to T cell exhaustion during manufacturing. Emerging evidence suggests that cholesterol metabolism plays a critical role in T cell differentiation and function, yet its impact during CAR-T cell production is poorly understood. We investigated the effects of cholesterol modulation during CAR-T cell expansion by using low-dose fluvastatin (FL), a clinically approved HMG-CoA reductase inhibitor. We found that cholesterol accumulation during expansion promotes CAR-T cell exhaustion. Low-dose FL reduces cholesterol to physiological levels, preserving a less-differentiated, memory-enriched phenotype and attenuating exhaustion, thereby enhancing CAR-T cell cytotoxicity and persistence without affecting viability. In multiple xenograft models, FL-primed CAR-T cells demonstrate superior expansion, persistence, and tumor control. Mechanistically, FL enhances ERK phosphorylation to remodel CAR-T cell metabolism from glycolysis to oxidative phosphorylation. Inhibiting ERK or ATP synthesis abrogates these benefits, indicating that ERK-dependent mitochondrial metabolism is required for CAR-T cell functional improvements conferred by FL. These findings establish cholesterol metabolism as a tunable axis during CAR-T cell manufacturing and propose a clinically feasible, GMP-compatible strategy to enhance CAR-T cell fitness and therapeutic efficacy.
Targeting Tumor-Associated Macrophages to Reshape the Immuno-Mechanical Landscape: Molecular Mechanisms and Therapeutic Strategies.
Liu G, Yu Y, Guo Z … +3 more , Liu L, Chen W, Sun C
Int J Biol Sci · 2026 · PMID 42212312 · Full text
The progression and therapeutic resistance of solid tumors are profoundly influenced by the mechanical microenvironment, in which extracellular matrix stiffening, elevated interstitial pressure, and aberrant mechanotrans...
The progression and therapeutic resistance of solid tumors are profoundly influenced by the mechanical microenvironment, in which extracellular matrix stiffening, elevated interstitial pressure, and aberrant mechanotransductive signaling constitute critical physical barriers. Tumor-associated macrophages (TAMs) occupy a central position in this process. They not only act as active architects that remodel the matrix and exacerbate fibrosis, but their phenotypes and functions are also reciprocally regulated by the mechanical microenvironment, thereby forming a self-reinforcing malignant loop. Accordingly, targeting TAMs to mechanically soften tumors has emerged as an important therapeutic strategy, encompassing TAMs depletion, reprogramming, inhibition of TAM-mediated the extracellular matrix (ECM) modification, and disruption of mechanosensing pathways. In addition, mechanical immunoengineering and combination therapeutic strategies provide new tools for modulating the tumor mechanical-immune microenvironment. This review systematically examines the bidirectional regulatory mechanisms of TAMs within the mechanical microenvironment and the corresponding therapeutic strategies, and highlights that overcoming spatiotemporal heterogeneity and developing precision intervention paradigms are key to achieving future clinical translation.
Huaier Polysaccharides Sensitize Anti-PD-L1 Therapy via Promoting Antitumor Immune Response in Triple-Negative Breast Cancer.
Zhou LX, Wu ZW, Tian Y … +11 more , Luo KF, Pan QW, Xi YY, Tang P, Zeng LJ, Zhong L, Jiang J, Zhang Y, Hou L, Zheng H, Wang MH
Int J Biol Sci · 2026 · PMID 42212311 · Full text
Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and resistance to conventional therapies. Although immune checkpoint inhibitors (ICIs) have shown promise in cancer treatment, TNBC patients res...
Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and resistance to conventional therapies. Although immune checkpoint inhibitors (ICIs) have shown promise in cancer treatment, TNBC patients respond suboptimally to ICIs as monotherapy. Our prior clinical research demonstrated that Huaier significantly improved 5-year overall survival and disease-free survival when used as an adjunct to chemotherapy in TNBC patients. However, whether PS-T (the primary component of Huaier granules) enhances the efficacy of ICIs against TNBC and the underlying mechanisms remain unclear. In this study, we found that combining anti-PD-L1 antibodies with PS-T synergistically suppressed tumor growth and cell proliferation in TNBC, accompanied by enhanced antitumor immune responses. Mechanistically, PS-T promoted the autophagic degradation of PD-L1, which in turn facilitated the accumulation and activation of CD45+, CD3+ T, CD4+ T, CD8+ T, and dendritic cells, while reducing immunosuppressive regulatory T cells, ultimately enhancing the efficacy of anti-PD-L1 antibodies.
A Scorpion Venom-Derived Peptide M6 Endowed with Anti-Aging Ability via Enhanced Antioxidant Activity in Cells, and Mouse Models.
Luo S, Qin H, Zuo W … +4 more , Prypoten V, Norton RS, Assaraf YG, Kwok HF
Int J Biol Sci · 2026 · PMID 42212310 · Full text
With an aging population and the prevalence of oxidative damage-related ailments, the quest for effective antioxidant and anti-aging agents has emerged as a focal point of biomedical research. Within this domain, peptide...
With an aging population and the prevalence of oxidative damage-related ailments, the quest for effective antioxidant and anti-aging agents has emerged as a focal point of biomedical research. Within this domain, peptides have garnered considerable attention for their potential activities. Hence, the current study investigates the antioxidant and anti-aging properties of a scorpion venom-derived peptide M6. We demonstrated that this peptide decreases HO-dependent apoptosis by binding to the TNFR1 receptor, which activates the NF-κB signaling pathway, thereby enhancing the capacity of cells to mitigate oxidative damage induced by HO treatment. Moreover, M6 prolonged the lifespan of and enhanced their thermal stress resistance. Further studies demonstrated that M6 inhibits the IIS/PI3K/AKT signaling pathway and activates and (homologous to Nrf-2), thereby enhancing the antioxidant capacity of nematodes and alleviating oxidative damage. Furthermore, M6 also alleviated D-galactose-induced oxidative damage in mice by enhancing the activity of catalase and superoxide dismutase. We also showed that M6 treatment protects liver and kidney tissues from oxidative damage induced by D-galactose. These results highlight the beneficial antioxidant and anti-aging properties of the peptide M6, which appear to be a promising lead for addressing related diseases and mitigating the effects of aging.
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