International Journal Of Biological Sciences[JOURNAL]
Sun
200 papers
CD44/POU2F2/BCL9L axis mediates MIF-driven SPP1TAM activation in colorectal cancer metastasis.
Zhang F, Zhao B, Fan X … +6 more , Shi Z, Guo P, Zhang H, Kwan HY, Liu Z, Su T
Int J Biol Sci · 2026 · PMID 41800265 · Full text
BACKGROUND: Tumor-associated macrophages (TAMs), especially SPP1TAMs are associated with poor prognosis of colorectal cancer (CRC). However, the underlying mechanism remains unclear, and the therapeutic targets have yet...
BACKGROUND: Tumor-associated macrophages (TAMs), especially SPP1TAMs are associated with poor prognosis of colorectal cancer (CRC). However, the underlying mechanism remains unclear, and the therapeutic targets have yet to be identified. METHODS: Single-cell RNA sequencing (scRNA-seq) data were used to explore the interactions between SPP1TAMs and CRC cells. TAM co-culture model, liver metastasis models and clinical tissue microarray (n=42) were used to validate the key secreted cellular factor and its associated receptor that mediated the interactions between SPP1TAMs and CRC cells. RESULTS: We found that migration inhibitory factor (MIF) was the most important signaling molecule involved in the interaction between SPP1TAMs and CRC cells, as revealed by cellular interaction analysis of integrated scRNA-seq datasets. Interestingly, SPP1 was co-expressed with MIF receptor CD44 on SPP1TAMs. When SPP1TAMs was activated, CD44 was crucial for MIF-mediated angiogenesis. Our data showed that CRC cells activated SPP1TAMs, which was abolished by blocking the MIF signaling both and . Furthermore, the pathological role of MIF is suggested by the elevated expression of MIF and activation of SPP1TAMs in CRC patients, as demonstrated in clinical tissue microarray. Further mechanistic studies revealed that POU2F2 was a crucial transcription factor mediating MIF-driven activation of SPP1TAMs, and that BCL9L was a direct downstream target of POU2F2. CONCLUSIONS: Our findings suggest that the MIF/CD44/POU2F2/BCL9L signaling axis is involved in the proangiogenic capacity of activated SPP1TAMs, thereby enhances CRC metastasis. Targeting this novel signaling axis can effectively suppress the SPP1TAM activation, which represents a promising and pivotal strategy for managing CRC metastasis.
USP20, a Super-enhancer Regulated Gene, Promotes Acute Myeloid Leukemia Progression through CTNNB1 Deubiquitination.
Cheng J, Fang F, Li Z … +25 more , Wang J, Cai L, Xu L, Tao Y, Yu J, Li G, Zhang Z, Cui Z, Yang Y, Li T, Wu D, Li X, Ding Y, Zhai Z, Gu M, Li X, Wu X, Yang P, Shi C, Bai H, Wang X, Han L, Shi L, Li J, Pan J
Int J Biol Sci · 2026 · PMID 41800264 · Full text
Acute Myeloid Leukemia (AML) is a heterogeneous hematologic malignancy driven by genetic and epigenetic alterations, where super-enhancers (SEs) play key oncogenic roles, representing promising therapeutic targets in AML...
Acute Myeloid Leukemia (AML) is a heterogeneous hematologic malignancy driven by genetic and epigenetic alterations, where super-enhancers (SEs) play key oncogenic roles, representing promising therapeutic targets in AML. Through H3K27ac ChIP-seq profiling of 7 AML cell lines and 13 primary samples, we identified USP20 as the deubiquitinase that most frequently associated with super-enhancers. Public database analysis confirmed USP20 overexpression in AML and its correlation with adverse prognosis. Genetic knockdown of USP20 via shRNA significantly induced apoptosis and suppressed proliferation in AML cells , while depletion of USP20 attenuated leukemia development and improved overall survival. AS1517499, a novel USP20 inhibitor identified via virtual screening, recapitulated these anti-leukemic effects and with low toxicity. Mechanistically, USP20 interacts with CTNNB1 and stabilizes the CTNNB1 protein via deubiquitination. Cut&tag analysis indicated that USP20 co-localizes with CTNNB1 on the genome, where they jointly regulate target genes in AML. Collectively, our study identified USP20 as a super-enhancer-regulated oncogene maintaining AML cell survival and proliferation through CTNNB1 stabilization. Pharmacologic targeting of USP20 with AS1517499 presents a promising therapeutic strategy targeting the SE-USP20- CTNNB1 axis.
ANXA1-mediated mTOR/FABP4 Inhibition Drives Antifibrotic Macrophage Reprogramming in Lupus Nephritis.
Tao J, Cheng Q, Zhang P … +12 more , Yu G, Chen Q, Yang M, Wu Q, Fang H, Wu H, Song X, Chen Z, Chen M, Meng X, Lei M, Jin T
Int J Biol Sci · 2026 · PMID 41800263 · Full text
Inflammation and fibrosis are central pathological processes in lupus nephritis (LN). Annexin A1 (ANXA1), a protein highly expressed in myeloid cells, is a key modulator of inflammation and fibrosis. In this study, we fo...
Inflammation and fibrosis are central pathological processes in lupus nephritis (LN). Annexin A1 (ANXA1), a protein highly expressed in myeloid cells, is a key modulator of inflammation and fibrosis. In this study, we found that renal ANXA1 expression was elevated in LN patients and correlated positively with the severity of fibrosis. Single-cell RNA sequencing identified a distinct monocyte-derived macrophage subset that expands during nephritis and displays a profibrotic transcriptional signature. Mechanistically, ANXA1 signals the FPR2/ALX receptor to inhibit mTOR/FABP4 activity in macrophages, enhance fatty acid oxidation, and thereby drive a polarization shift toward an antifibrotic phenotype. Consequently, treatment with the ANXA1-mimetic peptide Ac2-26 attenuated macrophage-driven fibrosis, reduced renal lipid accumulation, and ameliorated kidney injury in lupus-prone mice. These findings underscore the critical role of ANXA1 and macrophages in renal fibrosis progression, offering novel therapeutic targets for LN.
DNA Polymerase Gamma Acetylation Governs Mitochondrial Homeostasis and Vascular Cell Senescence.
Wang P, Yu L, Cao K … +11 more , Guo X, Sun L, Zhang S, Zhao T, Yu Y, Xiong M, Liu C, Zhang N, Sun Y, Sun G, Cao L
Int J Biol Sci · 2026 · PMID 41800262 · Full text
DNA polymerase gamma (Polγ), the sole polymerase for mitochondrial DNA (mtDNA), emerges as a critical regulator of metabolism-associated senescence. While lysine acetylation represents a key post-translational modificati...
DNA polymerase gamma (Polγ), the sole polymerase for mitochondrial DNA (mtDNA), emerges as a critical regulator of metabolism-associated senescence. While lysine acetylation represents a key post-translational modification (PTM) influencing mitochondrial function, its mechanistic role in Polγ-mediated vascular aging remains undefined. Through combinatorial approaches employing acetylation models and mice, a validated model of mitochondrial dysfunction and senescence, we identify Lys 1039 (K1039) as a novel acetylation site which was dynamically regulated during aging process. Both D257A mutation-driven hyper-acetylation of Polγ K1039 reduced human aortic smooth muscle cell (HASMC) contractility, triggering pathological hyperproliferation and mitochondrial dysfunction, collectively culminating in premature cellular senescence. Pathological stimulation or genetic manipulation inducing hyperacetylation at K1039 disrupts Polγ's binding capacity with mtDNA. This molecular deficiency manifested functionally as compromised contractile performance in HASMCs and accelerated senescence phenotypes. Based on the above foundation and mice model, we demonstrated that D257A mutation reduced Sirt3-Polγ complex formation constituted the pathologically relevant molecular pathway driving aberrant acetylation homeostasis and leading to the senescence. Our findings establish a previously unrecognized regulatory axis wherein Polγ acetylation status at K1039 serves as a molecular switch coordinating mtDNA homeostasis, HASMCs functionality, and senescence progression. This mechanism might explain the remarkably consistent phenotypic manifestations of Polγ-induced dysfunction across diverse tissues and aging models. This work provides fundamental insights into the epigenetic-metabolic crosstalk governing vascular aging processes, providing a unifying framework for age-related vascular pathologies.
Tumor-Induced Rewiring of Splenic Niches: from Immune Organ to Cancer Accomplice.
Yuan T, Liu J, Zhang C … +6 more , Lv X, Tan G, Xue L, Zhang E, Liang H, Huang Z
Int J Biol Sci · 2026 · PMID 41800261 · Full text
The spleen is the largest secondary lymphoid organ in humans. Beyond its classical role in clearance of senescent erythrocytes, it functions as a pivotal node in systemic immune surveillance. Emerging evidence indicates...
The spleen is the largest secondary lymphoid organ in humans. Beyond its classical role in clearance of senescent erythrocytes, it functions as a pivotal node in systemic immune surveillance. Emerging evidence indicates that tumor can remotely remodel splenic niches through a spectrum of soluble mediators, thereby accelerating tumor initiation and progression. Tumor-derived signals divert splenic hematopoietic stem and progenitor cells (HSPCs) toward myeloid- and erythroid-biased extramedullary hematopoiesis (EMH), expanding myeloid-derived suppressor cells (MDSCs) and erythroid progenitor cells (EPCs) that collectively foster immune evasion and metastatic cascades. Consequently, splenic resident immune cells, stromal cells and EMH-related pathways have surfaced as actionable therapeutic targets. In parallel, bidirectional crosstalk between the autonomic nervous system and splenic immunity fine-tunes homeostasis, systemic inflammation and antitumor responses-fueling rising interest in splenic neuromodulation as a therapeutic strategy. In addition, spleen-targeted nanoplatforms are emerging as promising tools to deliver immunomodulatory payloads with improved precision. Nonetheless, inherent structural and functional disparities between human and murine spleens complicate clinical translation of pre-clinical findings. This review provides a concise overview of human lymphoid organs and their functions, with a particular focus on splenic anatomy, cellular composition, and neural regulation. It further delineates tumor-induced splenic rewiring and discusses the prospects of exploiting the spleen as both a biomarker and a therapeutic target in oncology.
Gut Microbiota-driven Tryptophan Metabolism Towards the Indole Pathway Mediates Polysaccharide's Alleviation of Ulcerative Colitis and Comorbid Depression via Aryl Hydrocarbon Receptor.
Zhang J, Yan S, Gao T … +9 more , Li M, Li Y, Li L, Ji D, Bian Z, Huang W, Hou J, Lu T, Su L
Int J Biol Sci · 2026 · PMID 41800260 · Full text
Patients with ulcerative colitis (UC) exhibit heightened depression risk, linked to microbiota-gut-brain axis dysfunction. This study isolated a novel low-molecular-weight polysaccharide (SCP) that ameliorated UC and co...
Patients with ulcerative colitis (UC) exhibit heightened depression risk, linked to microbiota-gut-brain axis dysfunction. This study isolated a novel low-molecular-weight polysaccharide (SCP) that ameliorated UC and comorbid depression by remodeling gut microbiota, redirecting tryptophan (Trp) metabolism toward the indole pathway, and activating aryl hydrocarbon receptor (AhR). Structurally, SCP features a →4)-α-D-Glc backbone with -6 branched chains. In dextran sulfate sodium-induced UC mice, SCP mitigated colonic inflammation, restored intestinal barrier integrity, and improved depression-like behaviors by repairing blood-brain barrier, reducing neuroinflammation, preserving hippocampal neurons, and modulating synaptic plasticity. Multi-omics revealed SCP enriched beneficial microbiota (e.g., ) and rebalanced Trp metabolism along the gut-brain axis. SCP suppressed the hyperactive kynurenine (Kyn) pathway (reduced Kyn/Trp ratio) while elevating indole-3-propionic acid (IPA) levels in colon, serum, and hippocampus. Functioning as a pivotal molecule, IPA exerted dual anti-inflammatory effects in both colon and hippocampus via AhR activation and NF-κB inhibition. Antibiotic depletion and fecal microbiota transplantation validated SCP's microbiota-dependent efficacy, while IPA supplementation recapitulated SCP's benefits. AhR inhibition abolished SCP's therapeutic actions, confirming AhR as the critical target. Collectively, these findings propose a novel therapeutic strategy for UC and associated depression, highlighting SCP's potential value in targeting the Trp metabolism-AhR axis.
NPLOC4 Inhibition Remodels Tumor Microenvironment via M2-to-M1 Macrophage Reprogramming and Boosts Anti-PD-1 Response in Liver Cancer.
Gao X, Huang H, Pan C … +5 more , Huang J, Chen J, Yin S, Zhou L, Zheng S
Int J Biol Sci · 2026 · PMID 41800259 · Full text
The PD-1/PD-L1 axis represents a well-established immunotherapeutic target. Nevertheless, anti-PD-1/PD-L1 therapeutics have shown limited efficacy in the management of solid tumors, particularly in the context of hepatoc...
The PD-1/PD-L1 axis represents a well-established immunotherapeutic target. Nevertheless, anti-PD-1/PD-L1 therapeutics have shown limited efficacy in the management of solid tumors, particularly in the context of hepatocellular carcinoma (HCC). Among the various factors contributing to the resistance to anti-PD-1/PD-L1 therapy, tumor-associated macrophages (TAMs) have attracted significant interest because of the immunosuppressive properties. NPLOC4 has been explored as an antitumor drug target. However, whether NPLOC4 functions in TAMs or immunotherapy is unclear. Here, we report a new role for NPLOC4 TAMs in inhibiting antitumor immune responses by facilitating the proteasomal degradation of RIG-I. Clinical specimens revealed that the number of NPLOC4 TAMs are negatively correlated with the prognosis of patients with HCC. Proteomic data and / experiments demonstrated that NPLOC4 inhibits the type I interferon pathway in TAMs, promotes M2 polarization, and suppresses CD8 T-cell infiltration, thereby creating an immunosuppressive microenvironment in HCC. NPLOC4 can bind to RIG-I and mediate its ubiquitination-mediated degradation, thus suppressing the type I interferon pathway. Animal studies have indicated that disulfiram/copper (DSF/Cu) can target the NPLOC4 protein, and that the combination of DSF/Cu with PD-1 therapy significantly inhibits HCC growth. In conclusion, targeting NPLOC4 TAMs can significantly increase the resistance of HCC to anti-PD-1 therapy, which makes it a promising novel immune target for HCC treatment.
Triptonide-mediated PTGS2 Inhibition Induces Autophagic Cell Death to Suppress the Progression of Triple-negative Breast Cancer and Epithelial Ovarian Cancer.
Gong K, Song K, Wang H … +6 more , Li L, Sun X, Sun L, Hao W, Chen ZS, Huang Y
Int J Biol Sci · 2026 · PMID 41800258 · Full text
Triple-negative breast cancer (TNBC) and epithelial ovarian cancer (EOC) pose notable threats to the health of women. Given the poor prognosis associated with TNBC and EOC, new therapeutic agents must be explored urgentl...
Triple-negative breast cancer (TNBC) and epithelial ovarian cancer (EOC) pose notable threats to the health of women. Given the poor prognosis associated with TNBC and EOC, new therapeutic agents must be explored urgently. Here, we identified triptonide (TN), a natural compound derived from the traditional Chinese herb , as a potent antitumor agent. A series of functional assays showed that TN represses proliferation in TNBC and EOC cell lines, cell-derived xenograft, and patient-derived organoid models. Through molecular docking, molecular dynamics simulation, surface plasmon resonance, cell thermal shift assay, and drug affinity reaction target stability assays, we pinpointed PTGS2 as a direct target of TN. Mechanistically, TN binds to His-207 in PTGS2 and induces proteasome degradation of PTGS2 through recruiting E3 ubiquitin-protein ligase NEDD4. TN-induced PTGS2 downregulation leads to the inhibition of the JAK/STAT3/c-Myc signaling axis, resulting in suppression of tumor proliferation and the induction of autophagic cell death. In conclusion, our findings highlight TN as a promising candidate for TNBC and EOC treatment, acting through a novel mechanism involving targeted degradation of PTGS2 protein.
Gut Microbiota-Derived Tyrosol Alleviates Radiation-Induced Intestinal Injury via Targeting SCD1-MUFA Axis to Suppress ER Stress.
Jin X, Xue H, Shi X … +13 more , Zhou Y, Zhang J, Zeng L, Liu X, Xiao Y, Wang H, Zheng Y, Wang L, Bai Y, Pan Y, Zhang J, Xu Y, Shao C
Int J Biol Sci · 2026 · PMID 41800257 · Full text
Radiation-induced intestinal injury (RIII) represents a major, clinically recalcitrant complication of radiotherapy, with current protective options remaining extremely limited. In this study, we identify tyrosol, a gut-...
Radiation-induced intestinal injury (RIII) represents a major, clinically recalcitrant complication of radiotherapy, with current protective options remaining extremely limited. In this study, we identify tyrosol, a gut-derived phenolic metabolite enriched in the feces of irradiated mice, as a potent radioprotective agent. It reduced intestinal epithelial cell death and improved survival in lethally irradiated mice by preserving mucosal barrier and villus-crypt architecture, and downregulating pro-inflammatory cytokines. Mechanistically, we for the first time reveal that tyrosol directly targets stearoyl-CoA desaturase 1 (SCD1), a key enzyme involved in monounsaturated fatty acid (MUFA) biosynthesis. Tyrosol binds to conserved residues (Asn148, Asp156, Asn265) on SCD1, preventing valosin-containing protein (VCP)-mediated proteasomal degradation. This boosts SCD1 activity, increasing MUFAs (e.g., oleic acid, palmitoleic acid) to inhibit ER stress via the p-eIF2α/ATF4/CHOP axis and mitigate radiation-induced cytotoxicity. Importantly, inhibition of SCD1 in animal experiments abolishes tyrosol's protective effects, underscoring the essential role of SCD1. Additionally, MUFA supplementation rescues tyrosol's radioprotection in SCD1-deficient cells. These findings elucidate a novel mechanism whereby gut metabolites confer radioprotection through lipid remodeling and highlight SCD1 activation as a promising therapeutic strategy against gastrointestinal radiation injury.
β-Cryptoxanthin Confers Radioprotection against Intestinal Injury via NRF2-Mediated Antioxidant Response and Gut Microbiota Reprogramming.
Zhang M, Liu Y, Ma W … +13 more , Wang J, He N, Song H, Gu Y, Yang M, Lu X, Sun J, Xu C, Du L, Yuan Y, Wang Y, Ji K, Liu Q
Int J Biol Sci · 2026 · PMID 41800256 · Full text
Radiation-induced intestinal injury, a common complication of abdominal/pelvic radiotherapy for cancer patients and accidental irradiation, presents a major clinical challenge due to the lack of effective treatments. Thi...
Radiation-induced intestinal injury, a common complication of abdominal/pelvic radiotherapy for cancer patients and accidental irradiation, presents a major clinical challenge due to the lack of effective treatments. This study investigates the radioprotective potential of β-cryptoxanthin, a provitamin A carotenoid known for its antioxidant properties. , oral β-cryptoxanthin administration alleviated radiation-induced intestinal injury by enhancing the NRF2-mediated antioxidant response, which was confirmed by its lack of efficacy in mice. Additionally, it restored radiation-impaired microbiota by increasing beneficial bacterial populations and protective metabolites like short-chain fatty acids (SCFAs), thereby re-establishing a radioprotective gut ecosystem. At the cellular level, β-cryptoxanthin pretreatment significantly improved cell viability and proliferation while reducing reactive oxygen species (ROS), apoptosis, and DNA damage in irradiated MODE-K intestinal epithelial cells. Mechanistically, β-cryptoxanthin activated the AMPK-GSK3β signaling axis, which drove NRF2 nuclear translocation and upregulated NRF2-dependent cytoprotective genes. Knockdown of NRF2 or AMPK abolished the radioprotective effects, confirming the involvement of these pathways. Overall, this study demonstrates that β-cryptoxanthin protects against radiation-induced intestinal injury through dual mechanisms: activating the NRF2-mediated antioxidant response and reprogramming the gut microbiota to restore a radioprotective ecosystem. These findings position β-cryptoxanthin as a promising candidate for clinical radioprotection.
Targeting Macrophage-to-Myofibroblast Transition Mitigates Progression from Inflammation to Fibrosis in Rosacea.
Chen C, Wang P, Cao Y … +13 more , Sung D, Yang Y, Yang J, Liu J, Yan Y, Ruan Z, Dong J, Yan J, Chang Q, Li C, Liu X, Wang X, Zeng Q
Int J Biol Sci · 2026 · PMID 41800255 · Full text
Rosacea is a globally prevalent chronic inflammatory skin disorder that markedly impairs quality of life, yet treatment options are limited. A characteristic feature of rosacea is macrophage infiltration, whose role in d...
Rosacea is a globally prevalent chronic inflammatory skin disorder that markedly impairs quality of life, yet treatment options are limited. A characteristic feature of rosacea is macrophage infiltration, whose role in disease pathogenesis remains incompletely understood beyond inflammation; here, we identify their contribution to fibrotic remodeling through macrophage-to-myofibroblast transition (MMT). Serum proteomics revealed that TGF-β1 was prominently elevated in rosacea patients. Moreover, single-cell RNA sequencing (scRNA-seq), spatial transcriptomics (ST), and histological staining of skin biopsies demonstrated that fibrotic remodeling was already evident at inflammation-dominant stages, with macrophages progressively acquiring myofibroblast-like features through MMT. These observations were recapitulated in LL37-induced mouse models by scRNA-seq and ST, further validated by lineage tracing using -GFP knock-in mice. Interestingly, macrophage depletion markedly alleviated LL37-induced fibrotic remodeling, underscoring the pathogenic role of MMT. Through integrative screening, we subsequently identified Bruceine A (BA), a natural quassinoid that suppressed fibrotic remodeling by reducing MMT and attenuating keratinocyte-driven inflammation . BA directly targeted STAT3 and interfered with its palmitoylation-dependent activation, thereby disrupting profibrotic and inflammatory signaling. Our findings establish MMT as a driver of fibrotic remodeling in rosacea, define STAT3 palmitoylation as a therapeutic target, and position BA as a dual-acting candidate for mechanism-based intervention.
ARID1A deficiency activates OSM-STAT3 axis in endometrial cancer, creating vulnerability to JAK/STAT3 inhibition.
Chen LJ, Shi C, Yang EJ … +7 more , Ren G, Tao S, Pu Y, Zhang X, Shen X, Wu C, Shim JS
Int J Biol Sci · 2026 · PMID 41800254 · Full text
ARID1A, a key component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor frequently inactivated in many cancer types, including endometrial cancer. Exploiting ARID1A deficiency has emerged as a therapeu...
ARID1A, a key component of the SWI/SNF chromatin remodeling complex, is a tumor suppressor frequently inactivated in many cancer types, including endometrial cancer. Exploiting ARID1A deficiency has emerged as a therapeutic strategy in these types of cancer. We here employed a synthetic lethal drug screen for ARID1A and found that JAK/STAT3 pathway is a therapeutic vulnerability in ARID1A-deficient endometrial cancer. Inhibition of JAK/STAT3 selectively inhibited the growth of ARID1A deficient endometria cancer cells and in a mouse xenograft tumor model. Mechanistically, ARID1A deficiency activates JAK/STAT3 signaling through promoting the transcription of the pleiotropic cytokine Oncostatin M (OSM). Autocrine activation of JAK/STAT3 signal by OSM in ARID1A-deficient endometrial cancer cells promotes PLK1 levels, inducing mitotic abnormality. These cells are highly vulnerable to JAK/STAT3 and PLK1 inhibitors for mitotic arrest and death. ARID1A and OSM protein levels are inverse correlated in patients with endometrial cancer, where elevated OSM levels are associated with poor patient survival. Our study indicates that OSM-STAT3-PLK1 axis inhibition presents a new therapeutic approach for endometrial cancer with ARID1A loss.
GFPT2 drives sunitinib resistance of renal cell carcinoma via enzyme-dependent and -independent manners.
Wang S, Xing J, Wang X … +3 more , Wang Z, Shao P, Miao C
Int J Biol Sci · 2026 · PMID 41800253 · Full text
Intrinsic resistance to sunitinib in advanced renal cell carcinoma (RCC) remains a major barrier to improving patient survival outcomes. However, the molecular mechanisms driving this resistance remain incompletely eluci...
Intrinsic resistance to sunitinib in advanced renal cell carcinoma (RCC) remains a major barrier to improving patient survival outcomes. However, the molecular mechanisms driving this resistance remain incompletely elucidated. In this study, we first observed elevated glutamine levels in sunitinib-resistant RCC models; notably, glutamine deprivation substantially impaired the growth and proliferation of RCC cells. We further demonstrated that abnormal upregulation of GFPT2-a key enzyme in glutamine metabolism-was associated with reduced sunitinib sensitivity and enhanced drug resistance in RCC. Mechanistically, we uncovered that GFPT2 modulates cellular O-GlcNAcylation levels, which in turn enhances the stability and nuclear translocation of YAP1-ultimately contributing to reduced sunitinib sensitivity. In addition, we also identified an additional non-metabolic role of GFPT2: it directly interacts with the Kelch domain of KEAP1, thereby reducing NRF2 binding to this domain and suppressing NRF2 ubiquitination-dependent degradation. Consequently, this regulatory cascade dysregulates the transcription of downstream antioxidant genes (e.g., HMOX1 and NQO1), ultimately driving NRF2-dependent sunitinib resistance in RCC. Critically, this KEAP1-NRF2 axis-mediated mechanism operates independently of GFPT2's metabolic role in regulating O-GlcNAcylation. Collectively, our findings demonstrate that GFPT2 modulates sunitinib sensitivity and drives drug resistance in RCC via dual mechanisms: a metabolic pathway (O-GlcNAcylation-YAP1) and a non-metabolic pathway (KEAP1-NRF2). Targeting the non-metabolic functions of GFPT2 thus holds promise for enhancing sunitinib sensitivity in RCC while potentially mitigating treatment-related side effects.
MYC-Mediated Functional Manifestation of IDH1 Mutations in Intrahepatic Cholangiocarcinoma Confers Sensitivity to (+)-JQ1.
Wang F, Liu X, Zhang N … +1 more , Kong R
Int J Biol Sci · 2026 · PMID 41800252 · Full text
Intrahepatic cholangiocarcinoma (ICC) is one of most aggressive malignancies attributable to limited treatment options. IDH1 is commonly mutated and frequently cooccurred with other genetic alterations in ICC. The mechan...
Intrahepatic cholangiocarcinoma (ICC) is one of most aggressive malignancies attributable to limited treatment options. IDH1 is commonly mutated and frequently cooccurred with other genetic alterations in ICC. The mechanism by which they affect ICC patient prognosis and therapeutic resistance remains incompletely understood. We aimed to investigate the function of MYC in IDH1mutant ICC progression and develop the novel therapeutic strategies. We well-established spontaneous ICC mouse models using transposon-based Idh1 and Kras mutations system in liver-specific knockout Trp53 mice. We generated multiple independent primary ICC cells and organoids derived from tumor tissues and established subcutaneous allograft ICC tumors. Together, multiple models in our studies were utilized to elucidate the role of MYC in IDH1-mutant ICC progression and to investigate therapeutic strategies. We demonstrated that the IDH1 mutations correlated with a favorable outcome in ICC patients and murine models. However, MYC overexpression drove the malignant phenotypic manifestation of Idh1 mutations, reversing this phenotype. Mechanistically, Idh1-mutant ICC reprogrammed glutamine metabolism to regulate Myc expression. Notably, ICC with concurrent IDH1 mutations and MYC amplification exhibited sensitivity to the MYC inhibitor (+)-JQ1, but remained resistant to the IDH1 mutation inhibitor AG120. This study identified MYC as a critical pathogenic driver of malignant progression in IDH1-mutant ICC. MYC overexpression conferred resistance to IDH1 mutation inhibitor, while creating a therapeutic vulnerability to MYC-targeted agents. The selective efficacy of (+)-JQ1 against IDH1-mutant ICC identified MYC inhibition as a promising precision medicine strategy for this molecular subset.
Metabolic Adaptation of CD8⁺ T Cells Limits the Efficacy of Fatty Acid Oxidation Inhibition in Type 1 Diabetes.
Salzmann M, Boccuni L, Gibler P … +11 more , Brekalo M, Trimmel TS, Pichler ET, Haider P, Blesch JL, Hengstenberg C, Fischer MB, Podesser BK, Creusot RJ, Kral-Pointner JB, Hohensinner PJ
Int J Biol Sci · 2026 · PMID 41800251 · Full text
Type 1 Diabetes Mellitus (T1D) is an organ-specific autoimmune disease characterized by persistent hyperglycemia due to immune-mediated destruction of pancreatic islet β-cells. Targeting immune cell metabolism has emerge...
Type 1 Diabetes Mellitus (T1D) is an organ-specific autoimmune disease characterized by persistent hyperglycemia due to immune-mediated destruction of pancreatic islet β-cells. Targeting immune cell metabolism has emerged as a promising therapeutic strategy. We investigated whether the fatty acid oxidation (FAO) inhibitor trimetazidine (TMZ), one of only three approved drugs directly targeting cellular metabolism, can restrain autoreactive immunity and delay T1D in non-obese diabetic mice (NOD). TMZ enhanced mitochondrial membrane potential, suppressed FAO, and curtailed activation and proliferation of human CD8 T cells. In dysglycemic NOD mice, a clinically approved dose of TMZ delayed progression to T1D, reduced mean glycemia, and decreased islet CD4⁺/CD8⁺ infiltration. Single-cell RNA sequencing revealed depletion of FAO-high, stress-responsive cells and mitochondrially active stromal cells, indicating improved pancreatic health. Prolonged exposure induced compensatory upregulation of carnitine-palmitoyl-transferase-1A (CPT1A) in CD8⁺ subsets, counterbalancing early benefits. In summary, TMZ transiently restrains CD8⁺ T cell activity, reduces islet infiltration, and improves pancreatic health. The adaptive upregulation of CPT1A demonstrates a novel evasion mechanism to FAO inhibition and underscores the central role of FAO in sustaining pathogenic T cells. Our work highlights metabolic adaptation as a key determinant of autoimmune progression, validating FAO as a therapeutic target in T1D.
APP Deficiency Ameliorates FAD Presenilin 1 F105C and A246E Mutations-induced Mitochondrial Dysfunction in Human Cortical Neurons.
Yen YH, Yuan F, Tang D … +6 more , Luo JF, Ming C, Kang PJ, Su H, Chong CM, Zhang SC
Int J Biol Sci · 2026 · PMID 41800250 · Full text
BACKGROUND: Mitochondrial dysfunction is widely regarded as a central and early feature of Alzheimer's disease (AD) pathology. Prior studies suggest that the accumulation of amyloid precursor protein (APP) within mitocho...
BACKGROUND: Mitochondrial dysfunction is widely regarded as a central and early feature of Alzheimer's disease (AD) pathology. Prior studies suggest that the accumulation of amyloid precursor protein (APP) within mitochondria contributes to this dysfunction. Mutations in presenilin-1 (PS1), which account for most cases of early-onset familial AD (FAD), have also been shown to impair mitochondrial function. In this study, we investigated how APP influences PS1 mutation-induced mitochondrial dysfunction in human cortical neurons derived from patient induced pluripotent stem cells (iPSCs). METHODS: We analyzed transcriptomic and proteomic datasets from postmortem sporadic AD cortex to identify key dysregulated pathways. To functionally interrogate selected mechanisms, we established a panel of CRISPR/Cas9-engineered human iPSC lines, including PS1 mutant lines (PS1 and PS1), an APP knockout derivative (APP_PS1), and their isogenic wild-type controls. These iPSCs were differentiated into cortical neurons for functional studies. Following directed differentiation into cortical neurons, biochemical analyses and super-resolution imaging were conducted to evaluate mitochondrial and neuronal phenotypes. RESULTS: Analyses of sporadic AD cortical transcriptomes and proteomes identified mitochondrial dysfunction as a prominently altered pathway. In agreement, cortical neurons differentiated from FAD PS1 mutant (F105C and A246E) iPSCs displayed mitochondrial defects and AD-related phenotypes, both of which were mitigated by APP knockout. CONCLUSIONS: These findings provide critical insights into the bridging role of APP in FAD PS1 mutant-mediated mitochondrial dysfunction, advancing our understanding of the cellular mechanisms underlying AD.
PTPN1 Regulation via YBX1-PTBP1 Interaction Promotes Fibroblast Activation and Fibrotic Remodeling in the Lung.
Liu H, Xia C, Zhang Y … +12 more , Gan Y, Cheng L, Wang X, Chang A, Zhao W, Li B, Wang Y, Li Y, Rosas I, Yang J, Yu G, Wang L
Int J Biol Sci · 2026 · PMID 41800249 · Full text
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial pneumonia of unknown etiology. Its pathogenesis involves complex multicellular interactions and signaling pathways, with fibroblast-to-myofibrobl...
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial pneumonia of unknown etiology. Its pathogenesis involves complex multicellular interactions and signaling pathways, with fibroblast-to-myofibroblast transition (FMT) being critical for fibrogenesis. Although the transcription factor Y-box binding protein 1 (YBX1) regulates processes such as cell proliferation, transcription, translation, and DNA repair, its role in IPF remains undefined. Here, we demonstrate that YBX1 overexpression significantly promotes transforming growth factor-β1 (TGF-β1)-induced pulmonary FMT, leading to substantially increased extracellular matrix (ECM) deposition in primary human (PHLFs) and mouse (PMLFs) lung fibroblasts. Conversely, YBX1 inhibition markedly suppresses TGF-β1-driven aberrant fibroblast migration and activation. Mechanistically, YBX1 interacts with polypyrimidine tract-binding protein 1 (PTBP1) and binds to the protein tyrosine phosphatase nonreceptor type 1 (PTPN1) promoter to transcriptionally regulate PTPN1, thereby driving FMT. , intratracheal delivery of Ybx1-targeting shRNA via adeno-associated virus (AAV) robustly attenuates ECM deposition, hydroxyproline content, and fibrotic marker expression in a bleomycin (BLM)-induced murine fibrosis model. Our findings identify YBX1 as a promoter of lung FMT via the PTBP1/PTPN1 axis, offering mechanistic insights for the development of YBX1-targeted therapeutic strategies for IPF.
Interaction between m6A and YAP1 mechanotransduction pathways is essential for mechanical memory and matrix remodeling in pancreatic cancer.
Chen J, Wang G, Zhang H … +5 more , Hu Q, Zhao J, Shen Q, Duan Q, Yin T
Int J Biol Sci · 2026 · PMID 41800248 · Full text
Pancreatic cancer is a highly aggressive malignancy characterized by a progressively stiffened extracellular matrix, which promotes mechanical memory acquisition in cancer cells and facilitates malignant progression and...
Pancreatic cancer is a highly aggressive malignancy characterized by a progressively stiffened extracellular matrix, which promotes mechanical memory acquisition in cancer cells and facilitates malignant progression and metastasis. Despite its clinical significance, the mechanisms underlying matrix stiffening and mechanical memory formation remain poorly defined. This study demonstrates that a high-stiffness microenvironment induces mechanical memory in pancreatic tumor cells, which in further aggravates stromal remodeling and adversely affects prognosis. Under mechanically stiff conditions, pancreatic cancer cells exhibit pronounced enrichment of RNA modification-related and metabolic pathways, along with significantly increased m6A levels. Mechanistically, METTL14 enhances YAP1 expression through YTHDF3-mediated m6A-dependent translational regulation, while YAP1 in turn transcriptionally upregulates METTL14 via TEAD1, establishing a positive feedback loop that sustains mechanical memory. This METTL14-YAP1 axis activates CD166-EGFR-LOXL2 signaling, leading to enhanced collagen cross-linking and deposition, increased stromal stiffness, and maintenance of tumor stemness. These results identify the METTL14-YAP1 feedback loop as a core regulator of mechanical memory in pancreatic ductal adenocarcinoma, which drives stromal dysfunction and tumor progression through CD166-LOXL2 axis, and suggest targeting this loop as a potential therapeutic strategy to disrupt mechanical memory and ameliorate stiffness-induced remodeling.
O-GlcNAcylation stabilizes RSK4 by antagonizing GSK3β-mediated phosphorylation to enhance radioresistance in esophageal squamous cell carcinoma.
Liu J, Cao D, Xu T … +8 more , Xu J, Zhang B, Yang X, Zhao P, Wang P, Chen L, Jia Q, Li M
Int J Biol Sci · 2026 · PMID 41800247 · Full text
Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy characterized by significant radioresistance and poor prognosis. We previously reported that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal ro...
Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy characterized by significant radioresistance and poor prognosis. We previously reported that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting cancer stem cell (CSC) properties and radioresistance in ESCC. This study focuses on the regulation of post-translational modifications (PTMs) of RSK4 and their effects on CSC properties and radioresistance. We demonstrate that RSK4 stability and activity are tightly regulated by phosphorylation and O-GlcNAcylation. GSK3β phosphorylates RSK4 at Thr402/Ser406, promoting its degradation via the FBXW7-dependent proteasomal pathway. Additionally, O-GlcNAcylation of RSK4 at Thr405 by OGT inhibits GSK3β-mediated phosphorylation, stabilizing RSK4 and enhancing CSC properties and radioresistance. This antagonistic relationship between phosphorylation and O-GlcNAcylation highlights a novel regulatory mechanism of RSK4 in ESCC. Moreover, targeting RSK4 O-GlcNAcylation with OSMI-4 destabilizes RSK4 and sensitizes ESCC to radiotherapy in both patient-derived xenograft and organoid models. Collectively, this study provides critical insights into the molecular mechanisms underlying ESCC radioresistance and identifies RSK4 O-GlcNAcylation as a potential therapeutic target to improve radiotherapy efficacy and overcome treatment resistance.
Gut-Lung Microbiota Axis Shapes the Immune Microenvironment and Immunotherapeutic Response in Lung Cancer.
Liu Y, Wang S, Xiang X … +6 more , Du Y, Xue Q, Niu Y, Peng W, Ye L, Zhou Q
Int J Biol Sci · 2026 · PMID 41800246 · Full text
The gut-lung axis microbiota plays a pivotal role in shaping the tumor immune microenvironment (TIME) and regulating immunotherapeutic responses in lung cancer. This review highlights that pulmonary and gut microbial dys...
The gut-lung axis microbiota plays a pivotal role in shaping the tumor immune microenvironment (TIME) and regulating immunotherapeutic responses in lung cancer. This review highlights that pulmonary and gut microbial dysbiosis drives lung cancer development through inducing chronic inflammation, remodeling the immune microenvironment, and reprogramming metabolism. Lung cancer patients exhibit distinct microbial signatures characterized by altered microbiotal diversity and enrichment of specific taxa like Streptococcus, Veillonella, and Bacteroidetes in the airways, along with gut microbial shifts involving decreased Firmicutes/Bacteroidetes ratio. These microbial alterations promote tumor progression via activation of pro-inflammatory pathways (e.g., interleukin-17 (IL-17)/interleukin-23 (IL-23) axis) and suppression of antitumor immunity.Notably, the gut-lung microbiome exerts a profound impact on immunotherapeutic efficacy: responders are enriched with beneficial microbes like Akkermansia muciniphila and Bifidobacterium that enhance CD8⁺ T cell responses, while non-responders show elevated levels of Gammaproteobacteria and Fusobacterium associated with immunosuppression. Regulatory mechanisms include systemic immune modulation by microbial metabolites such as short-chain fatty acids, as well as activation of key signaling pathways including cGAS-STING and CD40L-CD40/NF-κB. Emerging translational applications encompass lung cancer diagnosis and immunotherapeutic response prediction via microbial biomarkers, as well as therapeutic interventions including fecal microbiota transplantation (FMT) and probiotic supplementation. Future studies should clarify microbe-host interaction mechanisms and develop personalized microbiota-based strategies to overcome immunotherapy resistance, offering the potential to revolutionize precision oncology through integrating microbiota modulation with conventional therapies.
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