International Journal Of Biological Sciences[JOURNAL]
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200 papers
TIM-4 skeletal muscle Resident Tissue Macrophages Ferroptosis mediated Rhabdomyolysis in Exertional Heatstroke.
Tang Y, An Q, Zhang K … +8 more , Liu C, Wei R, Li R, Wang Z, He S, Wang F, Ma L, Ma Q
Int J Biol Sci · 2026 · PMID 42003910 · Full text
Skeletal muscle resident tissue macrophages (smRTMs) are strategically positioned to sense myofiber injury and coordinate inflammatory responses, but their mechanistic contribution to exertional heatstroke (EHS)-associat...
Skeletal muscle resident tissue macrophages (smRTMs) are strategically positioned to sense myofiber injury and coordinate inflammatory responses, but their mechanistic contribution to exertional heatstroke (EHS)-associated rhabdomyolysis (RM) remains poorly defined. Here, we delineate a ferroptosis-dependent pathway in smRTMs that drives RM during EHS. Using mouse model of EHS, in combination with single-cell RNA sequencing, smRTM-targeted deletion and pharmacological modulation of ferroptosis and inflammasome activity, we identify a T cell membrane protein 4-positive (TIM-4⁺) smRTM subset as selectively vulnerable to ferroptosis. EHS robustly induces heme oxygenase-1 (HMOX1), iron-dependent lipid peroxidation and ferroptotic death in TIM-4⁺ smRTMs, accompanied by accumulation of the lipid peroxidation-derived aldehyde octanal. Octanal engages olfactory receptor 2 (Olfr2) and provides a proximal signal for activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, caspase-1 cleavage and interleukin-1β (IL-1β) release. Chromatin and functional assays further establish JunD as a transcription factor that binds the promoter and is required for upregulation downstream of HMOX1-driven ferroptosis. Genetic or pharmacological inhibition of HMOX1, or blockade of ferroptosis, reduces TIM-4⁺ smRTM ferroptosis, dampens the JunD-Olfr2-NLRP3-IL-1β axis and significantly attenuates RM in both species. These data identify HMOX1-dependent ferroptosis in TIM-4⁺ smRTMs as a central immunometabolic mechanism of EHS-associated RM and nominate smRTM ferroptosis and the Olfr2-NLRP3 pathway as rational therapeutic targets.
CCT2 Orchestrates Glycolysis and Exosome-Mediated M2 Macrophage Polarization in HCC tumorigenesis.
Guo WW, Dongzhi C, Ma T … +9 more , Zhang M, Gao M, Li X, Zhou J, Chen X, He W, Tian M, Yuan Y, Ma W
Int J Biol Sci · 2026 · PMID 42003909 · Full text
INTRODUCTION: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, driven by metabolic reprogramming and immune evasion. The role of T-complex protein 1 subunit beta (CCT2) in HCC remai...
INTRODUCTION: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with a poor prognosis, driven by metabolic reprogramming and immune evasion. The role of T-complex protein 1 subunit beta (CCT2) in HCC remains unclear. This study aimed to elucidate the function of CCT2 in HCC tumorigenesis. METHODS: Bioinformatics analysis and Clinical samples investigation were integrated with and experiments to investigate CCT2's role in HCC metabolism and immune modulation. The glycolytic activity was assessed by measuring extracellular acidification rate, glucose uptake, lactate levels, and metabolomic profiles. Coimmunoprecipitation or GST pulldown assays confirmed CCT2 interactions with aldolase A (ALDOA) and glutathione S-transferase P (GSTP1), while THP1 co-culture assays evaluated tumor immune crosstalk. RESULTS: CCT2 directly interacts with and stabilizes the glycolytic enzyme ALDOA, as shown by co-immunoprecipitation and metabolic assays revealing increased extracellular acidification rate, glucose uptake, and lactate production in HCC cells. Genetic depletion of CCT2 suppresses tumor cell proliferation and migration and inhibits tumor growth . Furthermore, co-culture and exosome treatment experiments reveal that CCT2 promotes M2 macrophage polarization and establishes an immunosuppressive tumor microenvironment through coordinated metabolic and exosome-mediated mechanisms. In mouse models, CCT2 knockdown significantly enhances the antitumor efficacy of PD-1 blockade. CONCLUSIONS: CCT2 stabilizes ALDOA and facilitates exosome-mediated immunosuppressive signaling, thereby linking metabolic reprogramming to immune evasion in HCC and supporting its potential as a mechanistically informed therapeutic target.
DHCR24 Drives Ovarian Cancer Chemoresistance Through Lipid Raft-mediated P-gp Stabilization and STAT3 Activation.
Fu X, Wang Z, Yang Z … +4 more , Xu Y, Dong Q, Cui Y, Wang K
Int J Biol Sci · 2026 · PMID 42003908 · Full text
OBJECTIVE: To investigate the role and mechanism of DHCR24 in chemoresistance of ovarian cancer and to identify potential therapeutic targets for overcoming treatment resistance. METHODS: We integrated bioinformatic anal...
OBJECTIVE: To investigate the role and mechanism of DHCR24 in chemoresistance of ovarian cancer and to identify potential therapeutic targets for overcoming treatment resistance. METHODS: We integrated bioinformatic analysis of GEO datasets and clinical survival data from KMplot to identify chemoresistance-associated genes. DHCR24 expression and function were systematically evaluated using cisplatin-resistant cell lines (A2780/DDP, SKOV3/DDP), patient-derived primary cells, xenograft models, and clinical specimens through molecular biology techniques, immunohistochemistry, and functional assays. Mechanistic studies employed RNA interference, cholesterol modulation, lipid raft disruption with MβCD, cycloheximide chase assays, and STAT3 pathway inhibition. RESULTS: DHCR24 was consistently upregulated in chemoresistant ovarian cancer models and significantly correlated with poor patient survival. Genetic or pharmacological inhibition of DHCR24 restored chemosensitivity and , while its overexpression induced cross-resistance to multiple chemotherapeutic agents. Mechanistically, DHCR24 enhanced cholesterol biosynthesis, which stabilized lipid raft microdomains to promote P-gp protein stability and facilitate STAT3 membrane recruitment and activation. Furthermore, activated STAT3 transcriptionally upregulated DHCR24 expression, establishing a positive feedback loop that perpetuates the chemoresistant phenotype. CONCLUSION: DHCR24 drives chemoresistance through a cholesterol-dependent circuit that stabilizes drug efflux pumps and activates pro-survival signaling, identifying DHCR24 as a promising therapeutic target for overcoming chemotherapy resistance in ovarian cancer.
TIMP1 Derived from Mesenchymal Stem Cells Promotes Bladder Cancer Progression by Regulating the Formation of VDIMs through the RAP1 Pathway.
Li P, Yang E, Zhang X … +11 more , Shi Y, Chen C, Fan G, Wang Y, Wang H, Liu N, Zhou H, Tian J, Cheng L, Dong Z, Wang Z
Int J Biol Sci · 2026 · PMID 42003907 · Full text
The pro-tumor function of mesenchymal stem cells (MSCs) in bladder cancer (BC) is not fully elucidated. This study integrates clinical cohorts, organoid models, and patient-derived xenografts (PDX) to dissect MSCs-derive...
The pro-tumor function of mesenchymal stem cells (MSCs) in bladder cancer (BC) is not fully elucidated. This study integrates clinical cohorts, organoid models, and patient-derived xenografts (PDX) to dissect MSCs-derived TIMP1 as a key driver of BC progression. Using multiplex fluorescent immunohistochemistry and enzyme-linked immunosorbent assays, we found that elevated infiltration level of MSCs in BC tissues and TIMP1 levels in tissues/urine correlated with advanced tumor-stage, lymphovascular invasion, and reduced recurrence-free survival time, with MSCs infiltration positively associated with TIMP1 expression. Single-cell data analysis and mass spectrometry revealed TIMP1 as the predominant cytokine secreted by MSCs. Mechanistically, MSC-derived TIMP1 binds to ADAM10 to inhibit its extracellular shedding, thereby stabilizing cMet phosphorylation and activating the RAP1 signaling axis. Functional studies revealed that TIMP1 enhances intracellular Ca levels and VDAC1 expression through the RAP1 pathway, promoting the formation of vesicles derived from the inner mitochondrial membrane (VDIMs) to regulate mitochondrial quality control. Crucially, the TIMP1 inhibitor FXR agonist 3 suppressed MSCs-driven BC proliferation and attenuated tumor growth in PDX models by disrupting the cMet-RAP1 signaling pathway without systemic toxicity. Our findings propose targeting the MSCs-TIMP1-RAP1 axis as a novel therapeutic strategy for BC.
Exosomal transfer of macrophage-derived NEAT1 enhances DNA damage response and confers cisplatin resistance in lung adenocarcinoma via the MAD1L1/p53 axis.
Yang Y, Meng M, Zhao Y … +3 more , Yu F, Patel H, Chen ZS
Int J Biol Sci · 2026 · PMID 42003906 · Full text
Cisplatin (DDP) resistance remains a major therapeutic obstacle in non-small-cell lung cancer (NSCLC). Tumor-associated macrophages (TAMs) are known to promote chemoresistance via exosomal signals, but whether exosomal l...
Cisplatin (DDP) resistance remains a major therapeutic obstacle in non-small-cell lung cancer (NSCLC). Tumor-associated macrophages (TAMs) are known to promote chemoresistance via exosomal signals, but whether exosomal long non-coding RNA NEAT1 contributes to this process is unclear. In this study, we found that exosomes derived from DDP-treated macrophages were enriched with NEAT1 and delivered it to A549 cells. This transfer enhanced the DNA damage response, promoted cell-cycle progression, and reduced DDP-induced apoptosis. Through RNA-sequencing and luciferase reporter assays, we identified MAD1L1 as a key downstream target of NEAT1. NEAT1 was enriched at the MAD1L1 promoter, upregulated its expression, and subsequently suppressed the p53/p21/Bax axis, thereby fostering a chemoresistant phenotype. , exosomal NEAT1 promoted tumor growth in DDP-treated xenografts, while NEAT1 knockdown reversed this effect and restored p53 pathway activity. Collectively, our work unveils a novel TAM-exosome-NEAT1-MAD1L1/p53 signaling axis that drives cisplatin resistance in lung adenocarcinoma, highlighting NEAT1 and its intercellular delivery as potential therapeutic targets to overcome chemoresistance.
eEF2K-Mediated Stabilization of PCBP2 Promotes Oncogenic mRNA Programs in Triple-Negative Breast Cancer.
Cheng Y, Jiang T, Zhu W … +6 more , He L, Chen Z, Li H, Zhao R, Jiang S, Cheng Y
Int J Biol Sci · 2026 · PMID 42003905 · Full text
Triple-negative breast cancer (TNBC), characterized by the absence of effective therapeutic targets, remains a major clinical challenge with poor prognosis. The identification of novel molecular targets is therefore cruc...
Triple-negative breast cancer (TNBC), characterized by the absence of effective therapeutic targets, remains a major clinical challenge with poor prognosis. The identification of novel molecular targets is therefore crucial for developing effective treatment strategies. Eukaryotic elongation factor 2 kinase (eEF2K) is highly expressed in TNBC and known to promote tumor progression; however, the precise mechanisms underlying its oncogenic role remain elusive. In this study, we identified poly(rC)-binding protein 2 (PCBP2) as a previously unrecognized downstream substrate of eEF2K. Analysis of clinical TNBC specimens revealed a positive correlation between eEF2K and PCBP2 protein expression levels. Further studies demonstrated that site-specific phosphorylation of PCBP2 at serine 189 (Ser189) markedly promoted the malignant phenotype of TNBC cells. Mechanistically, eEF2K-mediated phosphorylation at Ser189 stabilized PCBP2 by preventing its ubiquitin-proteasome-dependent degradation. This phosphorylation-dependent stabilization, in turn, enabled PCBP2 to promote the mRNA stability of pro-oncogenic genes, including TNC, SOX5, and ITGB3, thereby driving TNBC progression. Collectively, these findings not only reveal PCBP2 as a critical downstream effector of eEF2K, but also highlight the eEF2K-PCBP2 signaling axis as a promising therapeutic target for TNBC.
LINC-EPS Protects Against Neurodegeneration by Driving a PGC-1α-Mediated Anti-Ferroptosis Program in Parkinson's Disease.
Liu Z, Wang R, Lan X … +11 more , Shen M, Jiang M, Li R, Zhao J, Li J, Wang S, Wang Q, Xu X, Li W, Gong W, Qian L
Int J Biol Sci · 2026 · PMID 42003904 · Full text
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic (DA) neuron loss and currently lacks disease-modifying treatments. We found that the long intergenic non-coding RNA LINC-...
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopaminergic (DA) neuron loss and currently lacks disease-modifying treatments. We found that the long intergenic non-coding RNA LINC-EPS was markedly reduced in peripheral blood of PD patients, correlating with greater clinical severity. Similar downregulation was observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) PD mice and 1-methyl-4-phenylpyridinium-treated DA neurons. Knockout of LINC-EPS, either systemically or specifically in DA neurons, aggravated motor deficits and DA neurodegeneration, whereas AAV-mediated overexpression rescued these phenotypes. LINC-EPS protected DA neurons by suppressing ferroptosis, acting as a scaffold that binds both PGC-1α protein and a T-box element in its promoter, thereby recruiting PGC-1α to enhance its own transcription through a positive feedback loop. This activation improved mitochondrial function, lowered reactive oxygen species, inhibited lipid peroxidation, and conferred ferroptosis resistance. Pharmacological activation of PGC-1α with ZLN005 rescued neurodegeneration in LINC-EPS-deficient PD mice. Our study identifies a novel LINC-EPS/PGC-1α axis that mitigates ferroptotic DA neuron loss and supports PGC-1α activation as a promising therapeutic strategy for PD progression.
Exosomal Long Noncoding RNA H19 as a Biomarker and Therapeutic Target in Atrial Fibrillation.
Kang JY, Mun D, Park M … +3 more , Yoo G, Yun N, Joung B
Int J Biol Sci · 2026 · PMID 42003903 · Full text
Although exosomal long noncoding RNAs (lncRNAs) have emerged as promising theragnostic targets in various diseases, their role in atrial fibrillation (AF) remains largely unexplored. Herein, we aimed to identify AF-speci...
Although exosomal long noncoding RNAs (lncRNAs) have emerged as promising theragnostic targets in various diseases, their role in atrial fibrillation (AF) remains largely unexplored. Herein, we aimed to identify AF-specific serum exosomal lncRNAs and to evaluate their potential as theragnostic targets. RNA sequencing and qRT-PCR analyses consistently demonstrated significant downregulation of lncRNA in serum exosomes of patients with AF compared with those without AF. Notably, serum exosomal lncRNA levels showed significant diagnostic validity for AF and were closely associated with AF pathophysiology. In angiotensin II (Ang II)-treated iPSC-derived atrial cardiomyocytes, both loss- and gain-of-function experiments revealed that lncRNA markedly modulated Ang II-induced hypertrophic responses, including increased expression of , , and , as well as enlargement of cell surface area. Moreover, experiments showed that cardiac-specific overexpression of lncRNA significantly attenuated Ang II-induced cardiac dysfunction and hypertrophy ( < 0.05). Mechanistically, lncRNA sponges and , thereby regulating the PTEN pathway and contributing to cardiac hypertrophic remodeling and subsequent AF. Collectively, these findings identify a novel association between circulating exosomal lncRNA and AF and further elucidate its mechanistic role in cardiac hypertrophy, highlighting its potential as a diagnostic biomarker and therapeutic target for AF.
The Quartet of Core Oncogenic Drivers in Neuroendocrine Prostate Cancer: Multi-Omics Dataset Integration to Forge a Translational Link Between Biology and Precision Therapy.
Wang Y, Wu N, Li J … +3 more , Cao Q, Ye J, Zhang S
Int J Biol Sci · 2026 · PMID 42003902 · Full text
Prostate cancer (PC) is the most common cancer among American men and the second leading cause of cancer-related deaths. For advanced or metastatic PC, anti-androgen therapies, including androgen deprivation therapy (ADT...
Prostate cancer (PC) is the most common cancer among American men and the second leading cause of cancer-related deaths. For advanced or metastatic PC, anti-androgen therapies, including androgen deprivation therapy (ADT), are considered standard treatment options. However, these therapies often result in the development of castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC), both of which present significant treatment challenge. The molecular mechanisms driving the progression from androgen - sensitive PC to castration-resistant and neuroendocrine phenotypes are still being actively investigated. This review aims to comprehensively evaluate the cellular and molecular mechanisms underlying the development of NEPC. Specifically, it will focus on the roles of cancer stem cells (CSCs), epithelial - mesenchymal transition (EMT), and autophagy in the pathogenesis and progression of NEPC. Furthermore, the review will explore the potential of targeting these processes for therapeutic intervention in advanced P. This review will integrate current findings from clinical trials, pre-clinical models, and molecular research to clarify the promising approaches for improving treatment outcomes for patients with advanced PC.
SphK1/S1P signaling-mediated crosstalk between pancreatic acinar cell and macrophage M1 polarization aggravates acute pancreatitis progression.
Wang J, Zhao G, Hu P … +10 more , Han S, Hu Y, Zeng Z, Li Y, Zhao Y, Huang Y, Zhuo W, Lv G, Wang H, Zhao G
Int J Biol Sci · 2026 · PMID 42003901 · Full text
Studies have shown that M1 polarization of macrophages plays a crucial role in pathogenesis of acute pancreatitis (AP), although the underlying mechanisms remain incompletely understood. In this study, an AP model was i...
Studies have shown that M1 polarization of macrophages plays a crucial role in pathogenesis of acute pancreatitis (AP), although the underlying mechanisms remain incompletely understood. In this study, an AP model was induced in mice using caerulein or L-arginine, while an AP model was established by treating pancreatic acinar cells (PACs) with cholecystokinin (CCK). We observed a significant upregulation of SphK1/S1P in both CCK-treated PACs and the pancreatic tissue of AP mice. In contrast, inflammation and M1 macrophage polarization were markedly attenuated in SphK1 AP mice and upon treatment with pharmacological inhibitors targeting SphK1 or S1PR2. Similarly, M1 polarization of macrophages was notably induced by injured pancreatic acinar cells (iPACs), but this effect was suppressed by SphK1 knockdown or inhibition. Mechanistically, S1P derived from iPACs specifically bound to S1PR2 on macrophages, activating PI3K/JNK and ERK pathways to induce M1 polarization. Moreover, TNF-α secreted by M1 macrophages enhanced SphK1 transcription in PACs through NF-κB activation, forming a positive feedback loop between iPACs and macrophage M1 polarization. Collectively, our findings reveal that the SphK1/S1P/S1PR2/TNF-α axis mediates a reciprocal interaction between iPACs and M1 macrophages, which significantly contributes to AP pathogenesis.
The Implications of Radiotherapy-Induced Cellular Senescence for Cancer Treatment and Tumor Microenvironment Modulation.
Jiang C, Tuo Z, Wusiman D … +6 more , Wang J, Yao H, Cho WC, Lyu Z, Zhang Q, Feng D
Int J Biol Sci · 2026 · PMID 42003900 · Full text
Radiotherapy is a cornerstone of cancer management, yet ionizing radiation can induce cellular senescence in tumor cells and in normal or stromal compartments. Senescent cells undergo durable cell-cycle arrest but remain...
Radiotherapy is a cornerstone of cancer management, yet ionizing radiation can induce cellular senescence in tumor cells and in normal or stromal compartments. Senescent cells undergo durable cell-cycle arrest but remain metabolically active and develop the senescence-associated secretory phenotype (SASP), a bioactive secretome that remodels the tumor microenvironment (TME). This review summarizes principal pathways that couple radiation injury to senescence, including persistent DNA damage signaling, oxidative stress driven by reactive oxygen species, telomere dysfunction, and epigenetic reprogramming, and discusses their downstream consequences. We highlight the time- and context-dependent nature of senescence: early after treatment, senescence can constrain proliferation and enhance immune surveillance; when senescent cells persist, chronic SASP signaling can promote extracellular matrix remodeling, angiogenesis, immune dysfunction, cellular plasticity, and ultimately recurrence and therapy resistance, while also contributing to late normal-tissue toxicity and fibrosis. Finally, we evaluate emerging therapeutic strategies to modulate this biology, including senolytics that eliminate senescent cells, senomorphics that attenuate harmful SASP outputs, immunotherapeutic approaches that augment senescence surveillance, and optimization of radiotherapy delivery to limit normal-tissue senescence. Defining robust biomarkers, treatment windows, and safety profiles will be essential for translating senescence-targeted combinations into durable tumor control with reduced long-term toxicity.
Monocyte Preprogramming by Tobacco Carcinogens and Fructose Intake Accelerates Lung Cancer Progression via Metabolic and Epigenetic Pathways.
Ahn JH, Min HY, Kim J … +3 more , Wei X, Kim N, Lee HY
Int J Biol Sci · 2026 · PMID 42003899 · Full text
Although tobacco smoking is the leading cause of lung cancer (LC), excessive sugar intake has also emerged as a potential risk factor, yet its mechanistic contribution remains poorly defined. In this study, we investigat...
Although tobacco smoking is the leading cause of lung cancer (LC), excessive sugar intake has also emerged as a potential risk factor, yet its mechanistic contribution remains poorly defined. In this study, we investigated how high-fructose intake modulates the tobacco carcinogen-induced LC progression. Co-exposure to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and benzo[a]pyrene (NNK and BaP; collectively referred to as NB) combined with a high-fructose diet markedly accelerated tumor progression in multiple mouse models, including Kras-driven LC and LKB1-deficient (LKB1) lung tumors. NB-induced LC progression was suppressed by restricting glucose metabolism, indicating a metabolic dependency. Mechanistically, NB exposure stimulated transcriptional programs that promote monocyte/macrophage recruitment within the tumor microenvironment and enhanced fructose uptake through both transcriptional and post-transcriptional upregulation of fructose transporters, including glucose transporter 8 (GLUT8). This metabolic reprogramming increased acetylation of histones and signal transducer and activator of transcription 3 (STAT3), leading to transcriptional upregulation of genes governing macrophage differentiation and M2 polarization. Analysis of human LC samples revealed enrichment of pro-metastatic IL-10 and VEGFA M2 macrophages, which correlated with poor clinical outcomes. Collectively, these findings demonstrate that NB-driven fructose metabolism induces epigenetic reprogramming of macrophages to promote LC progression and identify pro-metastatic M2 macrophages as potential prognostic biomarkers and therapeutic targets.
Identification of Trogocytosis as an Essential Limitation Factor in hPSC-derived CAR Macrophages.
Kang B, Wang S, Guo X … +11 more , Lin H, Yan H, Wang M, Song T, Zhang Z, Hu X, Zhu Y, Feng B, Nie J, Liu J, Pan G
Int J Biol Sci · 2026 · PMID 41943855 · Full text
Generation of CAR macrophages from induced pluripotent stem cells(iPSCs) hold great potential for immunotherapy, particularly against T-cell malignancies which are challenging in CAR-T therapy. However, the tumoricidal a...
Generation of CAR macrophages from induced pluripotent stem cells(iPSCs) hold great potential for immunotherapy, particularly against T-cell malignancies which are challenging in CAR-T therapy. However, the tumoricidal activity of human iPSCs derived CAR-macrophages (iCAR-Ms) remains less extensively analyzed. Here, we generated human iCAR-Ms targeting CD5 for T-cell malignancy therapy. iCAR-Ms show up-regulation of immunity related functions as well as tumoricidal activity against different T malignant cells expressing CD5. However, the tumoricidal activity of iCAR-Ms is highly related to CD5 density on tumor cells and depends on high dose treatment . We further reveal that the tumor cells resisting iCAR-M killing show reversible CD5 loss mediated by iCAR-M trogocytosis. In contrast, the retrieved iCAR-Ms from tumor cell co-culture retained tumoricidal activity on new tumor cell expressing CD5. Thus, we identify trogocytosis as an important limiting factor on iCAR-Ms therapy, providing a rationale for developing enhanced CAR-M therapies.
A crosstalk between tumor cells and adipocytes facilitates tumor cell migration and invasion.
Garrido-Jiménez L, Del Valle-Pérez B, Pastor J … +5 more , Alechaga É, Sala-Vila A, Pozo ÓJ, Peña R, de Herreros AG
Int J Biol Sci · 2026 · PMID 41943854 · Full text
Cancer cell invasion is modulated by their interaction with the tumor microenvironment (TME). In this article we have analyzed the cooperation of one of the TME cellular components, adipocytes, and breast tumor cells. Co...
Cancer cell invasion is modulated by their interaction with the tumor microenvironment (TME). In this article we have analyzed the cooperation of one of the TME cellular components, adipocytes, and breast tumor cells. Co-culture of these two types of cells increase tumor cell invasion and migration. This effect is associated to the de-differentiation of adipocytes that lose lipids and experience a transition to a mesenchymal phenotype. Furthermore, tumor cells are activated by adipocytes and undergo a partial epithelial-to-mesenchymal transition (EMT), which is characterized by a slow upregulation of Snail1. While partial EMT and increased migration both require fatty acid internalization, the adipocyte effect in our system does not rely on direct fatty acid transfer; instead, the tumor cells take these compounds directly from the culture medium. Moreover, adipocytes stimulate tumor cell metabolism by increasing glucose consumption and the production of reactive oxygen species (ROS); this metabolic shift is associated with the upregulated expression of NADPH oxidases (NOX) 1 and 5. Accordingly, a NOX inhibitor or NOX1 down-regulation prevents adipocyte-enhanced ROS generation, Snail1 expression and tumor cell migration. These results show that a bidirectional crosstalk between the two types of cells drives adipocyte dedifferentiation and tumor cell migration and invasion.
Identification of a Novel PDRG1-EZH2-p21 Pathway Controlling Senescence and Tumor Progression in Hepatocellular Carcinoma.
Yang Q, Zhang L, Li W … +4 more , Zhang Z, Tao J, Rong Y, Wang W
Int J Biol Sci · 2026 · PMID 41943853 · Full text
Hepatocellular carcinoma (HCC) remains a major global health burden with limited therapeutic options and poor prognosis. PDRG1 is upregulated in several malignancies, yet its clinical relevance and mechanistic role in HC...
Hepatocellular carcinoma (HCC) remains a major global health burden with limited therapeutic options and poor prognosis. PDRG1 is upregulated in several malignancies, yet its clinical relevance and mechanistic role in HCC are not fully understood. Here, we investigated the contribution of PDRG1 to HCC progression and delineated the underlying molecular mechanism. Using public datasets, patient specimens, functional assays, and subcutaneous xenograft models, we evaluated PDRG1 expression, biological functions, and downstream pathways. Transcriptome profiling, pathway enrichment analysis, rescue experiments, co-immunoprecipitation, and ChIP-qPCR were performed to define the PDRG1-EZH2-p21 axis. PDRG1 was significantly upregulated in HCC tumor tissues compared with adjacent non-tumor liver tissues and was associated with worse patient survival. Functionally, PDRG1 enhanced HCC cell proliferation, migration, invasion, colony formation, and tumor growth . RNA-seq and enrichment analyses identified cellular senescence as a prominent downstream program regulated by PDRG1. Mechanistically, PDRG1 directly interacted with EZH2, increased H3K27me3 enrichment at the p21 promoter, and suppressed p21 transcription. Restoration of p21 expression attenuated the oncogenic effects of PDRG1, whereas EZH2 overexpression rescued the impaired malignant phenotypes caused by PDRG1 knockdown. Domain-mapping further indicated that the N-terminal residues 36-70 of PDRG1 contribute to its interaction with EZH2. Collectively, our findings identify PDRG1 as a clinically relevant oncogene in HCC and reveal an epigenetic mechanism by which PDRG1 cooperates with EZH2 to repress p21 and bypass senescence. The PDRG1-EZH2-p21 axis may represent a potential biomarker and therapeutic target for HCC.
Piezo1-Fstl1 Axis in Fracture Healing: Modulation of the Chondrocyte Inflammation-ROS-Mitochondrial Damage Cascade and Application of Smart Delivery System.
Zhang T, Wang H, Hou G … +11 more , Jia S, Ding K, Xiao Q, Liu J, Dai Y, Lv G, Hou Z, Zhang Y, Wang J, Lv H, Chen W
Int J Biol Sci · 2026 · PMID 41943852 · Full text
This study investigated the regulatory role of an intelligent drug delivery system in promoting fracture healing via Piezo1-Fstl1 signaling axis. It also verified its modulation of chondrocyte inflammatory response, mito...
This study investigated the regulatory role of an intelligent drug delivery system in promoting fracture healing via Piezo1-Fstl1 signaling axis. It also verified its modulation of chondrocyte inflammatory response, mitochondrial oxidative stress, and osteoblast differentiation. Inflammation triggers the accumulation of pro-inflammatory factors, and reactive oxygen species (ROS) in chondrocytes. This leads to oxidative damage in mitochondria, a decrease in mitochondrial membrane potential (MMP), and the induction of mitochondrial permeability transition pore (mPTP) opening, thereby hindering fracture healing. Single-cell RNA sequencing revealed that Piezo1 deficiency markedly upregulated the expression of follistatin-like protein 1 (Fstl1) in chondrocytes. This upregulation exacerbated chondrocyte inflammation and impaired the chondrocyte-to-osteoblast differentiation. Inhibition of Fstl1 attenuated the inflammatory response and ROS accumulation associated with Piezo1 deficiency, alleviated mitochondrial oxidative stress, and improved mitochondrial function and homeostasis. It also restored mitochondrial cristae ultrastructure, thereby improving MMP and mitochondrial activity. This intervention concurrently upregulated osteogenic markers and accelerated endochondral ossification. Based on these, we developed a HA-PBA/TA self-healing hydrogel incorporating chondrocyte-targeting lipid nanoparticles (C-LNP) to suppress Fstl1 expression. Local injection of this hydrogel into murine femoral fracture sites significantly reduced inflammatory cytokines in callus tissue and promoted fracture healing, offering new insights and therapeutic strategies for fracture treatment.
FAM177A1 disrupts SIRT3-SOD2 signaling to drive mitochondrial dysfunction-mediated VSMC phenotypic switching in vascular remodeling.
Mao R, Guo Y, Jiang L … +10 more , Bu S, Chen M, Liang M, Gao X, Wu Y, Xu W, Chen Z, Huang K, Li X, Wang C
Int J Biol Sci · 2026 · PMID 41943851 · Full text
AIMS: Vascular remodeling involves structural and functional vascular changes in response to injury, aging, and disease. A key pathological feature is vascular smooth muscle cells (VSMCs) phenotypic switching, which is a...
AIMS: Vascular remodeling involves structural and functional vascular changes in response to injury, aging, and disease. A key pathological feature is vascular smooth muscle cells (VSMCs) phenotypic switching, which is accompanied by mitochondrial dysregulation. Metabolic reprogramming resembling the Warburg effect alongside mitochondrial oxidative damage collectively drive this pathological VSMC transdifferentiation. We hypothesized that targeting mitochondrial ROS could restore mitochondrial integrity and enhance oxidative phosphorylation (OXPHOS) to counteract both oxidative damage and metabolic reprogramming in cardiovascular diseases associated with vascular remodeling. We proposed that the uncharacterized membrane-associated protein FAM177A1 drives VSMC mitochondrial oxidative impairment and metabolic reprogramming, thereby promoting VSMC phenotypic switching and vascular dysfunction. METHODS AND RESULTS: We modeled vascular remodeling using global knockout rats subjected to carotid balloon injury, VSMC-specific AAV-mediated knockdown in carotid artery ligation mice, and using mice fed a 12-week high-fat diet to induce atherosclerosis; in vitro VSMCs with platelet-derived growth factor-bb (PDGF-BB) stimulation further elucidated FAM177A1's role in phenotypic switching. FAM177A1 expression was significantly elevated in injured and atherosclerotic aortas, while its deficiency suppressed neointimal hyperplasia and atherosclerosis development. FAM177A1 deficiency upregulated mitochondrial functional genes, enhanced mtDNA biogenesis, reduced ROS accumulation, maintained redox homeostasis, and preserved mitochondrial membrane potential (ΔΨm). Moreover, FAM177A1 deficiency enhanced oxidative phosphorylation (OXPHOS) while reducing glycolytic flux, thereby improving bioenergetic efficiency and promoting a contractile phenotype. Molecular analysis revealed that FAM177A1 disrupted SIRT3-SOD2 binding, leading to elevated SOD2 K68 acetylation which decreased SOD2 activity and stability. Under pathological condition, this dysregulated cascade increased mitochondrial ROS, impaired mitochondrial function, thereby accelerating VSMC phenotypic switching. CONCLUSION: We identify FAM177A1 as a key mitochondrial regulator that drives VSMC switching through SIRT3-SOD2 axis disruption. Targeting FAM177A1 restores redox-metabolic homeostasis through scavenging ROS and improving OXPHOS, establishing it as a novel therapeutic target against vascular remodeling.
Mitochondria transfer in tissue homeostasis and diseases.
Qin L, Gan D, Chen Z … +8 more , Xu Z, Wu M, Gao B, Long Y, Mou X, Li W, Yi W, Xiao G
Int J Biol Sci · 2026 · PMID 41943850 · Full text
Mitochondria serve as the essential powerhouse for virtually all eukaryotic cells and have been implicated in other crucial functions in both physiological and disease contexts. As cytoplasmic organelles, mitochondria ar...
Mitochondria serve as the essential powerhouse for virtually all eukaryotic cells and have been implicated in other crucial functions in both physiological and disease contexts. As cytoplasmic organelles, mitochondria are segregated and transported from parent to daughter cells during division or differentiation, a process known as vertical mitochondria transfer (VMT). A growing body of literature indicates that various cell types can export mitochondria for delivery to developmentally unrelated cell types without division, a process termed horizontal mitochondria transfer (HMT). In this review, we summarize current understanding of the modes of mitochondria transfer and illustrate the phenomenon of HMT across different tissue backgrounds, including the immune, cardiovascular, respiratory, hepatic, renal, musculoskeletal, adipose, and reproductive systems. Moreover, updated applications and functions of mitochondria transfer are discussed. Additionally, we also highlight the therapeutic potential of mitochondria transfer in current preclinical and clinical trials for inherited mitochondrial diseases, cancer, wound healing, and injuries of the respiratory and central nervous systems.
Caffeic Acid Modulates Protein Disulfide Isomerase-NLRP3 Inflammasome Signaling to Mitigate Inflammation in Acute Pneumonia.
Li G, Yang T, Zhang Y … +9 more , Ma A, Zhou L, Wang C, Gao P, Liu C, Zhang J, Zhu YH, Tang H, Wang J
Int J Biol Sci · 2026 · PMID 41943849 · Full text
Caffeic acid (CA) is a polyphenol found in various of plants and daily beverages including coffee. It possesses diverse biological effects, including anti-inflammatory properties. Acute pneumonia represents a widespread...
Caffeic acid (CA) is a polyphenol found in various of plants and daily beverages including coffee. It possesses diverse biological effects, including anti-inflammatory properties. Acute pneumonia represents a widespread inflammatory process; however, whether CA can mitigate acute pneumonia and its specific molecular mechanisms remain elusive. Here, we have demonstrated the robust anti-inflammatory effect of CA both and . Additionally, protein disulfide isomerase (PDI) was identified as a potential target of CA via activity-based protein profiling strategy coupled with a chemical probe of CA. Moreover, CA was found to covalently bind to PDI through cysteine sites. Subsequent and experiments further revealed the inhibition of PDI-mediated NLRP3 inflammasome signaling constituted the specific mechanism through which CA exerts anti-inflammatory effect. In conclusion, our study elucidates the molecular mechanisms underlying the amelioration of acute pneumonia by CA, providing valuable insights into its potential therapeutic application for inflammation-related diseases.
Targeting STARD10 Alleviates Steatotic Liver Injury by Suppressing YBX1/ACSL1-Mediated Ferroptosis.
Yang Z, Zhang W, Gao W … +9 more , Song J, Kuang H, Hong X, Zhao L, Gou C, Lin Z, Wang Q, Zhang X, Dou K
Int J Biol Sci · 2026 · PMID 41943848 · Full text
INTRODUCTION: Steatotic donor livers exhibit high graft failure rates after transplantation, primarily because of their increased vulnerability to ischemia‒reperfusion injury (IRI), in which ferroptosis serves as a criti...
INTRODUCTION: Steatotic donor livers exhibit high graft failure rates after transplantation, primarily because of their increased vulnerability to ischemia‒reperfusion injury (IRI), in which ferroptosis serves as a critical pathological mechanism. STARD10, an evolutionarily conserved member of the steroidogenic acute regulatory lipid transfer (START/StARd) domain-containing protein family, is a hepatic-enriched lipid transport protein that mediates phospholipid transport and modulates plasma membrane composition and fluidity. However, the role of STARD10 in hepatic IRI under steatotic conditions and its potential direct relationship with ferroptosis-driven lipid peroxidation remain poorly understood. METHODS: The correlation between STARD10 expression and the severity of liver injury was first assessed in clinical liver transplant recipients. A mouse model of metabolic dysfunction-associated steatotic liver disease (MASLD) was established using a high-fat diet (HFD), followed by the induction of hepatic IRI. Hepatic STARD10 expression was modulated through adeno-associated virus serotype 8 (AAV8)-mediated delivery and CRISPR/Cas9. Liver injury was evaluated by histopathological examination, serum transaminase assays, and inflammatory response profiling. Mechanistic insights were obtained through integrated multiomic analyses, including lipidomics, transcriptomics, co-immunoprecipitation followed by mass spectrometry (IP-MS), and functional validation studies, which collectively elucidated the role of STARD10 in promoting IRI in steatotic livers. RESULTS: STARD10 expression is significantly upregulated in steatotic donor livers and is positively correlated with the severity of ischemia-reperfusion injury after transplantation. In murine models, hepatocyte-specific knockout of STARD10 markedly attenuated IRI-induced hepatic pathology, including necrosis, inflammation, apoptosis, and reactive oxygen species generation, whereas its overexpression exacerbated these injuries. Interestingly, STARD10 deficiency suppressed ferroptosis, as indicated by diminished accumulation of polyunsaturated fatty acid-containing sphingolipids rather than phospholipids, reduced iron deposition, and improved mitochondrial function. Mechanistically, loss of STARD10 promoted the nuclear translocation of Y-box binding protein 1 (YBX1), which bound to the promoter region of and transcriptionally repressed acyl-CoA synthetase long-chain family member 1 (ACSL1). The subsequent downregulation of ACSL1 led to decreased levels of long-chain polyunsaturated sphingolipids and attenuated lipid peroxidation, thereby inhibiting the ferroptosis cascade. Finally, the overexpression of ACSL1 largely abolished the protective effects of STARD10 knockout against IRI and ferroptosis in steatotic livers. CONCLUSION: Our study revealed that STARD10 is a key inducer of steatotic liver IRI via the YBX1-ACSL1 signaling axis. Targeting this pathway presents a novel therapeutic strategy to protect marginal livers from transplantation-associated injury.
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