BONE
·
2022
·
IF 4.626
Miaomiao Bie,Yi Tang,Yuxing Xia,Qian Zhang,Yuanye Tian,Chunan Cheng,Xinzhao Li,Xin Qi,Feiwu Kang
Osteoporosis induced by disuse because of bed rest or the aerospace industry has become one of the most common skeletal disorders. However, mechanisms underlying the disuse osteoporosis remain largely unknown. We validated the tail-suspended model in mice and demonstrated that there is bone loss in the trabecular and cortical bones of the femur. Importantly, we showed that genetical deletion of hypoxia-inducible factor-1α (HIF-1α) in osteoclasts ameliorated osteoclastic bone resorption in the trabecular bone whereas pharmacological treatment with HIF-1α inhibitor protected the hindlimb-unloaded mice from disuse-induced osteoporosis in the trabecular and cortical bones. The HIF-1α knockout RAW264.7 cells and RNA-sequencing proved that HIF-1α is vital for osteoclastogenesis and bone resorption because it regulated the level of inosine monophosphate dehydrogenase (IMPDH) and cytidine triphosphate synthetase (CTPS) via cellular myelocytomatosis (c-Myc) oncogene. The IMPDH and CTPS are vital nucleotide metabolic enzymes which have an important functional role in cell metabolism, and they can assemble into intracellular linear or ring-shaped structures to cope with cell stress. Interestingly, both in vitro and in vivo, the IMPDH and CTPS cytoophidia were found in osteoclasts, and the level of HIF-1α correlated with osteoclastogenesis and bone-resorbing activity. Our data revealed that HIF-1α/c-Myc/cytoophidia signalling might be required for osteoclasts to mediate cell metabolism in disuse-induced osteoporosis. Overall, our results revealed a new role of HIF-1α/c-Myc/cytoophidia in supporting osteoclastogenesis and bone resorption and exposed evidence for its role in the pathogenesis of disuse osteoporosis, which might provide promising therapeutic targets.
研究领域:
骨科
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分子生物学
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细胞生物学
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高影响因子
FEBS Journal
·
2026
·
IF 4.2
Baopeng Tian,Jie Shen,Xuanning Chu,Yannan Zhou,Hao Li,Lei Wang,Min Guo,Jie Dou
Mitophagy, the process of removing mitochondria through the autophagy–lysosome pathway, is crucial for maintaining cellular homeostasis. However, its regulatory mechanisms and pathological implications remain poorly understood. In our study, we revealed that decidual protein induced by progesterone (DEPP) plays a significant role in mitophagy through the DEPP–HIF-1α–BNIP3/NIX axis. Our findings indicate that interaction between DEPP and hypoxia-inducible factor 1-alpha (HIF-1α) enhances HIF-1α stability, thereby promoting the transcription of HIF-1 target genes. The enhanced protein stability of HIF-1α not only activates mitophagy by stimulating the transcription of BCL2-interacting protein 3 ( BNIP3 ) and BCL2-interacting protein 3-like ( BNIP3L ; also known as NIX ) mRNA but also influences cellular metabolic reprogramming by promoting the transcription of glycolysis-related genes. In conclusion, our findings suggest that DEPP may act as a potential regulator of mitophagy and HIF-1α, playing an important role in maintaining cellular metabolic and energy homeostasis.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Jie Chen,Dexian Li,Xiaohu Chen,Qiuxing He,Anna Zuo,Baizhao Peng,Ying Yang,Chuanghai Wu,Qinghong Chen,Zihao Jiang,Ziwei Li,Wen Fang,Jingxin Lin,Hiu Yee Kwan,Xiaomin Sun,Lin Zhou,Xiaoshan Zhao
Limonin alleviates hyperuricemia-induced cognitive impairment and neuroinflammation in UOX −/− rat models. • Limonin exerts neuroprotective effects by inhibiting microglial activation and subsequent neuronal apoptosis. • Limonin modulates the HIF-1α/iNOS pathway to exert anti-inflammatory and neuroprotective effects. Background Hyperuricemia (HUA), a highly prevalent metabolic disorder, is increasingly linked to cognitive impairment. Limonin (LIM), a natural compound with anti-inflammatory and neuroprotective properties, has the therapeutic benefits, but its underlying mechanisms remain unclear. Purpose This study aimed to investigate the therapeutic effect and mechanism of LIM on HUA-induced cognitive impairment. Methods A rat model of HUA-induced cognitive impairment was established using urate oxidase gene knockout (UOX −/− ) rat. Uric acid (UA) levels of serum and cerebrospinal fluid (CSF) were measured to confirm hyperuricemia. Cognitive function was assessed using morris water maze test, while neuronal morphology and synaptic integrity were evaluated via Nissl staining and synaptic plasticity biomarkers. Microglial activation and polarization were examined through double immunofluorescence staining of CD86/IBA1 and ARG1/IBA1, inflammatory and oxidative stress markers were quantified using ELISA, qRT-PCR and Western blot. In vitro , BV2 microglial cells were stimulated with UA to model activation and inflammatory responses. HT22 neuronal cells were co-cultured using conditioned medium to assess apoptosis via TUNEL assay and expression of apoptosis-related biomarkers. RNA sequencing was performed to identify key signaling pathways modulated by LIM, and the findings were validated through targeted gene overexpression or inhibition experiments. Results The UOX −/− rat model successfully recapitulated HUA-induced cognitive impairment, as evidenced by elevated UA levels, alongside significant cognitive deficits. LIM treatment ameliorated these cognitive impairments, attenuated neuropathological alterations, modulated microglial M1/M2 polarization, and reduced neuroinflammation and oxidative damage. In vitro , LIM suppressed UA-induced microglial activation and inflammatory response, while also rescuing neuronal apoptosis in HT22 cells. RNA sequencing revealed involvement of the HIF-1 pathway. HIF-1α inhibitor YC-1 enhanced LIM's effects, whereas HIF-1α activator DMOG reversed them, suggesting that the modulation of the HIF-1α/iNOS pathway contributes to redox homeostasis and neuroinflammation. Conclusion LIM ameliorates HUA-induced cognitive impairment by suppressing microglial activation and neuroinflammation, which is associated with the inhibition of the HIF-1α/iNOS signaling pathway, underscoring its therapeutic potential. Download: Download high-res image (110KB) Download: Download full-size image
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Chinese Medicine
·
2026
·Vol. 21
·期 1
·154
·
IF 7.4
Ding Wei,Zhang Ni,Xiao Lei,Yu Le,Wu Tian-Shi,Feng Yuan-Jie,Chen Wei
Background Hypertrophic cardiomyopathy (HCM) is often complicated by coronary microvascular dysfunction (CMD), which precipitates localized myocardial ischemia and metabolic disturbance, triggering compensatory cardiomyocyte hypertrophy. This hypertrophy, in turn, exacerbates microvascular insufficiency, forming a pathological feedback loop and culminating in persistent cellular stress, inflammatory infiltration, and myocardial fibrosis. This “ischemia–hypertrophy–inflammation–fibrosis” interrelationship not only drives pathological remodeling but also significantly elevates the risk of heart failure, arrhythmias, and adverse prognosis. The traditional formula Huayu Qutan Formula (HYQT), used clinically for years, has been shown to significantly enhance cardiac function in HCM patients. However, its underlying mechanisms remain poorly elucidated. This study aims to explore HYQT’s therapeutic effects on HCM and to reveal its intrinsic mechanisms. Methods Blood-absorbed constituents of HYQT were identified using UHPLC-MS, followed by network pharmacology analysis and molecular docking to predict potential targets and key signaling pathways. An isoproterenol (ISO)-induced HCM mouse model, along with parallel in vitro injury models using H9C2 cardiomyocytes and human cardiac microvascular endothelial cells (HCMECs), was established to systematically assess the in vivo and in vitro effects of HYQT. To comprehensively evaluate HYQT’s modulation of myocardial hypertrophy, fibrosis, and angiogenesis, echocardiography, laser speckle perfusion imaging, immunohistochemistry, western blotting, reactive oxygen species (ROS) assays, and wound-healing assays were performed. Results UHPLC-MS analysis identified 31 blood-absorbed bioactive components of HYQT. Integrated network pharmacology and molecular docking analyses identified the MAPK and HIF-1α-signaling pathways as key therapeutic targets. In ISO-induced HCM mice, HYQT significantly improved cardiac morphology and function, reduced hypertrophic markers (ANP and BNP), inhibited myocardial collagen deposition, attenuated fibrosis, restored microvascular perfusion and density, and suppressed oxidative stress (MDA and ROS) and pro-inflammatory cytokine expression (TNF-α and IL-6). Mechanistically, in vitro experiments supported a cell-type–resolved, parallel regulatory effect: in HCMECs, HYQT-containing serum enhanced migration and viability, reduced ROS accumulation, and activated HIF-1α/VEGF-mediated angiogenic signaling, thereby alleviating microvascular dysfunction; concurrently, in H9C2 cardiomyocytes, HYQT inhibited phosphorylation of ERK, p38, and JNK, restored mitochondrial membrane potential, and reduced cell death, thereby mitigating hypertrophic remodeling and its downstream fibrotic progression. Conclusion HYQT effectively ameliorates key pathological features of HCM, including myocardial hypertrophy, fibrosis, and microvascular dysfunction. As a clinically used herbal formulation, this study provides mechanistic insight into its therapeutic effects by revealing a cell-type–resolved, myocardium–microvasculature regulatory framework. Specifically, HYQT suppresses MAPK signaling to attenuate cardiomyocyte hypertrophy while enhancing HIF-1α–mediated angiogenesis to improve the microvascular environment. These simultaneous effects are associated with mitigation of pathological cardiac remodeling, suggesting that HYQT may serve as a promising multi-target therapeutic strategy for HCM.
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FASEB JOURNAL
·
2026
·Vol. 40
·期 14
·e72154
·
IF 4.3
Ya‐Ping Li,Fei‐Hong Huang,Meng‐Ting Wu,Meng‐Yi Chen,Yong‐Ping Wen,Xiang Li,Lu Yu,An‐Guo Wu,Jian‐Ming Wu,Xiao‐Gang Zhou
Ferroptosis contributes to aging‐associated functional decline, yet compounds with robust organismal efficacy and defined upstream regulatory mechanisms remain limited. Here, we established a diethyl maleate (DEM)‐induced glutathione depletion model in wild‐type (N2) Caenorhabditis elegans as a survival‐based screening platform and identified syringaresinol (Syr) as a leading hit from an in‐house small‐molecule library. In nematodes, Syr improved survival under DEM challenge, reduced lipid peroxidation, reactive oxygen species (ROS), and malondialdehyde levels, and alleviated age‐associated oxidative lipid stress and iron imbalance during natural aging, accompanied by extended lifespan and improved healthspan‐related phenotypes. In primary human foreskin fibroblasts, Syr conferred dose‐dependent protection against RSL3‐ or erastin‐induced ferroptosis, preserved cellular integrity, suppressed lipid peroxidation and ROS, and restored expression of GPX4, SLC7A11, and ferritin. In two senescence models, Syr also attenuated senescence‐associated phenotypes and ferroptosis‐related oxidative lipid stress, concomitant with recovery of GPX4 expression. Network‐based prediction and functional perturbation identified HIF‐1α as a candidate mediator of Syr‐associated cytoprotection. HIF‐1α knockdown weakened Syr‐mediated protection and largely prevented GPX4 restoration, whereas GPX4 knockdown did not alter HIF‐1α abundance. These findings support a functional HIF‐1α–GPX4 defense axis in fibroblasts, while direct transcriptional regulation remains to be clarified. Overall, Syr attenuates ferroptosis‐relevant oxidative lipid stress and aging‐associated phenotypes in C. elegans and human fibroblast models, supporting further mechanistic and mammalian in vivo validation. A 220‐compound screen in DEM‐challenged C. elegans identified syringaresinol (Syr) as a lead protective compound. Syr alleviated aging‐ and ferroptosis‐associated phenotypes in C. elegans and human foreskin fibroblasts by reducing lipid peroxidation, ROS accumulation, MDA levels, labile Fe 2+ , cell death, and SA‐β‐gal activity, while restoring GPX4/SLC7A11/ferritin‐associated defense responses. The proposed mechanism suggests that Syr attenuates senescence‐associated functional decline through a HIF‐1α‐associated GPX4 protective axis. The dashed arrow denotes a hypothesized mediator or interaction that remains to be experimentally validated.
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CELLULAR SIGNALLING
·
2025
·
IF 3.7
Jiaoquan Chen,Hui Zou,Bihua Liang,Yeqing Gong,Shaoyin Ma,Runxiang Li,Jiacong Zeng,Chao Bi,Huilan Zhu
Drug resistance poses a significant challenge in the clinical management of melanoma, primarily driven by the hypoxic tumor microenvironment. This study aims to elucidate the molecular mechanisms underlying drug resistance in melanoma under hypoxic conditions. Exosomes were isolated from melanoma cells cultured under normoxic (Nor-exos) and hypoxic (Hypo-exos) environments. The proliferative capacity of tumor cells was assessed using CCK-8 and colony formation assays, while relevant molecular expressions were evaluated through qPCR, Western blotting, immunofluorescence, and immunohistochemistry. Additionally, mitochondrial damage was examined via transmission electron microscopy, and reactive oxygen species (ROS) levels were quantified using flow cytometry. Xenograft models further facilitated the investigation into the molecular mechanisms of drug resistance. Hypo-exos promote drug resistance in melanoma cells by inhibiting ferroptosis; mechanistically, Hypo-exos inhibiting p53 and OTUB1 expression through HIF-1α transfer. Furthermore, OTUB1 enhances SLC7A11 stability, thereby reducing ferroptosis levels and fostering drug resistance in melanoma. Our findings indicate that Hypo-exos inhibit ferroptosis to augment drug resistance in melanoma by delivering HIF-1α to modulate the p53/OTUB1/SLC7A11 axis. Exosomal HIF-1α may represent a promising biomarker and therapeutic target for addressing drug resistance in melanoma.
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ENVIRONMENTAL POLLUTION
·
2022
·
IF 9.988
Jiawei Huang,Yunqiu Pu,Kai Xu,Qin Ding,Rongli Sun,Lihong Yin,Juan Zhang,Yuepu Pu
Benzene exposure can cause pancytopenia and immunosuppression , leading to serious diseases such as aplastic anemia (AA) or acute myeloid leukemia (AML), but the underlying mechanism has not been fully elucidated. Hypoxia-inducible factor 1 (HIF-1) is an important transcription factor that regulates many downstream target genes. In this study, we reported a novel mechanism by which high expression of HIF-1α alleviated benzene toxicity. Mice with high expression of HIF-1α (HIF-1α + ) were obtained by the Tet-on system and doxycycline induction, and they and wild-type (WT) mice were exposed to 150 mg/kg benzene for 0, 1, 3, 7, 10, 14, and 28 days. Dynamic changes in hematopoietic and immune-related indicators and the role of HIF-1α were explored. The level of white blood cells in mice reached the highest level on the third day, and immunity was activated and then suppressed within 10 days. Significant pancytopenia and immunosuppression occurred at 14 days and were more pronounced at 28 days. The levels of HIF-1α, EPO, VEGF, RORγt, and IL-17 in WT mice gradually decreased with increasing benzene exposure days, while the levels of Foxp3 and IL-10 increased. These changes were alleviated in HIF-1α + mice. High expression of HIF-1α increased the levels of EPO and VEGF, which helped to maintain the stability of the hematopoietic microenvironment. Simultaneously, it attenuated benzene-induced immunosuppression by alleviating the Th17/Treg imbalance. HIF-1α is expected to be a new target for benzene-induced diseases such as AA and AML.
研究领域:
毒理学
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免疫学
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血液学
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分子生物学
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Bioactive Materials
·
2025
·
IF 20.3
Shengming Zhang,Weixian Hu,Yanzhi Zhao,Yuheng Liao,Kangkang Zha,Wenqian Zhang,Chenyan Yu,Jiewen Liao,Hui Li,Wu Zhou,Faqi Cao,Bobin Mi,Guohui Liu
Fracture healing in patients with type 2 diabetes mellitus (T2D) is markedly impaired, characterized by a prolonged inflammation phase and defective osteoblast differentiation at the fracture site. In this study, we identified aberrant cellular glycolysis at T2D fracture sites, with bone marrow mesenchymal stem cells (BMSCs) exhibiting suppressed glycolysis and macrophages displaying enhanced glycolysis, mediated by the dysregulation of hypoxia-inducible factor-1α (HIF-1α). To rectify these metabolic imbalances, we developed a multifunctional nanocomposite PN@MHV hydrogel. Myricitrin, a flavonoid glycoside, forms the MHV hydrogel by cross-linking with HA-PBA and PVA via hydrogen bonds, and upregulates glycolysis through HIF-1α, thus promoting osteoblast differentiation under high glucose environment. To further regulate the inflammatory microenvironment, we incorporated nanoparticles loaded with PX-478, a HIF-1α specific inhibitor, into the hydrogel, with folic acid covalently modified to target proinflammatory M1 macrophages. This PN@MHV hydrogel bidirectionally regulated glycolysis via HIF-1α, enhancing osteoblast differentiation while attenuating macrophage-mediated inflammation. Comprehensive in vitro and in vivo experiments in a T2D fracture mouse model confirmed the hydrogel's ability to improve the inflammatory microenvironment and accelerate bone healing. Our findings underscore the therapeutic potential of targeting cellular glycolysis as a promising approach for enhancing fracture healing in diabetic patients.
研究领域:
医学
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生物材料学
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代谢生物学
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Journal of Gastrointestinal Oncology
·
2025
·Vol. 16
·期 6
·2703
·
IF 2
Tang Pingfei,Wu Yueming,Tan Lin,Zhang Chao,Qin Liping,Wu Dajun
Background Our preliminary experiments confirmed that follistatin-like 3 (FSTL3) expression is elevated in colorectal cancer (CRC) cells following CoCl 2 treatment. In this study, we investigated the regulatory role of FSTL3 in CRC progression and the molecular mechanisms underlying its high expression. Methods CoCl 2 (150 µM) was used to mimic hypoxia. Cell proliferation was measured by colony formation assay, wound healing assays were performed to assess cell migration, and Transwell assays were performed to evaluate invasion. The glucose metabolism pathways were assessed by detecting extracellular acidification rate, oxygen consumption rate, glucose uptake, and lactate production. The binding sites of zinc finger protein 454 (ZNF454) and FSTL3 gene promoter were analyzed by JASPAR databases, and were confirmed by chromatin immunoprecipitation (ChIP) and luciferase reporter assay. The expression levels of molecules at mRNA and protein levels were determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot, respectively. Results We found that both FSTL3 and hypoxia-inducible factor 1α (HIF-1α) were upregulated in CRC tissues and in CRC cells under hypoxic conditions, with a positive correlation between their expression in clinical samples. Silencing FSTL3 reduced HIF-1α expression and suppressed the expression of glycolytic enzymes (glucose transporter 1, hexokinase 2, lactate dehydrogenase A, and pyruvate kinase muscle isozyme M2). Knockdown of FSTL3 increased oxygen consumption while decreasing extracellular acidification, glucose uptake, and lactate production. Moreover, FSTL3 downregulation markedly inhibited the proliferation, migration, and invasion of CoCl 2 -treated CRC cells. We further identified ZNF454 as a potential transcription factor for FSTL3 and confirmed its binding to the FSTL3 promoter. Upregulation of ZNF454 significantly suppressed CRC cell proliferation, migration, invasion, and glycolysis, effects that were reversed by FSTL3 overexpression. In vivo , ZNF454 overexpression effectively inhibited tumor growth and reduced HIF-1α and glycolytic enzyme expression, whereas these effects were rescued by FSTL3 overexpression. Conclusions Collectively, our findings demonstrate that ZNF454 suppresses CRC development by inhibiting FSTL3/HIF-1α-mediated glycolysis through transcriptional repression of FSTL3. This study is the first to reveal the molecular mechanism responsible for FSTL3 overexpression in CRC, providing a novel perspective for CRC treatment.
研究领域:
肿瘤学
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分子生物学
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癌症代谢
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转录调控
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细胞信号传导
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BIOORGANIC & MEDICINAL CHEMISTRY
·
2021
·
IF 3.641
Zichen Xu,Bin Zhang,Zhixin Liao,Shaohua Gou
Hypoxia is one of the unique features of tumor physiology. Hypoxia inducible factor (HIF-1α), as a major transcription factor in response to hypoxia, has been considered as a promising tumor-specific target for anticancer therapy. The formation of a hypoxic microenvironment in tumors can decrease the curative effect of cytotoxic chemotherapeutic drugs. To promote the antitumor efficacy of chemotherapy by suppressing hypoxia, we designed and prepared a novel gemcitabine-based drug conjugate ( GEM -5 ) containing a HIF-1α inhibitor (YC-1). As expected, GEM -5 showed excellent antiproliferative activity (IC 50 = 0.03 μΜ under hypoxia) and remarkably induced the apoptosis of A2780 cells in vitro . Additionally, western blot analysis demonstrated that GEM -5 significantly down-regulated the expression of HIF-1α and up-regulated the expression of tumor suppressor p53. More importantly, GEM -5 effectively inhibited tumor growth in the A2780 xenograft mouse model and significantly ameliorated tumor hypoxia in vivo . This novel, simple, and effective strategy for overcoming tumor hypoxia and enhancing the antitumor effect of chemotherapeutic drugs has great potential in cancer therapy.
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CURRENT NEUROVASCULAR RESEARCH
·
2022
·Vol. 19
·期 1
·61-72
·
IF 2.294
Xu Shu-Ying,Zeng Chun-Li,Ni Si-Ming,Peng Yong-Jun
Background: Acupuncture has been recommended as an alternative and complementary therapy for preventing and treating cerebral ischemia by the World Health Organization (WHO) for years. However, the mechanisms remain unclear. Accumulating evidence has shown that acupuncture can promote
angiogenesis to attenuate brain damage after ischemic stroke. In recent years, exosome- carried microRNAs (miRNAs) activated by acupuncture have proven effective in regulating pathological changes. We, therefore, investigated whether electro-acupuncture (EA) enhanced angiogenesis in cerebral
stroke via exosome-carried miR-210. Methods: We extracted and identified the exosomes from the serum of MCAO with EA treatment and injected them into MCAO rats for further observation. Simultaneously, miR-120 siRNA and HIF-1α inhibitor were transfected. Then, we evaluated the volume
of infarction, pathological changes, and expression levels of angiogenic related factors of each group of rats by TTC and HE staining, transmission electron microscope (TEM), western blot, and quantitative PCR (qPCR). Results: Compared with the MCAO group, EA-Exosome (EA-EXO) treatment
significantly decreased the infarct volume and the pathological damage, but miR-210 siRNA or HIF-1α inhibitor reversed the protective outcomes induced by EA-EXO. Moreover, EA-EXO treatment upregulated miR-210 and increased CD34, HIF-1α, VEGF, Notch1 protein, and mRNA expressions
compared to the MCAO group. MiR-210 siRNA or HIF-1α inhibitor treatments both down-regulated those angiogenic related proteins and mRNAs. Conclusion: EA treatment could activate the HIF-1α/VEGF/Notch 1 signal pathway to facilitate angiogenesis after ischemic stroke via exosomal
miR-210.
研究领域:
神经科学
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分子生物学
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中医药学
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中风研究
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PubMed
高影响因子
Acta Biomaterialia
·
2026
·
IF 10.4
Jiakun Guo,Jintao Huang,Yan Wang,Juan Sun,Shang Liu,Chao Deng,Jian Lu,Zhiyuan Zhong
Transarterial chemoembolization (TACE) is a primary treatment option for unresectable hepatocellular carcinoma (HCC). Its clinical efficacy is, however, challenged by hypoxic and immunosuppressive tumor microenvironment. Herein, we report that absorbable microspheres (Asphere) with sustained co-delivery of hypoxia-inducible factor 1 (HIF-1) inhibitor, acriflavine (ACF), effectively reverse tumor hypoxia and boost TACE therapy of advanced HCC. Interestingly, Asphere demonstrates nearly quantitative loading of both epirubicin (EPI) and ACF within 1 min, while achieving sustained release of the dual drugs over 8 weeks. EPI/ACF-loaded Aspheres (EA@Asphere) greatly inhibit hypoxia-associated proteins and augment immunogenic cell death in HCC cells under hypoxic conditions, which in turn triggers maturation of dendritic cells (DCs) and secretion of pro-inflammatory cytokines. In H22 murine hepatoma model, EA@Asphere markedly boosts DC maturation, CD8 + T cell infiltration, and macrophage polarization from M2 to M1, achieving complete tumor regression in 2 out of 7 mice. EA@Asphere further blocks tumor vasculature in orthotopic VX2 liver tumor in rabbits, alleviates hypoxia, and suppresses tumor progression and metastasis. Thus, Asphere co-delivering HIF-1 inhibitors holds significant translational potential to boost TACE therapy in advanced HCC. Statement of significance This work introduces an approach to enhance transarterial chemoembolization (TACE) for advanced hepatocellular carcinoma (HCC) by co-delivering HIF-1 inhibitor acriflavine (ACF) and epirubicin (EPI) via absorbable microspheres (Asphere). Asphere demonstrates swift dual drug loading, sustained 8-week release, and simultaneous reversal of hypoxia and immunosuppression, addressing critical challenges of current TACE therapy. In preclinical studies, EA@Asphere significantly suppresses hypoxia-associated protein expression, enhances immunogenic cell death, promotes dendritic cell maturation, and reprograms tumor microenvironment, achieving significant inhibition of the tumor progression and metastasis. These findings offer transformative potential to improve clinical outcomes in advanced HCC, holding broad interest for researchers and clinicians in oncology and drug delivery.
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