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         headline:Histidine phosphatase-ferroptosis crosstalk modulation for efficient hepatocellular carcinoma treatment
         description:Altering the mechanisms of tumor cell death and overcoming the limitations of traditional chemotherapy is pivotal to contemporary tumor treatment. Inducing ferroptosis, while circumventing safety concerns associated with ferrous vectors, through nonferrous ferroptosis is a promising but underexplored frontier in cancer therapy. Histidine phosphatase (LHPP) has emerged as a novel therapeutic target in treating hepatocellular carcinoma (HCC), but the precise mechanism of LHPP against HCC remains unclear. Herein, we explore the effects of upregulating LHPP expression on ferroptosis and tumor immunogenicity induction by simply delivering a miRNA-363-5p inhibitor (miR-363-5pi) via a previously optimized gemcitabine-oleic acid (GOA) prodrug. Efficient miRNA encapsulation was achieved through hydrogen bonding at an optimized GOA/miRNA molar feed ratio of 250:1, affording spherical nanoparticles with a uniform hydrodynamic size of 147.1 nm and a negative potential of -21.5 mV. The mechanism of this LHPP-ferroptosis crosstalk is disclosed to be an inhibited phosphorylation of the PI3K/Akt pathway, leading to a remarkable tumor inhibition rate of 88.2% in nude mice bearing Bel-7402 tumor xenografts via a combination of LHPP-triggered nonferrous ferroptosis and GOA-induced chemotherapy. The biocompatibility of GOA/miR-363-5pi is strongly supported by their non-hematologic toxicity and insignificant organ damage. In addition, the tumor immunogenic activation potential of GOA/miR-363-5pi was finally explored. Overall, this study is the first work that elucidates the precise mechanism of LHPP for treating HCC via ferroptosis induction and achieves the transformation of chemotherapy and gene therapy into ferroptosis activation with tumor cell immunogenicity, which lays a new therapeutic foundation for the clinical treatment of HCC.
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            Gemcitabine prodrug
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      headline:Histidine phosphatase-ferroptosis crosstalk modulation for efficient hepatocellular carcinoma treatment
      description:Altering the mechanisms of tumor cell death and overcoming the limitations of traditional chemotherapy is pivotal to contemporary tumor treatment. Inducing ferroptosis, while circumventing safety concerns associated with ferrous vectors, through nonferrous ferroptosis is a promising but underexplored frontier in cancer therapy. Histidine phosphatase (LHPP) has emerged as a novel therapeutic target in treating hepatocellular carcinoma (HCC), but the precise mechanism of LHPP against HCC remains unclear. Herein, we explore the effects of upregulating LHPP expression on ferroptosis and tumor immunogenicity induction by simply delivering a miRNA-363-5p inhibitor (miR-363-5pi) via a previously optimized gemcitabine-oleic acid (GOA) prodrug. Efficient miRNA encapsulation was achieved through hydrogen bonding at an optimized GOA/miRNA molar feed ratio of 250:1, affording spherical nanoparticles with a uniform hydrodynamic size of 147.1 nm and a negative potential of -21.5 mV. The mechanism of this LHPP-ferroptosis crosstalk is disclosed to be an inhibited phosphorylation of the PI3K/Akt pathway, leading to a remarkable tumor inhibition rate of 88.2% in nude mice bearing Bel-7402 tumor xenografts via a combination of LHPP-triggered nonferrous ferroptosis and GOA-induced chemotherapy. The biocompatibility of GOA/miR-363-5pi is strongly supported by their non-hematologic toxicity and insignificant organ damage. In addition, the tumor immunogenic activation potential of GOA/miR-363-5pi was finally explored. Overall, this study is the first work that elucidates the precise mechanism of LHPP for treating HCC via ferroptosis induction and achieves the transformation of chemotherapy and gene therapy into ferroptosis activation with tumor cell immunogenicity, which lays a new therapeutic foundation for the clinical treatment of HCC.
      datePublished:2024-10-15T00:00:00Z
      dateModified:2024-10-15T00:00:00Z
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         LHPP
         Gemcitabine prodrug
         miRNA inhibitor
         Biotechnology
         Nanotechnology
         Molecular Medicine
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      address:
         name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
         type:PostalAddress
      name:University of South China
      address:
         name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
         type:PostalAddress
      name:Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine
      address:
         name:Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha, China
         type:PostalAddress
ImageObject:
      url:https://www.springernature.com/app-sn/public/images/logo-springernature.png
Person:
      name:Yang Qin
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Xiaoli Ling
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Yunxian Li
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Jieqiong Wang
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Jiaqi Wang
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Zhuoyi Rong
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Yao Cheng
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Zhenghao Tao
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      name:Haitao Zhang
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Hua Wei
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Cui-Yun Yu
      affiliation:
            name:University of South China
            address:
               name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
               type:PostalAddress
            type:Organization
            name:Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine
            address:
               name:Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha, China
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Pharmaceutical and Biomedical Polymers Research Laboratory, Institute of Pharmacy & Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, School of Pharmaceutical Science & MOE Key Lab of Rare Pediatric Disease, Hengyang Medical School, University of South China, Hengyang, China
      name:Affiliated Hospital of Hunan Academy of Chinese Medicine, Hunan Academy of Chinese Medicine, Changsha, China

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