Histidine phosphatase-ferroptosis crosstalk modulation for efficient hepatocellular carcinoma treatment.
Animals
Carcinoma, Hepatocellular
/ drug therapy
Liver Neoplasms
/ drug therapy
Ferroptosis
/ drug effects
Humans
Mice, Nude
Mice
Cell Line, Tumor
MicroRNAs
/ metabolism
Mice, Inbred BALB C
Nanoparticles
/ chemistry
Prodrugs
/ pharmacology
Deoxycytidine
/ analogs & derivatives
Gemcitabine
Phosphoric Monoester Hydrolases
/ metabolism
Proto-Oncogene Proteins c-akt
/ metabolism
Xenograft Model Antitumor Assays
Signal Transduction
/ drug effects
Inorganic Pyrophosphatase
Ferroptosis
Gemcitabine prodrug
LHPP
miRNA inhibitor
Journal
Journal of nanobiotechnology
ISSN: 1477-3155
Titre abrégé: J Nanobiotechnology
Pays: England
ID NLM: 101152208
Informations de publication
Date de publication:
15 Oct 2024
15 Oct 2024
Historique:
received:
29
05
2024
accepted:
09
10
2024
medline:
15
10
2024
pubmed:
15
10
2024
entrez:
14
10
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 39402673
doi: 10.1186/s12951-024-02918-2
pii: 10.1186/s12951-024-02918-2
doi:
Substances chimiques
MicroRNAs
0
Prodrugs
0
Deoxycytidine
0W860991D6
Gemcitabine
0
Phosphoric Monoester Hydrolases
EC 3.1.3.2
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
phospholysine phosphohistidine inorganic pyrophosphate phosphatase, human
EC 3.6.1.1
Inorganic Pyrophosphatase
EC 3.6.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
622Subventions
Organisme : Naional Natural Science Foundation of China, China
ID : 82373826
Informations de copyright
© 2024. The Author(s).
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