Abstract 25P
Background
Liver pathogenesis, including metabolic-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC), involves chronic inflammation and fibrosis. Despite the growing incidence, early intervention options for MASH-related HCC are limited. Signal transducer and activator of transcription 3 (STAT3), a key mediator in inflammation and tumorigenesis, presents a potential target to reduce disease progression and tumour development in the liver.
Methods
Recognizing the need for precise interventions, we developed a selective STAT3-targeting RNA interfering oligo duplex as a gene therapy for STAT3-driven cancers. We employed a customized GalNAc conjugation for liver-specific delivery. Using a STAM mouse model, the Stat3-GalNAc agent was administered either before MASH formation or HCC development to evaluate the impact of STAT3 inhibition at different stages of MASH-HCC progression.
Results
The novel siRNA duplex demonstrated specificity in inhibiting STAT3 activity without interfering with other STAT family members, with significant inhibition in clonogenicity in STAT3-driven cancer cell lines. In vivo observation suggests that administration of GalNAc-Stat3 conjugate in the STAM mouse model delayed the onset of hepatocarcinogenesis, while steatosis remained unchanged.
Conclusions
Our research underscores the critical role of precise molecular targeting in cancer therapy and introduces a novel genetic therapeutic strategy to address the limitations of existing RNA-based technologies. By elucidating the impact of STAT3 on liver pathogenesis, we aim to advance the development of effective, personalized treatments to manage MASLD driven HCC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
National University Cancer Institute, Singapore.
Disclosure
All authors have declared no conflicts of interest.