KEY driver of liver cancer growth identified in a new study suggests that a mitochondrial protein may play a central role in reprogramming how cells store and utilise glycogen, highlighting a previously underappreciated metabolic pathway in cancer development and offering a potential new therapeutic target for hepatocellular carcinoma (HCC).

The findings indicate that disruptions in glycogen metabolism are not merely a by-product of tumour growth but may actively contribute to disease progression. This raises the possibility that targeting metabolic pathways involved in glycogen storage and regulation could represent a novel and more precise treatment strategy for HCC, particularly in cases where current therapeutic options remain limited.

AKAP1 Identified as Key Regulator of Glycogen-Driven Liver Cancer Progression

Currently, the molecular mechanism underpinning glycogen dysregulation is largely unknown. Research from Yang et al. using liver specific AKAP1 depletion and overexpression mouse models demonstrated that AKAP1 deficiency reduced hepatic glycogen content and subsequently suppressed HCC. Equally, AKAP1 overexpression promoted spontaneous hepatocarcinogenesis through promoting glycogen accumulation.

It was found that AKAP1 promoted HCC progression by triggering the breakdown of mRNA through an RNA modification pathway involving YTH proteins. This was an effect driven by AKAP1-dependent phosphorylation signalling via PKA, ultimately leading to an increased glycogen accumulation and tumour growth in the liver. In HCC cells, AKAP1 expression was found to be transcriptionally upregulated by Myc-associated zinc-finger protein (MAZ).

Targeting AKAP1 Activity Suppresses Tumour Growth in Preclinical Models Of HCC

When treated with a competitive peptide inhibitor that disrupts mitochondrial localisation of AKAP1, glycogen content significantly decreased and hepatocarcinogenesis was suppressed without observable toxicity. These findings suggest that interfering with AKAP1 activity can effectively reverse the metabolic changes that support tumour growth.

Overall, the study positions AKAP1 as a central regulator of glycogen metabolism in liver cancer and a potential therapeutic target for HCC. With findings based on preclinical models, the authors suggest that targeting metabolic reprogramming pathways could open new avenues for hepatocellular carcinoma treatment, particularly those aimed at disrupting the energy supply that fuels tumour development and progression.

Reference

Yang T et al. AKAP1 enhances glycogen accumulation and hepatocarcinogenesis through YTHDF2-mediated G6PC mRNA decay. Signal Transduct Target Ther. 2026;11:236. DOI:10.1038/s41392-026-02733-1.

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