Loss of hepatocyte PI3Kα reduces hepatocellular carcinoma and hepatocyte proliferation in association with altered lipid metabolism.
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Becattini B, Sardi C, Edelbroek B, Chand Gupta A, Parris T, Helou K, Solinas G
JHEP Rep 8 (7) 101847 [2026-07-00; online 2026-04-15]
Hepatocellular carcinoma (HCC) is a disease with an increasing incidence and a high mortality rate. Thus, targeted therapies for HCC are urgently needed. Phosphoinositide 3-kinase (PI3K)-AKT-mTORC1 signaling is frequently induced in solid tumors and is associated with tumor progression and with the most aggressive type of HCC. However, complete inhibition of all PI3K isoforms is unlikely to achieve a favorable therapeutic index for HCC treatment because of on-target side effects. In this study, we determined the role of hepatocyte PI3Kα activity in HCC. We investigated the role of hepatocyte PI3Kα in HCC using conditional knockout mice in the N-nitrosodiethylamine (DEN) plus high-fat diet (HFD) model of HCC. Mice lacking PI3Kα in hepatocytes were protected from DEN-induced HCC (n = 8-17, p <0.005). PI3Kα in hepatocytes was dispensable for AKT phosphorylation in HCC and normal liver (n = 4). It was also dispensable for AKT phosphorylation in hepatocytes during compensatory proliferation following acute administration of the hepatocarcinogen (n = 3-4). AKT phosphorylation induced by hepatocyte growth factor (HGF) and epidermal growth factor (EGF) was mediated by redundant PI3Kα and PI3Kβ activities (n = 3-4). Nonetheless, mice lacking hepatocyte PI3Kα showed reduced HCC proliferation and reduced hepatocyte proliferation acutely induced by DEN and by HGF and EGF (n = 3, p <0.05). This phenotype was associated with a gene expression signature indicating altered lipid metabolism and reduced formation of lipid droplets (n = 7). Together, these results indicate PI3Kα as a promising target for the treatment of HCC. Class-1 PI3Ks are frequently activated in tumors, but complete inhibition of PI3K signaling is associated with liver damage and HCC. We showed that selective ablation of the PI3Kα isoform in hepatocytes drastically reduced HCC development in mice injected with a hepatocarcinogen. This phenotype was associated with reduced hepatocyte proliferation and a gene expression signature indicative of altered lipid metabolism and reduced lipid droplet formation. Overall, our results indicate PI3Kα as a promising drug target for the treatment of HCC.
Clinical Genomics Gothenburg [Service]
PubMed 41997233
DOI 10.1016/j.jhepr.2026.101847
Crossref 10.1016/j.jhepr.2026.101847
pmc: PMC13310634
pii: S2589-5559(26)00118-7