*Purpose: HCC is the second and fastest-growing cause of cancer- related mortality worldwide, with an estimate of 0.84million cases/year. In the Western countries, due to the epidemic of obesity, NASH has become the major cause of HCC and liver transplantation. Intriguingly, the molecular mechanisms that underpin the tumorigenesis of HCC from NASH are largely unknown.

*Methods: Expression of Cav-1/SMAC/Survivin proteins was performed by confocal-microscopy on immuno-stained human HCC cell lines (Hep3b & SNU475), livers from a NASH-HCC rodent model, and tissue from human patients. Liver tissue from human subjects included normal liver (n=10), NASH (n=20), NASH-HCC (n=11) and liver metastases (n=12). Signaling pathway studies guided by mRNA sequencing were explored in-vitro. Selective blockage of pSrc at its kinase domain was performed by administration of a synthetic peptide (pNaKtide= 33aa, developed from the N-domain of the α1-subunit of the Na/K-ATPase). Significant differences among groups were accepted at p<0.05 using ANOVA/t-test.

*Results: Here we show that in NASH-related malignancy, caveolar Src- phosphorylation at the α1-Na/K-ATPase (NKA) causes upregulation of the anti-apoptotic protein survivin and downregulation of the proapoptotic protein SMAC, via the activation of the PI3K → Akt pro-survival pathway with concomitant inhibition of the FoxO cascade, favoring cell division and primary liver carcinogenesis. pNaKtide resets the apoptotic “switch” from off-to-on in malignant cells, attenuating cancer progression and reducing liver fibrosis.

*Conclusions: Src-phosphorylation at the α1-NKA modulated Survivin/SMAC expressions, and its blockage resulted in a cellular “switch” from cellular division to apoptosis, characteristics of a tumor suppressor and a putative target for clinical HCC therapy.

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