PPM1G‒MET axis sustains AKT signaling to drive Twist‐associated EMT and drug resistance in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) frequently exhibits resistance to multikinase inhibitors (MKIs) such as sorafenib and lenvatinib, limiting durable therapeutic responses. We identified protein phosphatase Mg 2+ /Mn 2+ ‐dependent 1G (PPM1G), a serine/threonine phosphatase, as a key regulator of oncogenic signaling and MKI resistance in HCC. PPM1G is highly expressed in human HCC tissues and correlates with poor patient prognosis. Genetic silencing of PPM1G suppressed HCC cell proliferation, migration, and the epithelial‒mesenchymal transition (EMT), while sensitizing tumors to sorafenib and lenvatinib in vitro and in vivo. Mechanistically, co‐immunoprecipitation assays revealed that PPM1G physically interacts with the receptor tyrosine kinase mesenchymal‐epithelial transition factor (MET). We found that PPM1G post‐translationally stabilizes MET by reducing its ubiquitination and preventing its proteasomal degradation, thereby prolonging its half‐life and sustaining downstream protein kinase B (AKT) signaling activity associated with Twist‐dependent EMT programs. Restoration of MET abundance rescued AKT activation and EMT markers in PPM1G‐deficient cells, whereas MET knockdown abrogated the protumorigenic effects of PPM1G overexpression. These findings identify PPM1G as a regulator of a signaling network involving MET, AKT, and Twist that contributes to tumor progression and therapeutic resistance. Targeting this phosphatase‐related mechanism may help improve the efficacy of kinase‐directed therapies in HCC.