PPDPF suppresses the development of hepatocellular carcinoma through TRIM21-mediated ubiquitination of RIPK1

Pancreatic progenitor cell differentiation and proliferation factor (PPDPF) has been reported to play a role in tumorigenesis. However, its function in hepatocellular carcinoma (HCC) remains poorly understood. In this study, we report that PPDPF is significantly downregulated in HCC and the decreased PPDPF expression indicates poor prognosis. In the dimethylnitrosamine (DEN)-induced HCC mouse model, hepatocyte-specific depletion of Ppdpf promotes hepatocarcinogenesis, and reintroduction of PPDPF into liver-specific Ppdpf knockout (LKO) mice inhibits the accelerated HCC development. Mechanistic study shows that PPDPF regulates nuclear factor κB (NF-κB) signaling through modulation of RIPK1 ubiquitination. PPDPF interacts with RIPK1 and facilitates K63-linked ubiquitination of RIPK1 via recruiting the E3 ligase TRIM21, which catalyzes K63-linked ubiquitination of RIPK1 at K140. In addition, liver-specific overexpression of PPDPF activates NF-κB signaling and attenuates apoptosis and compensatory proliferation in mice, which significantly suppresses HCC development. This work identifies PPDPF as a regulator of NF-κB signaling and provides a potential therapeutic candidate for HCC. [Display omitted] •Decreased expression of PPDPF is associated with poor prognosis of patients with HCC•PPDPF promotes TRIM21-mediated ubiquitination of RIPK1 and facilitates NF-κB activation•Hepatic deletion of PPDPF leads to increased apoptosis and compensatory proliferation•Liver-specific overexpression of PPDPF significantly suppresses HCC development PPDPF plays an important role in HCC development. Wang et al. show that PPDPF exerts beneficial effects through modulating the TRIM21-mediated ubiquitination of RIPK1 and activation of NF-κB signaling. PPDPF may be a promising therapeutic candidate for the treatment of HCC.