Suppression of LRRC41-mediated oncogenicity in hepatocellular carcinoma via USP7-targeted small molecule inhibitors.

[BACKGROUND] LRRC41 is critical for the progression of multiple cancers, especially hepatocellular carcinoma (HCC), yet its oncogenic mechanism in HCC remains unclear. This study aimed to explore the molecular mechanism by which LRRC41 promotes HCC malignancy and investigate the therapeutic potential of inhibiting its mediated signalling pathway.

[METHODS] LRRC41 expression in HCC was analysed via the TCGA, HPA databases and experimental detection. Its biological functions were assessed by in vitro CCK-8, Transwell, colony formation assays and in vivo xenograft models. IP-MS, Co-IP and ubiquitination assays were used to elucidate the molecular mechanism, and the anti-tumour effect of the USP7 inhibitor P6620 was verified in vitro and in vivo.

[RESULTS] LRRC41 was abnormally overexpressed in HCC and correlated with poor prognosis, promoting HCC cell proliferation, invasion and tumorigenesis. USP7 stabilised LRRC41 via deubiquitination, and LRRC41 activated the NF-κB pathway by targeting HNRNPC in a K63-linked ubiquitination-dependent manner. P6620 inhibited the USP7/LRRC41 axis to suppress HCC malignancy, and its combination with lenvatinib enhanced in vivo anti-tumor efficacy.

[CONCLUSIONS] LRRC41 overexpression drives HCC progression and poor prognosis; the novel USP7/LRRC41/HNRNPC/NF-κB axis is identified in HCC. USP7 inhibitor P6620 blocks this axis and may serve as a potential agent for HCC combination chemotherapy. The regulatory mechanism of the USP7/LRRC41/HNRNPC/NF-κB signalling axis in HCC. Created with Figdraw.