CRSP8-driven fatty acid metabolism reprogramming enhances hepatocellular carcinoma progression by inhibiting RAN-mediated PPARα nucleus-cytoplasm shuttling.

Abstract

Background: In-depth exploration into the dysregulation of lipid metabolism in hepatocellular carcinoma (HCC) has contributed to the development of advanced antitumor strategies. CRSP8 is a critical component of mediator multiprotein complex involved in transcriptional recruiting. However, the regulatory mechanisms of CRSP8 on fatty acid metabolism reprogramming and HCC progression remain unclear.

Methods: In-silico/house dataset analysis, lipid droplets (LDs) formation, HCC mouse models and targeted lipidomic analysis were performed to determine the function of CRSP8 on regulating lipid metabolism in HCC. The subcellular colocalization and live cell imaging of LDs, transmission electron microscopy, co-immunoprecipitation and luciferase reporter assay were employed to investigate their potential mechanism.

Results: CRSP8 was identified as a highly expressed oncogene essential for the proliferation and aggressiveness of HCC in vitro and in vivo. The tumor promotion of CRSP8 was accompanied by LDs accumulation and increased de novo fatty acids (FAs) synthesis. Moreover, CRSP8 diminished the colocalization between LC3 and LDs to impair lipophagy in a nuclear-localized PPARα-dependent manner, which decreased the mobilization of FAs from LDs degradation and hindered mitochondrial fatty acid oxidation. Mechanistically, the small ras family GTPase RAN was transcriptionally activated by CRSP8, leading to the reinforcement of RAN/CRM1-mediated nuclear export. CRSP8-induced enhanced formation of RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer orchestrated cytoplasmic translocation of PPARα, attenuated nPPARα-mediated lipophagy and fatty acid catabolism, subsequently exacerbated HCC progression. In CRSP8-enriched HCC, lipid synthesis inhibitor Orlistat effectively reshaped the immunosuppressive tumor microenvironment (TME) and improved the efficacy of anti-PD-L1 therapy in vivo.

Conclusion: Our study establishes that CRSP8-driven fatty acid metabolism reprogramming facilitates HCC progression via the RAN/CRM1/PPARα nucleus-cytoplasm shuttling heterotrimer and impaired lipophagy-derived catabolism. Targeting the energy supply sourced from lipids could represent a promising therapeutic strategy for treating CRSP8-sufficient HCC.