Impaired mitochondrial degradation of CHCHD2 promotes metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma by upregulating VEGFA.

Metabolic dysfunction-associated steatohepatitis (MASH) is the fastest-growing cause of liver cancer. The liver microenvironment of patients with MASH supports the development of hepatocellular carcinoma (HCC). Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2), which is located in both the mitochondria and nucleus, is increased in MASH liver. Its role in the development of MASH-HCC remain unknown. In this study, we found CHCHD2 protein levels were elevated in both tumor and para-tumor tissues of patients with MASH-HCC and diethylnitrosamine- and high-fat diet-induced MASH-HCC mice. Chchd2-knockout mice were generated. CHCHD2 was overexpressed in hepatocytes using AAV with TBG promoter. Chchd2 knockout inhibited the progression of MASH-HCC in mice. CHCHD2 protein-targeted ChIP-sequencing data revealed that CHCHD2 target genes encoding secretory proteins were enriched in cancer pathways. Among these genes, vascular endothelial growth factor A (VEGFA) level increased in CHCHD2-overexpressing livers and hepatocytes. Chchd2 knockdown reduced palmitate-induced VEGFA expression. Palmitate-treated hepatocyte increased the angiogenic activity of endothelial cells in a paracrine manner, and this was suppressed by Chchd2 knockdown in hepatocytes. CHCHD2-overexpressing hepatocytes promoted the angiogenic activity of endothelial cells. We futher employed an orthotopic murine model of HCC to demonstrate that elevated CHCHD2 protein levels in para-tumor tissues support HCC growth. In addition, we found that the degradation of CHCHD2 was primarily mediated by mitochondrial protease ClpXP, which was repressed in the MASH liver. In conclusion, the mitochondrial degradation of CHCHD2 is impaired in MASH, and elevated CHCHD2 levels in hepatocytes promote VEGFA transcription and support the growth of HCC.