In this work, we find the high expression of an exon 10-inclusive form of SREK1 (SREK1L) in HCC tumor tissues (HCC-T) that is associated with poor prognosis of the patients, and demonstrate that SREK1L promotes the oncogenesis of HCC cells in vitro and in vivo through its interactions with NMD components to regulate the expression of BLOC1S5-TXNDC5 (B-T). Here, BLOC1S5 is linked to hepatocellular carcinoma.