RNA N6-methyladenosine (m6A) is a common RNA modification in eukaryotes, and its abnormal regulation is closely related to cancer progression. Aerobic glycolysis is a main way for cancer cells to obtain energy. It was found that beaded filament structural protein 1 (BFSP1) is a m6A related gene in liver cancer. However, the effect of m6A-modified BFSP1 on aerobic glycolysis and how it is regulated in liver cancer progression have not been explored. Here, we found that BFSP1 was upregulated in liver cancer cells and tissues. Overexpression of BFSP1 promoted the viability, invasion, and aerobic glycolysis of liver cancer cells, whereas knockdown of BFSP1 showed the opposite effects. Co-immunoprecipitation, immunofluorescence and GST pull down analyses showed that BFSP1 directly interacted with tropomodalin 4 (TMOD4), and knockdown of TMOD4 reversed BFSP1 overexpression-induced malignant phenotypes and aerobic glycolysis in liver cancer cells. Moreover, methyltransferase-like 3 (METTL3) enhanced BFSP1 stability by augmenting m6A modification of BFSP1 mRNA, which is achieved in a YTHDF1-dependent manner. In vivo experiments in mice confirmed that METTL3 increased BFSP1 stability by promoting m6A modification of BFSP1 mRNA, and knockdown of BFSP1 inhibited tumor growth and metastasis. In summary, METTL3-mediated m6A methylation of BFSP1 mRNA plays an important role in the aerobic glycolysis and progression of liver cancer, providing a potential therapeutic strategy for liver cancer.

The N6‐methyladenosine (m6A) methylase WTAP has been identified as a proto‐oncogene in multiple cancers, including hepatocellular carcinoma (HCC). Interestingly, although WTAP expression does not differ between normal liver and HCC tissues or across different stages of HCC, patients with higher WTAP expression exhibit significantly shorter median survival times (MSTs). Here, we found that WTAP was upregulated in tumor‐infiltrating CD8 ⁺ T cells, which were more enriched in HCC patients compared to the controls. HCC patients also displayed higher PD1 levels and a greater proportion of exhausted CD8 ⁺ T cells (TCF ⁺ PD1 ⁺ ). Moreover, WTAP promoted PD1 expression and suppressed the proliferation and immune activity of CD8 ⁺ T cells. In the co‐culture system, WTAP‐overexpressing CD8 ⁺ T cells enhanced the malignancy of HCC cells. Notably, WTAP silencing further augmented the boosting effect of PD1 silencing on CD8 ⁺ T cell immune activity and strengthened its inhibitory effect on HCC cell growth. As an m6A “writer”, WTAP increased the m6A level of PD1 mRNA, thereby promoting YTHDF1‐mediated translation of PD1. Finally, in the HuNSG xenograft tumor model, WTAP knockdown not only alleviated CD8 ⁺ T cell exhaustion and inhibited tumor progression but also synergistically enhanced the antitumor efficacy of anti‐PD1 therapy. In conclusion, WTAP promoted CD8 ⁺ T cell exhaustion and HCC progression by facilitating the m6A modification and translation of PD1 mRNA.