Dysregulation of PCSK9 via m⁶A-dependent epitranscriptomic programs fosters hepatocellular carcinoma progression

PCSK9, besides its established role in cholesterol metabolism in the liver, has recently emerged as a tumor-promoting gene in various types of cancer including hepatocellular carcinoma (HCC). However, the regulatory pathways governing oncogenic PCSK9 in HCC remain poorly understood, particularly those involving epitranscriptomic modifications. Here, we identify PCSK9 as a novel mRNA target of METTL3 in HCC. Furthermore, METTL3 promotes tumor cell growth by upregulating PCSK9 mRNA through m⁶A methylation in the 3' UTR. Additionally, IGF2BP3 exerts its m⁶A reading function to maintain PCSK9 mRNA stability in an m⁶A-dependent manner, thereby fostering the capacity of tumor growth. Moreover, ILF3 interacts with IGF2BP3 to collaboratively enhance PCSK9 mRNA stability and ultimately contributes to tumor growth. The METTL3-IGF2BP3-ILF3-PCSK9 signaling pathway is additionally confirmed in HCC patient cohorts. In summary, our findings highlight that PCSK9 is controlled by m⁶A-dependent METTL3-IGF2BP3-ILF3 epitranscriptomic programs and contributes to HCC progression. The study provides a rationale for repurposing PCSK9-depleting therapeutics into a potential antitumor treatment.