| Summary: | Abstract Solute carrier family 27 member 5, a key enzyme in fatty acid transport and bile acid metabolism in the liver, is frequently expressed in low quantities in patients with hepatocellular carcinoma, resulting in poor prognosis. However, it is unclear whether SLC27A5 plays non‐canonical functions and regulates HCC progression. Here, an unexpected non‐canonical role of SLC27A5 is reported: regulating the alternative splicing of mRNA to inhibit the metastasis of HCC independently of its metabolic enzyme activity. Mechanistically, SLC27A5 interacts with IGF2BP3 to prevent its translocation into the nucleus, thereby inhibiting its binding to target mRNA and modulating PIP4K2A pre‐mRNA splicing. Loss of SLC27A5 results in elevated levels of the PIP4K2A‐S isoform, thus positively regulating phosphoinositide 3‐kinase signaling via enhanced p85 stability in HCC. SLC27A5 restoration by AAV‐Slc27a5 or IGF2BP3 RNA decoy oligonucleotides exerts an inhibitory effect on HCC metastasis with reduced expression of the PIP4K2A‐S isoform. Therefore, PIP4K2A‐S may be a novel target for treating HCC with SLC27A5 deficiency.
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