Lefamulin overcomes drug resistance of hepatocellular carcinoma (HCC) by targeting interleukin enhancer‐binding factor 3 (ILF3) and interfering with general control non‐depressible 5 (GCN5) and CREB binding protein (CBP)‐mediated acetylation, which inhibits mitochondrial ribosomal protein L12 (MRPL12) transcription and regulates mitochondrial homeostasis. This evidence concerns the gene MRPL12 and hepatocellular carcinoma.