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The interaction between RNA‐binding proteins (RBPs) and RNA plays an important role in regulating cellular function. However, decoding genome‐wide protein–RNA regulatory networks as well as how cancer‐related mutations impair RNA regulatory activities in hepatocellular carcinoma (HCC) remains mostly undetermined. We explored the genetic alteration patterns of RBPs and found that deleterious mutations are likely to occur on the surface of RBPs. We then constructed protein–RNA interactome networks by integration of target binding screens and expression profiles. Network analysis highlights regulatory principles among interacting RBPs. In addition, somatic mutations selectively target functionally important genes (cancer genes, core fitness genes, or conserved genes) and perturb the RBP–gene regulatory networks in cancer. These regulatory patterns were further validated using independent data. A computational method (Mutational Effect on RNA Interactome Topology) and a web‐based, user‐friendly resource were further proposed to analyze the RBP–gene regulatory networks across cancer types. Pan‐cancer analysis also suggests that cancer cells selectively target “vulnerability” genes to perturb protein–RNA interactome that is involved in cancer hallmark–related functions. Specifically, we experimentally validated four pairs of RBP–gene interactions perturbed by mutations in HCC, which play critical roles in cell proliferation. Based on the expression of perturbed RBP and target genes, we identified three subtypes of HCC with different survival rates.  Conclusion:  Our results provide a valuable resource for characterizing somatic mutation‐perturbed protein–RNA regulatory networks in HCC, yielding valuable insights into the genotype–phenotype relationships underlying human cancer, and potential biomarkers for precision medicine.

MERIT: Systematic Analysis and Characterization of Mutational Effect on RNA Interactome Topology