RNF135 and liver cancer: Each centre independently reported sensitivities and specificities exceeding 90%, demonstrating robust geographic performance.<h4>Conclusions</h4>Using a systematic marker-discovery pipeline and a multi-centre prospective cohort, we developed a methylation-based liquid biopsy that reliably detects early liver cancer in high-risk populations.<h4>Clinical trial number</h4>Chictr.org identifier: ChiCTR2400092883.<h4>Key points</h4>Three cfDNA methylation markers, RNF135, CHFR and PAX5, were identified for liver cancer liquid biopsy.