Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005).
Younossi, Z. M. & Henry, L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep. 3, 100305 (2021).
Ferreira-Gonzalez, S., Rodrigo-Torres, D., Gadd, V. L. & Forbes, S. J. Cellular senescence in liver disease and regeneration. Semin. Liver Dis. 41, 50–66 (2021).
Carlessi, R. et al. Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential. Cell Genom. 3, 100301 (2023).
He, G. et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384–396 (2013).
Schmitt, C. A., Wang, B. & Demaria, M. Senescence and cancer—role and therapeutic opportunities. Nat. Rev. Clin. Oncol. 19, 619–636 (2022).
Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).
Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nat. Rev. Cancer 6, 472–476 (2006).
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Huda, N. et al. Hepatic senescence, the good and the bad. World J. Gastroenterol. 25, 5069–5081 (2019).
Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017).
Llovet, J. M. et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat. Rev. Gastroenterol. Hepatol. 20, 487–503 (2023).
Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).
Hunter, R. W. et al. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat. Med. 24, 1395–1406 (2018).
Hirata, H. et al. Decreased expression of fructose-1,6-bisphosphatase associates with glucose metabolism and tumor progression in hepatocellular carcinoma. Cancer Res. 76, 3265–3276 (2016).
Li, F. et al. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat. Cell Biol. 22, 728–739 (2020).
Gorce, M. et al. Fructose-1,6-bisphosphatase deficiency causes fatty liver disease and requires long-term hepatic follow-up. J. Inherit. Metab. Dis. 45, 215–222 (2022).
Gu, L. et al. Fructose-1,6-bisphosphatase is a nonenzymatic safety valve that curtails AKT activation to prevent insulin hyperresponsiveness. Cell Metab. 35, 1009–1021 (2023).
Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014).
He, F. et al. NRF2 activates growth factor genes and downstream AKT signaling to induce mouse and human hepatomegaly. J. Hepatol. 72, 1182–1195 (2020).
Yuan, H., Xu, Y., Luo, Y., Wang, N. X. & Xiao, J. H. Role of Nrf2 in cell senescence regulation. Mol. Cell. Biochem. 476, 247–259 (2021).
Raghunath, A., Sundarraj, K., Arfuso, F., Sethi, G. & Perumal, E. Dysregulation of Nrf2 in hepatocellular carcinoma: role in cancer progression and chemoresistance. Cancers 10, 481 (2018).
Jiang, Y. et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 567, 257–261 (2019).
Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).
Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).
Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat. Metab. 2, 1034–1045 (2020).
Olson, E., Nievera, C. J., Klimovich, V., Fanning, E. & Wu, X. RPA2 is a direct downstream target for ATR to regulate the S-phase checkpoint. J. Biol. Chem. 281, 39517–39533 (2006).
Ganguly, S. et al. Nonalcoholic steatohepatitis and HCC in a hyperphagic mouse accelerated by Western diet. Cell. Mol. Gastroenterol. Hepatol. 12, 891–920 (2021).
Govaere, O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat. Metab. 5, 572–578 (2023).
Font-Burgada, J. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766–779 (2015).
Anstee, Q. M., Reeves, H. L., Kotsiliti, E., Govaere, O. & Heikenwalder, M. From NASH to HCC: current concepts and future challenges. Nat. Rev. Gastroenterol. Hepatol. 16, 411–428 (2019).
Porteiro, B. et al. Hepatic p63 regulates steatosis via IKKβ/ER stress. Nat. Commun. 8, 15111 (2017).
Hou, X., Du, Y., Deng, Y., Wu, J. & Cao, G. Sleeping Beauty transposon system for genetic etiological research and gene therapy of cancers. Cancer Biol. Ther. 16, 8–16 (2015).
Dietrich, P. et al. Neuroblastoma RAS viral oncogene homolog (NRAS) is a novel prognostic marker and contributes to sorafenib resistance in hepatocellular carcinoma. Neoplasia 21, 257–268 (2019).
Beurel, E., Grieco, S. F. & Jope, R. S. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther. 148, 114–131 (2015).
Todoric, J. et al. Stress-activated NRF2-MDM2 cascade controls neoplastic progression in pancreas. Cancer Cell 32, 824–839 (2017).
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
Rada, P. et al. Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis. Mol. Cell. Biol. 32, 3486–3499 (2012).
Umemura, A. et al. p62, upregulated during preneoplasia, induces hepatocellular carcinogenesis by maintaining survival of stressed HCC-initiating cells. Cancer Cell 29, 935–948 (2016).
Su, H. et al. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis. Cancer Cell 39, 678–693 (2021).
Jin, X. et al. MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation. Oncogenesis 6, e312 (2017).
Sun, H. et al. p53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth. EMBO Rep. 22, e52537 (2021).
Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature 593, 405–410 (2021).
Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).
Saini, N. & Gordenin, D. A. Hypermutation in single-stranded DNA. DNA Repair 91-92, 102868 (2020).
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).
Ogawara, Y. et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J. Biol. Chem. 277, 21843–21850 (2002).
Samuel, V. T. & Shulman, G. I. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 27, 22–41 (2018).
Gu, L. et al. Amplification of glyceronephosphate O-acyltransferase and recruitment of USP30 stabilize DRP1 to promote hepatocarcinogenesis. Cancer Res. 78, 5808–5819 (2018).
Koboldt, D. C. et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 22, 568–576 (2012).
McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).
Fan, Y. et al. MuSE: accounting for tumor heterogeneity using a sample-specific error model improves sensitivity and specificity in mutation calling from sequencing data. Genome Biol. 17, 178 (2016).
Bergstrom, E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genom. 20, 685 (2019).
Filliol, A. et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610, 356–365 (2022).
Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396 (2022).
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
Razaghi, R. et al. Modbamtools: analysis of single-molecule epigenetic data for long-range profiling, heterogeneity, and clustering. Preprint at bioRxiv https://doi.org/10.1101/2022.07.07.499188 (2022).
Hao, Y. et al. Dictionary learning for integrative, multimodal and scalable single-cell analysis. Nat. Biotechnol. 42, 293–304 (2024).
Rui, T. et al. The chromosome 19 microRNA cluster, regulated by promoter hypomethylation, is associated with tumour burden and poor prognosis in patients with hepatocellular carcinoma. J. Cell. Physiol. 235, 6103–6112 (2020).
Ando, M. et al. Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers. Nat. Commun. 10, 2188 (2019).
Zhang, J. et al. Pan-cancer analyses reveal genomics and clinical characteristics of the melatonergic regulators in cancer. J Pineal Res. 71, e12758 (2021).
Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168, 644–656 (2017).
Hänzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 14, 7 (2013).
Wang, X. et al. Comprehensive assessment of cellular senescence in the tumor microenvironment. Brief Bioinform. 23, bbac118 (2022).
Ikeda, H. et al. Expression profile of cell cycle-related genes in human fibroblasts exposed simultaneously to radiation and simulated microgravity. Int. J. Mol. Sci. 20, 4791 (2019).