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).
Google Scholar
Younossi, Z. M. & Henry, L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep. 3, 100305 (2021).
Google Scholar
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).
Google Scholar
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).
Google Scholar
He, G. et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384–396 (2013).
Google Scholar
Schmitt, C. A., Wang, B. & Demaria, M. Senescence and cancer—role and therapeutic opportunities. Nat. Rev. Clin. Oncol. 19, 619–636 (2022).
Google Scholar
Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019).
Google Scholar
Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nat. Rev. Cancer 6, 472–476 (2006).
Google Scholar
Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).
Google Scholar
Huda, N. et al. Hepatic senescence, the good and the bad. World J. Gastroenterol. 25, 5069–5081 (2019).
Google Scholar
Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017).
Google Scholar
Llovet, J. M. et al. Nonalcoholic steatohepatitis-related hepatocellular carcinoma: pathogenesis and treatment. Nat. Rev. Gastroenterol. Hepatol. 20, 487–503 (2023).
Google Scholar
Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011).
Google Scholar
Shalapour, S. et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature 551, 340–345 (2017).
Google Scholar
Hunter, R. W. et al. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat. Med. 24, 1395–1406 (2018).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251–255 (2014).
Google Scholar
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).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Jiang, Y. et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 567, 257–261 (2019).
Google Scholar
Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).
Google Scholar
Nakagawa, H. et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell 26, 331–343 (2014).
Google Scholar
Todoric, J. et al. Fructose stimulated de novo lipogenesis is promoted by inflammation. Nat. Metab. 2, 1034–1045 (2020).
Google Scholar
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).
Google Scholar
Ganguly, S. et al. Nonalcoholic steatohepatitis and HCC in a hyperphagic mouse accelerated by Western diet. Cell. Mol. Gastroenterol. Hepatol. 12, 891–920 (2021).
Google Scholar
Govaere, O. et al. A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures. Nat. Metab. 5, 572–578 (2023).
Google Scholar
Font-Burgada, J. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766–779 (2015).
Google Scholar
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).
Google Scholar
Porteiro, B. et al. Hepatic p63 regulates steatosis via IKKβ/ER stress. Nat. Commun. 8, 15111 (2017).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Beurel, E., Grieco, S. F. & Jope, R. S. Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol. Ther. 148, 114–131 (2015).
Google Scholar
Todoric, J. et al. Stress-activated NRF2-MDM2 cascade controls neoplastic progression in pancreas. Cancer Cell 32, 824–839 (2017).
Google Scholar
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
Google Scholar
Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Su, H. et al. Cancer cells escape autophagy inhibition via NRF2-induced macropinocytosis. Cancer Cell 39, 678–693 (2021).
Google Scholar
Jin, X. et al. MAGE-TRIM28 complex promotes the Warburg effect and hepatocellular carcinoma progression by targeting FBP1 for degradation. Oncogenesis 6, e312 (2017).
Google Scholar
Sun, H. et al. p53 transcriptionally regulates SQLE to repress cholesterol synthesis and tumor growth. EMBO Rep. 22, e52537 (2021).
Google Scholar
Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature 593, 405–410 (2021).
Google Scholar
Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).
Google Scholar
Saini, N. & Gordenin, D. A. Hypermutation in single-stranded DNA. DNA Repair 91-92, 102868 (2020).
Google Scholar
Muzumdar, M. D., Tasic, B., Miyamichi, K., Li, L. & Luo, L. A global double-fluorescent Cre reporter mouse. Genesis 45, 593–605 (2007).
Google Scholar
Ogawara, Y. et al. Akt enhances Mdm2-mediated ubiquitination and degradation of p53. J. Biol. Chem. 277, 21843–21850 (2002).
Google Scholar
Samuel, V. T. & Shulman, G. I. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab. 27, 22–41 (2018).
Google Scholar
Gu, L. et al. Amplification of glyceronephosphate O-acyltransferase and recruitment of USP30 stabilize DRP1 to promote hepatocarcinogenesis. Cancer Res. 78, 5808–5819 (2018).
Google Scholar
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).
Google Scholar
McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).
Google Scholar
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).
Google Scholar
Bergstrom, E. N. et al. SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events. BMC Genom. 20, 685 (2019).
Google Scholar
Filliol, A. et al. Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis. Nature 610, 356–365 (2022).
Google Scholar
Guilliams, M. et al. Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches. Cell 185, 379–396 (2022).
Google Scholar
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
Google Scholar
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).
Google Scholar
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).
Google Scholar
Ando, M. et al. Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers. Nat. Commun. 10, 2188 (2019).
Google Scholar
Zhang, J. et al. Pan-cancer analyses reveal genomics and clinical characteristics of the melatonergic regulators in cancer. J Pineal Res. 71, e12758 (2021).
Google Scholar
Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168, 644–656 (2017).
Google Scholar
Hänzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinform. 14, 7 (2013).
Google Scholar
Wang, X. et al. Comprehensive assessment of cellular senescence in the tumor microenvironment. Brief Bioinform. 23, bbac118 (2022).
Google Scholar
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).
Google Scholar
