The crosstalk between deregulated hepatocyte metabolism and cells within the tumour microenvironment, as well as the consequent effects on liver tumorigenesis, are not completely understood. We show here that hepatocyte-specific loss of the gluconeogenic enzyme fructose 1,6-bisphosphatase 1 (FBP1) disrupts liver metabolic homeostasis and promotes tumour progression. FBP1 is universally silenced in both human and murine liver tumours. Hepatocyte-specific Fbp1 deletion results in steatosis, concomitant with activation and senescence of hepatic stellate cells (HSCs), exhibiting a senescence-associated secretory phenotype. Depleting senescent HSCs by 'senolytic' treatment with dasatinib/quercetin or ABT-263 inhibits tumour progression. We further demonstrate that FBP1-deficient hepatocytes promote HSC activation by releasing HMGB1; blocking its release with the small molecule inflachromene limits FBP1-dependent HSC activation, the subsequent development of the senescence-associated secretory phenotype and tumour progression. Collectively, these findings provide genetic evidence for FBP1 as a metabolic tumour suppressor in liver cancer and establish a critical crosstalk between hepatocyte metabolism and HSC senescence that promotes tumour growth.

中文翻译：

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FBP1 缺失会破坏肝脏代谢，并通过肝星细胞衰老分泌组促进肿瘤发生。


肝细胞代谢失调与肿瘤微环境内的细胞之间的串扰以及对肝脏肿瘤发生的后续影响尚不完全清楚。我们在此表明​​，肝细胞特异性损失糖异生酶果糖 1,6-双磷酸酶 1 (FBP1) 会破坏肝脏代谢稳态并促进肿瘤进展。 FBP1 在人类和小鼠肝脏肿瘤中普遍沉默。肝细胞特异性 Fbp1 缺失会导致脂肪变性，同时伴随肝星状细胞 (HSC) 的激活和衰老，表现出衰老相关的分泌表型。通过达沙替尼/槲皮素或 ABT-263 的“senolytic”治疗来消除衰老的 HSC，可抑制肿瘤进展。我们进一步证明，FBP1缺陷的肝细胞通过释放HMGB1来促进HSC活化；用小分子 inflachromene 阻断其释放，可限制 FBP1 依赖性 HSC 激活、随后衰老相关分泌表型的发展和肿瘤进展。总的来说，这些发现为 FBP1 作为肝癌代谢肿瘤抑制因子提供了遗传证据，并在肝细胞代谢和 HSC 衰老之间建立了促进肿瘤生长的关键串扰。