Cell：高脂饮食对肝脏的慢性代谢压力，会促进肿瘤发生

Core Viewpoint - The study published in Cell highlights that chronic metabolic stress from high-fat diets not only leads to fatty liver but also induces profound changes in liver stem cells, which can promote tumorigenesis [1][2]. Group 1: Research Findings - Chronic stress forces liver cells to choose between survival and maintaining organ function, leading to early adaptive changes that can "pre-program" future tumor development [3][4]. - The research utilized a high-fat diet mouse model to simulate human metabolic dysfunction related to fatty liver disease, tracking changes in liver cells through multi-omics analysis [5]. - Chronic metabolic stress activates two core programs in liver cells: an upregulation program that promotes cell survival and regeneration while downregulating liver-specific functions, leading to decreased liver function [6]. Group 2: Key Mechanisms - The decline of the ketogenesis rate-limiting enzyme HMGCS2 is crucial, as its knockout in liver cells under high-fat diet stress exacerbates stress responses and significantly increases tumor incidence [8]. - The transcription factors SOX4 and RELB play a central role in promoting liver cell dedifferentiation and proliferation under stress, with high expression levels in patients with metabolic dysfunction-associated fatty liver disease (MASLD) indicating poor prognosis [10]. Group 3: Clinical Implications - The study reveals a "memory effect" of chronic stress and suggests monitoring the expression of genes like HMGCS2 and SOX4 as early risk markers for liver cancer [14]. - Targeting metabolic pathways, such as ketogenesis, or transcription factors like SOX4 may block precancerous states, providing potential intervention strategies [15]. - Overall, the adaptation of the liver to chronic metabolic stress enhances short-term cell survival but sacrifices long-term liver function, emphasizing the importance of healthy diets and metabolic stress control in preventing liver cancer [17].