High‐Fat Diet–Induced Metabolic Stress Durably Reprograms the Liver Regenerative Compartment Toward a Senescence‐Like State

Abstract

ABSTRACT Chronic metabolic stress is increasingly recognized as a driver of aging‐like tissue dysfunction, but whether it durably reprograms liver regenerative cells, potentially compromising tissue maintenance and repair, remains unknown. Here, we show that high‐fat diet (HFD)–induced metabolic stress promotes a persistent senescence‐like state in the liver regenerative compartment. In male rats, chronic HFD feeding induced hepatic steatosis together with oxidative stress, inflammatory responses, and senescence‐associated changes. Following carbon tetrachloride‐induced liver injury, HFD‐fed animals exhibited reduced proliferative responses. To determine whether these abnormalities were durably retained within regenerative cell populations, we established liver organoids from control and HFD‐fed rats. HF‐derived organoids showed reduced formation efficiency and impaired serial propagation capacity outside the original metabolic environment. Senescence‐associated abnormalities, including increased senescence‐associated β‐galactosidase staining, reduced Lamin B1 staining, and decreased Ki67 positivity, remained detectable through Passage 3. Transcriptomic and functional analyses revealed mitochondrial dysfunction and enhanced oxidative and inflammatory responses. These organoids also exhibited enhanced lipid accumulation and inflammatory secretion following fatty acid challenge. Treatment with the mitochondria‐targeted antioxidant MitoQ reduced oxidative stress and inflammatory secretion, improved oxygen consumption, and partially restored organoid formation efficiency, supporting a functional contribution of mitochondrial dysfunction to regenerative impairment. Together, these findings support a model in which chronic metabolic stress leaves persistent senescence‐like dysfunction within the liver regenerative compartment, extending its consequences beyond abnormalities in mature liver tissue.