Roh Yeon Jin, Kim Hyeonki, Choi Dong Wook
Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
Diabetes Metab J. 2025 May;49(3):368-385. doi: 10.4093/dmj.2025.0195. Epub 2025 May 1.
The liver plays a fundamental role in metabolic homeostasis, integrating systemic fuel utilization with the progression of various metabolic diseases. Hepatic stellate cells (HSCs) are a key nonparenchymal cell type in the liver, which is essential for maintaining hepatic architecture in their quiescent state. However, upon chronic liver injury or metabolic stress, HSCs become activated, leading to excessive extracellular matrix deposition and pro-fibrotic signaling, ultimately positioning them as key players in liver pathology. Emerging evidence highlights the critical roles of metabolic reprogramming and epigenetic regulation in HSCs activation. HSCs activation is driven by both intrinsic fuel metabolism reprogramming and extrinsic metabolic cues from the microenvironment, while the metabolic intermediates actively reshape the epigenetic landscape, reinforcing fibrogenic transcriptional programs. In this review, we summarize recent advances in understanding how metabolic and epigenetic alterations drive HSCs activation, thereby shaping transcriptional programs that sustain fibrosis, and discuss potential therapeutic strategies to target these interconnected pathways in human metabolic diseases.
肝脏在代谢稳态中发挥着基础性作用，将全身的燃料利用与各种代谢性疾病的进展联系起来。肝星状细胞（HSCs）是肝脏中一种关键的非实质细胞类型，在其静止状态下对于维持肝脏结构至关重要。然而，在慢性肝损伤或代谢应激时，肝星状细胞会被激活，导致细胞外基质过度沉积和促纤维化信号传导，最终使其成为肝脏病理过程中的关键因素。新出现的证据突出了代谢重编程和表观遗传调控在肝星状细胞激活中的关键作用。肝星状细胞的激活由内在的燃料代谢重编程和来自微环境的外在代谢信号共同驱动，而代谢中间产物则积极重塑表观遗传格局，强化纤维化转录程序。在这篇综述中，我们总结了在理解代谢和表观遗传改变如何驱动肝星状细胞激活从而形成维持纤维化的转录程序方面的最新进展，并讨论了针对人类代谢性疾病中这些相互关联途径的潜在治疗策略。
