<p>Data.</p>

Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized primarily by hepatocellular steatosis and lipid accumulation, which leads to hepatocyte apoptosis, autophagy, inflammation, and intracellular oxidative stress. NAFLD is recognized as one of the most prevalent and complex chronic liver diseases globally, with its occurrence and associated mortality rates rising swiftly each year. Due to the high similarity between chicken fatty liver syndrome (FLS) and NAFLD, as well as the easy availability of diseased chickens, the chicken is considered an ideal model for studying the pathogenesis of NAFLD. Previous studies have pinpointed several circular RNAs (circRNAs) implicated in the pathogenesis of NAFLD, yet the underlying functions and mechanisms of numerous circRNAs continue to remain elusive. In this experiment, we utilized circRNA sequencing of chicken livers to identify a novel circRNA, named circACACA, and discovered that it disrupts the metabolic homeostasis of lipids within hepatocytes. Consequently, this disruption leads to oxidative stress and the induction of autophagy, ultimately exerting an adverse effect on chicken liver health. Mechanistically, circACACA functions as a molecular sponge for miR-132b-5p and miR-101-2-5p to modulate the expression of the downstream CBFB/PIM1 complex. Consequently, it influenced the activity of the AKT/mTOR and PPAR-γ signaling pathways to perform its physiological functions. Crucially, we noticed substantial sequence similarity of circACACA across diverse species by comprehensively searching databases. Further, our research with a mouse model confirmed that the functional conservation of circACACA across livers of different species. Overall, this study built a mechanistic network for circACACA and confirmed its sequence conservation and functional relevance across various species. Our results not only provide new targets for the prevention and treatment of NAFLD but also present fresh perspectives for progress in healthy production of laying hens.

非酒精性脂肪性肝病（Non-alcoholic fatty liver disease, NAFLD）是一类以肝细胞脂肪变性与脂质蓄积为核心特征的临床综合征，可诱发肝细胞凋亡、自噬、炎症反应及细胞内氧化应激。该疾病被认为是全球范围内最具流行性与复杂性的慢性肝病之一，其发病率及相关病死率正逐年快速上升。由于鸡脂肪肝病综合征（Chicken Fatty Liver Syndrome, FLS）与NAFLD具有高度相似的病理特征，且病源鸡易于获取，因此鸡被视作研究NAFLD发病机制的理想动物模型。既往研究已证实数种环状RNA（circular RNAs, circRNAs）参与NAFLD的发病进程，但绝大多数circRNAs的具体功能与作用机制仍有待阐明。本研究通过对鸡肝脏组织开展circRNA测序，鉴定出一种新型环状RNA，命名为circACACA，并发现其可破坏肝细胞内的脂质代谢稳态，进而引发氧化应激并诱导自噬，最终对鸡肝脏健康造成负面影响。机制层面，circACACA可作为miR-132b-5p与miR-101-2-5p的分子海绵，调控下游CBFB/PIM1复合物的表达水平，继而影响AKT/mTOR与PPAR-γ信号通路的活性，以此实现其生理功能。通过全面检索公共数据库，我们发现circACACA在多个物种间存在显著的序列同源性。进一步借助小鼠模型开展的验证实验证实，circACACA在不同物种的肝脏组织中具有功能保守性。本研究构建了circACACA的完整机制调控网络，并证实其序列保守性与跨物种功能相关性。本研究结果不仅为NAFLD的临床防治提供了全新靶点，也为蛋鸡健康养殖领域的研究提供了崭新视角。