RNA-Binding Proteins in NAFLD: Roles and Emerging Drug Target

Understanding the Global Burden of NAFLD

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide, affecting more than 25% of the adult population. It is characterized by the build-up of fat in liver cells and elevated liver enzymes, occurring in people who consume little or no alcohol.

A diagnosis of steatosis is made when at least 5% of liver cells contain excess fat. NAFLD encompasses a range of conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), which involves inflammation and cell death. NASH can progress to fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Hepatic fibrosis is considered the main predictor of liver-related mortality, and a recent model predicts a 178% increase in NASH-related deaths by 2030.

The disease is closely linked to metabolic syndrome, type 2 diabetes, obesity, dyslipidemia, and cardiovascular disease. Insulin resistance (IR) is central to its development, promoting fat synthesis in the liver and increasing the delivery of free fatty acids from adipose tissue. Other contributing factors include oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), bile acid metabolism disturbances, changes in gut microbiota, and genetic predisposition.

Why Focus on RNA-Binding Proteins?

RNA-binding proteins (RBPs) regulate the fate of RNA molecules after transcription, influencing RNA stability, localization, and translation. By controlling the expression of genes at the post-transcriptional level, RBPs can impact many metabolic pathways. Loss of RBP function or mutations can disrupt cell balance and contribute to metabolic disorders, including NAFLD.

While individual studies have linked certain RBPs to NAFLD, findings have often been fragmented. This review aims to provide a comprehensive picture of how RBPs contribute to NAFLD and to explore therapeutic strategies targeting these proteins.

Key RBPs in NAFLD

HuR: A Central Regulator With Context-Dependent Effects

Human antigen R (HuR) is widely expressed and stabilizes mRNAs encoding proteins involved in inflammation, lipid metabolism, and oxidative stress defense.

• Protective actions: HuR stabilizes PTEN mRNA, helping reduce hepatic fat accumulation. It also promotes cholesterol efflux via ABCA1 and supports antioxidant defenses through manganese superoxide dismutase (MnSOD) and heme oxygenase-1 (HO-1).

• Potential risks: Hepatocyte-specific HuR deletion worsens diet-induced NAFLD, increasing triglycerides, inflammation, and fibrosis, and in some cases leading to HCC-like tumors.

• Mechanistic links: HuR interacts with lncRNAs such as H19 and LINC01018 to regulate fatty acid metabolism and ERS. It also influences lipid transport by affecting ApoB mRNA splicing.

HuR’s diverse effects suggest that therapies modulating its activity may need to be combined with other treatments, such as insulin sensitizers.

PTBP1: Driving Lipogenesis Through lncRNA Interaction

Polypyrimidine tract-binding protein 1 (PTBP1) works with the lncRNA H19 to enhance the stability and activity of SREBP1c, a master regulator of fat synthesis. This creates a feedforward loop that promotes lipogenesis and NAFLD progression. PTBP1 also contributes to cholesterol metabolism through other lncRNA interactions.

hnRNP Family: Multiple Roles in Lipid and Glucose Regulation

• hnRNPU: Regulates VLDL secretion through the lncRHL/BMAL1/MTTP axis. Loss of hnRNPU destabilizes this network, increasing lipid accumulation and liver inflammation.

• hnRNPA1: Supports insulin sensitivity by regulating glycogen synthesis and fatty acid oxidation genes. It also works with lncRNA SHGL to suppress both gluconeogenesis and lipogenesis.

• hnRNPA2B1: Forms complexes with lnc-HC to control cholesterol metabolism genes.

• hnRNPC: Can be modulated by therapeutic extracellular vesicles to reduce liver cell death in diabetes-related NAFLD.

p62/IGF2BP2: Promoting Steatosis and NASH

The p62 isoform of IGF2BP2 enhances lipid synthesis and elongation, leading to triglyceride accumulation, inflammation, and fibrosis. Overexpression in mice accelerates NAFLD and its progression to NASH.

Other RBPs of Interest

• TTP: Destabilizes pro-inflammatory cytokine mRNAs but may also affect lipid metabolism.

• CPEB1: Involved in NASH progression via the circRNA-002581–miR-122 axis and autophagy regulation.

• YAP: A transcriptional co-activator linked to lipid accumulation, inflammation, and fibrosis in NAFLD.

• YB-1: Promotes adipogenesis by enhancing autophagy-related gene expression.

• AEG-1: Drives steatosis by inhibiting fatty acid oxidation and activating inflammatory pathways.

• LIN28: Regulates glucose metabolism and can be targeted to reduce lipogenesis.

• RPL8: Associated with lipid accumulation and ERS via interactions with circRNAs.

Cross-Talk Between RBPs

Some RBPs interact competitively on the same RNA targets. For instance, TTP promotes mRNA decay, while HuR stabilizes those same transcripts. This interplay may influence NAFLD outcomes, but combined regulation of RNAs by multiple RBPs in NAFLD is still poorly understood.

Therapeutic Opportunities

The review identifies several compounds that modulate RBPs and have shown promise in preclinical NAFLD models:

Implications for Research and Clinical Practice

The authors note that most findings come from animal or in vitro studies. Clinical validation is urgently needed before RBP-targeted therapies can be recommended. Still, RBPs represent promising intervention points due to their central role in coordinating metabolic and inflammatory processes.

Technological advances such as RNA sequencing and CRISPR-Cas9 genome editing could accelerate the discovery of new RBP targets and enable the creation of precise disease models. Such approaches may lead to therapies that mimic protective RBPs or block harmful ones, with the potential for fewer side effects and improved patient outcomes.

Conclusion

NAFLD is a complex, multifactorial disease where post-transcriptional regulation plays a significant role. RBPs act as central hubs in this network, influencing lipid metabolism, inflammation, and fibrosis. A better understanding of these proteins could open the door to innovative RNA-based treatments. As the authors conclude, “Correcting gene expression abnormalities through targeted modulation of RBPs holds promise as an effective therapeutic strategy” — but the path from bench to bedside will require robust human studies.

 

The translation of the preceding English text in Chinese:

 

理解非酒精性脂肪性肝病的全球负担

非酒精性脂肪性肝病（NAFLD）是全球最常见的慢性肝脏疾病，影响着超过 25% 的成年人口。其特征是在几乎不饮酒或不饮酒的人群中，肝细胞内脂肪堆积及肝酶水平升高。

当至少 5% 的肝细胞含有过量脂肪时，即可诊断为脂肪变性（steatosis）。NAFLD 包括从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH）的一系列疾病，后者伴随炎症和细胞死亡。NASH 可进一步发展为纤维化、肝硬化，甚至肝细胞癌（HCC）。肝纤维化被认为是肝脏相关死亡率的主要预测因素，近期模型预测，到 2030 年，NASH 相关死亡将增加 178%。

该疾病与代谢综合征、2 型糖尿病、肥胖、血脂异常及心血管疾病密切相关。胰岛素抵抗（IR）在其发病中起核心作用，促进肝脏脂肪合成并增加脂肪组织向肝脏输送游离脂肪酸。其他促病因素包括氧化应激、线粒体功能障碍、内质网应激（ERS）、胆汁酸代谢紊乱、肠道菌群变化以及遗传易感性。

为什么关注 RNA 结合蛋白（RBPs）？

RNA 结合蛋白（RBPs）在转录之后调控 RNA 分子的命运，影响其稳定性、定位和翻译。通过在转录后水平上控制基因表达，RBPs 可影响多种代谢通路。RBP 功能缺失或突变会破坏细胞稳态，促成包括 NAFLD 在内的代谢性疾病。

虽然一些研究已将特定 RBP 与 NAFLD 联系起来，但研究结果往往是零散的。本综述旨在全面阐述 RBPs 在 NAFLD 中的作用，并探索靶向这些蛋白的治疗策略。

NAFLD 中的关键 RBP

HuR：具有情境依赖效应的核心调节因子

HuR（Human antigen R）广泛表达，可稳定参与炎症、脂质代谢及抗氧化防御的 mRNA。

保护作用：HuR 稳定 PTEN mRNA，有助于减少肝脏脂肪堆积；通过 ABCA1 促进胆固醇外排，并通过锰超氧化物歧化酶（MnSOD）和血红素加氧酶-1（HO-1）支持抗氧化防御。

潜在风险：肝细胞特异性 HuR 缺失会加重饮食诱导的 NAFLD，增加甘油三酯、炎症和纤维化，部分情况下可导致类似 HCC 的肿瘤。

机制关联：HuR 与长链非编码 RNA（lncRNA）H19 和 LINC01018 相互作用，调控脂肪酸代谢及 ERS；还可通过影响 ApoB mRNA 剪接来调节脂质转运。

HuR 的多样效应提示，调节其活性的疗法可能需要与其他治疗（如胰岛素增敏剂）联合使用。

PTBP1：通过与 lncRNA 相互作用驱动脂质生成

多聚嘧啶结合蛋白 1（PTBP1）与 lncRNA H19 协作，增强 SREBP1c（脂质合成主调节因子）的稳定性和活性，形成正反馈回路，促进脂质生成和 NAFLD 进展。PTBP1 还通过与其他 lncRNA 相互作用参与胆固醇代谢。

hnRNP 家族：在脂质与葡萄糖调控中的多重作用

• hnRNPU：通过 lncRHL/BMAL1/MTTP 轴调控极低密度脂蛋白（VLDL）分泌。hnRNPU 缺失会破坏该网络，增加脂质堆积和肝脏炎症。

• hnRNPA1：通过调控糖原合成和脂肪酸氧化基因支持胰岛素敏感性，并与 lncRNA SHGL 协作抑制糖异生和脂质生成。

• hnRNPA2B1：与 lnc-HC 形成复合物，控制胆固醇代谢相关基因。

• hnRNPC：可通过治疗性细胞外囊泡调节，以减少糖尿病相关 NAFLD 中的肝细胞死亡。

p62/IGF2BP2：促进脂肪变性和 NASH

IGF2BP2 的 p62 亚型可增强脂质合成与延长，导致甘油三酯堆积、炎症和纤维化。小鼠中过表达会加速 NAFLD 及其向 NASH 的发展。

其他值得关注的 RBP

• TTP：使促炎性细胞因子 mRNA 不稳定，但可能也影响脂质代谢。

• CPEB1：通过 circRNA-002581–miR-122 轴及自噬调控参与 NASH 进展。

• YAP：转录共激活因子，与 NAFLD 中的脂质堆积、炎症和纤维化相关。

• YB-1：通过增强自噬相关基因表达促进脂肪生成。

• AEG-1：通过抑制脂肪酸氧化和激活炎症通路驱动脂肪变性。

• LIN28：调节葡萄糖代谢，靶向其可减少脂质生成。

• RPL8：通过与 circRNA 相互作用与脂质堆积及 ERS 相关。

RBP 之间的交互

部分 RBP 会在相同 RNA 靶点上竞争性作用。例如，TTP 促进 mRNA 降解，而 HuR 稳定这些转录本。这种相互作用可能影响 NAFLD 结果，但多种 RBP 在 NAFLD 中的联合调控机制仍不清楚。

治疗机会

该综述指出了一些可调节 RBP 并在 NAFLD 动物模型中显示出前景的化合物：

对研究与临床实践的意义

作者指出，目前大多数发现来自动物或体外研究。在推荐 RBP 靶向治疗之前，亟需临床验证。尽管如此，RBP 由于其在代谢与炎症过程中的核心作用，仍是极具前景的干预靶点。

RNA 测序和 CRISPR-Cas9 基因编辑等技术进步可能加快新 RBP 靶点的发现，并建立精准的疾病模型。这些方法或可催生模拟保护性 RBP 或阻断有害性 RBP 的疗法，潜在副作用更少，疗效更佳。

结论

NAFLD 是一种复杂的多因素疾病，其中转录后调控发挥着重要作用。RBP 在这一网络中充当关键枢纽，影响脂质代谢、炎症和纤维化。深入理解这些蛋白质有望开启创新型 RNA 治疗的新途径。正如作者总结所言：“通过靶向调节 RBP 来纠正基因表达异常，有望成为有效的治疗策略”，但从实验室到临床仍需坚实的人体研究支撑。

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Reference:

Changjin Li, Fan Yang, Zuohui Yuan, Xiaoguo Wei

Review of roles of RNA-binding proteins on NAFLD and the related pharmaceutical measures.

Biomol Biomed [Internet]. 2025 May 16 [cited 2025 Aug. 13];

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12465

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