Liver diseases are a growing global health and economic challenge. High alcohol consumption, aging, and increased exposure to metabolism-related risk factors may contribute to an increase in mortality rates associated with alcohol-related liver disease (ALD) and metabolic-associated fatty liver disease (MAFLD), underscoring the need to understand their pathogenesis to develop better prevention and therapeutic strategies.

Lipid droplets (LDs) are dynamic organelles involved in storing neutral lipids and maintaining the cellular lipid and energy homeostasis. Accumulation of LDs in the liver is a hallmark of MAFLD. The expression of perilipin 2 (PLIN2), a member of the perilipin family and a constituent of the LD proteome, is closely related to the clinical outcomes of liver diseases.

In a recent review published in the Genes & Diseases journal, researchers from Xiamen University and Sun Yat-sen University Cancer Center provide a comprehensive overview of the roles and therapeutic implications of PLIN2 in liver diseases, while detailing the mechanisms through which PLIN2 regulates hepatic lipid metabolism.

The review provides a brief introduction to the biogenesis of LDs and their contact sites with various organelles (e.g., endoplasmic reticulum, mitochondria, peroxisomes, and lysosomes), which are sites that aid in the exchange and transport of lipids between organelles.

Additionally, the authors describe the structure and functions of PLIN2 in LD metabolism. Physiologically, PLIN2 regulates the contacts between LDs and other organelles, helps expand LD size, prevents lipase entry, inhibits LD lipophagy, and stabilizes lipid storage, whereas its overexpression can lead to LD metabolism disorders, resulting in impaired mitochondrial function, lipid toxicity, and related metabolic disorders, eventually leading to the development of various liver diseases. The authors then detail the role of PLIN2 and its associated mechanisms in hepatitis B, hepatitis C, alcohol-related liver disease, MAFLD, and hepatocellular carcinoma (HCC).

PLIN2 acts as a versatile diagnostic, prognostic, and predictive biomarker for different liver diseases. PLIN2 may also serve as a marker indicating susceptibility to cancer therapies and may also help in stratifying tumors based on their response to specific mitogen-targeting agents for personalized treatment with agents such as paclitaxel and TRIP13 inhibitors.

Research has also indicated that pharmacological inhibition of PLIN2 reduces infectious particle production, alleviates MAFLD by regulating lipid droplet metabolism, and prevents steatosis in ALD by regulating LD metabolism. PLIN2 is frequently up-regulated in HCC and promotes cell proliferation; therefore, targeting PLIN2 may improve existing therapies or create new opportunities for HCC treatment.

In conclusion, this review provides an extensive summary of the structure of PLIN2 and its functions in LD metabolism, with insights into its role in the pathogenesis of various liver diseases, its versatility as a diagnostic, prognostic, and predictive biomarker, and therapeutic implications in liver diseases.

Reference

Title of the original paper: Emerging roles and therapeutic implications of lipid droplet protein perilipin 2 in liver disease

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101712

Funding Information:

• National Natural Science Foundation of China (No. 82304180, 82103859)
• Fujian Province Natural Science Foundation (China) (No. 2023J011602)
• Guangdong Basic and Applied Basic Research Foundation (No. 2024A1515010893)
• Project funded by China Postdoctoral Science Foundation (No. 2022M713585, 2024T171083)
• Fujian Provincial Health and Medical Innovation Research Project (No. 2024CXB022)
• Xiamen Municipal Science and Technology Program for High-Quality Development in Health and Medicine–Medical Innovation Project (No. 2024GZL-CX23)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4 | Impact Factor: 9.4

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