The Role of Histone Demethylases in Autophagy and Inflammation

Background Introduction

Autophagy is an essential lysosomal degradation process in eukaryotic cells, playing a critical role in cellular component renewal and homeostasis maintenance. Dysregulation of autophagy is associated with various diseases, including cancer, inflammatory diseases, and neurodegenerative disorders. In recent years, the role of epigenetic modifications in autophagy regulation has gained increasing attention, with histone demethylases (KDMs) being recognized as important epigenetic regulators in autophagy and inflammation. However, the specific mechanisms by which KDMs regulate autophagy and inflammation remain incompletely understood. Therefore, this article aims to systematically review the regulatory roles of KDMs in autophagy and inflammation, providing a theoretical basis for the treatment of related diseases.

Source of the Paper

This article was co-authored by Yaoyao Ma, Wenting Lv, Yi Guo, and others, with affiliations including Hubei University of Science and Technology and Wuhan University. The paper was published in 2025 in the journal Cell Communication and Signaling under the title Histone Demethylases in Autophagy and Inflammation. This review article systematically summarizes the regulatory mechanisms of KDMs in autophagy and inflammation and their potential applications in disease treatment.

Main Content

1. Molecular Mechanisms of Autophagy and Their Relationship with KDMs

Autophagy is a highly complex cellular process, primarily categorized into macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). The initiation, elongation, maturation, and degradation of autophagy involve multiple autophagy-related genes (ATGs) and signaling pathways. Histone modifications, particularly histone lysine methylation, play a significant role in autophagy regulation. KDMs regulate the expression of autophagy-related genes by removing methylation marks on histones, thereby influencing the autophagy process.

2. Regulatory Roles of KDMs in Autophagy

The KDM family includes multiple subfamilies such as KDM1-KDM8, each regulating autophagy through different histone methylation sites. For example, KDM1A (also known as LSD1) inhibits autophagy by regulating the mTORC1 pathway, while KDM3A and KDM3B promote autophagy by activating autophagy-related genes such as TFEB, ATG5, and ATG7. Members of the KDM4 family (e.g., KDM4B) activate the expression of autophagy-related genes by demethylating H3K9me3 under nutrient-deficient conditions. The KDM6 family (e.g., KDM6A and KDM6B) promotes autophagy by regulating the expression of TFEB.

3. Regulatory Roles of KDMs in Inflammation

KDMs not only regulate autophagy but also participate in inflammatory responses by modulating the expression of inflammation-related genes. For instance, KDM1A promotes the production of inflammatory factors by regulating the TLR4/NF-κB signaling pathway, while KDM6B regulates macrophage polarization by demethylating H3K27me3, thereby influencing inflammatory responses. KDM4A and KDM4B also play significant roles in cardiovascular and neurological inflammation.

4. Potential of KDMs as Therapeutic Targets

KDM inhibitors have shown potential therapeutic value in regulating autophagy and inflammation. For example, KDM1A inhibitors (e.g., TCP and GSK-LSD1) promote autophagy by activating the SESN2/mTORC1 pathway, thereby inhibiting tumor growth. KDM6 inhibitors (e.g., GSK-J4) suppress the production of inflammatory factors by regulating H3K27me3, offering therapeutic potential for diseases such as inflammatory bowel disease and rheumatoid arthritis.

Significance and Value of the Paper

This article systematically summarizes the regulatory mechanisms of KDMs in autophagy and inflammation, providing new insights into the molecular mechanisms of these processes. Additionally, it explores the potential applications of KDM inhibitors in disease treatment, offering a theoretical basis for the development of novel therapeutic strategies. Although research on KDM inhibitors is still in its early stages, their potential in regulating autophagy and inflammation warrants further exploration.

Highlights and Innovations

1. Systematic Review: This article is the first to systematically summarize the regulatory roles of KDMs in autophagy and inflammation, filling a research gap in this field.
2. Multidimensional Analysis: The article not only discusses the regulatory mechanisms of KDMs in autophagy but also analyzes their roles in inflammation, providing comprehensive theoretical support for the treatment of related diseases.
3. Therapeutic Potential: The article thoroughly discusses the application prospects of KDM inhibitors in disease treatment, offering important references for future drug development.

Conclusion

As crucial epigenetic regulators, KDMs play a key role in autophagy and inflammation. By systematically reviewing the regulatory mechanisms of KDMs and their potential in disease treatment, this article provides a significant theoretical foundation for related research. In the future, the development of KDM inhibitors is expected to bring new breakthroughs in the treatment of autophagy- and inflammation-related diseases.