Dual roles of Makorin ring finger protein 1 in ubiquitination and RNA biology: regulatory mechanisms and therapeutic implications in human diseases

Jia-Le Wu; Zi-Xuan Wang; Jie Chen; Hai-Jing Zhong; Yang Guan-Jun

doi:10.1016/j.bcp.2025.117441

Dual roles of Makorin ring finger protein 1 in ubiquitination and RNA biology: regulatory mechanisms and therapeutic implications in human diseases

Biochem Pharmacol. 2025 Oct 21:117441. doi: 10.1016/j.bcp.2025.117441. Online ahead of print.

Authors

Jia-Le Wu¹, Zi-Xuan Wang², Jie Chen³, Hai-Jing Zhong⁴, Yang Guan-Jun⁵

Affiliations

¹ Zhejiang Lishui Service Platform for Technological Innovations in Traditional Chinese Medicine Industry, Lishui University, Lishui 323000, China.
² State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE) of China, School of Pharmacy, Jinan University, Guangzhou 510632, China.
³ Zhejiang Lishui Service Platform for Technological Innovations in Traditional Chinese Medicine Industry, Lishui University, Lishui 323000, China. Electronic address: jchen@lsu.edu.cn.
⁴ State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE) of China, School of Pharmacy, Jinan University, Guangzhou 510632, China. Electronic address: hjzhong@jnu.edu.cn.
⁵ State Key Laboratory for Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo 315211 Zhejiang, China. Electronic address: champion2014@16.com.

PMID: 41130303
DOI: 10.1016/j.bcp.2025.117441

Abstract

Ubiquitination dynamically regulates protein stability and signaling networks through post-translational modifications. Makorin ring finger protein 1 (MKRN1) is a unique member of the MKRN family that functions as E3 ubiquitin ligase and RNA-binding protein. It maintains cellular homeostasis via a dual regulatory mechanism involving ubiquitination and RNA biology. This review summarizes the regulatory mechanisms of MKRN1 in core pathways, such as p53-p21, Wnt/β-catenin, transforming growth factor beta, phosphatidylinositol 3 kinase/protein kinase, nuclear factor kappa B, and various pathological states, including metabolic disorders, tuberculosis, and cancer. We critically evaluated its structural architecture, disease-related functions, and pharmacological potential of MKRN1. We highlight that therapeutic targeting strategies, such as indirect inhibitors of KDM7A, discuss challenges in the development of direct MKRN1-targeting drugs, and propose that elucidating the interaction between MKRN1 in the ubiquitin-proteasome system and RNA regulatory system may open new avenues for the treatment of human diseases. Overall, MKRN1 exhibits complex, context-dependent roles across various diseases, making it a challenging yet compelling therapeutic target.

Keywords: Diseases; Inhibitor; Makorin ring finger protein 1; Signaling pathways; Ubiquitination.

Publication types

Review