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

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.