This review describes midnolin (MIDN) as a newly identified ubiquitin-independent proteasome adapter (via a CUHC domain) that selectively targets nuclear transcription factors, implicating MIDN in neurodevelopment, synaptic plasticity, cancer, metabolic homeostasis, and Parkinson's disease while…

MIDN reveals a novel intranuclear proteasomal pathway that could be exploited to modulate disease-relevant transcriptional regulators in Parkinson's disease, offering a potentially actionable therapeutic or biomarker axis although current evidence is review-based and requires experimental…

A seminal 2023 study uncovered a groundbreaking function of midnolin (MIDN): it acts as a novel proteasome adapter that directly targets nuclear transcription factors via its unique "capture-ubiquitin-α-helix-C-terminal (CUHC)" domain, thereby defining a novel midnolin-proteasome pathway. Before this pivotal discovery, midnolin was only known for its cellular localization and associations with nervous system, cancer, and cell differentiation, remaining a largely functionally uncharacterized protein in mammals. Importantly, this newly identified pathway plays indispensable roles in neurodevelopment, synaptic plasticity, and metabolic homeostasis. MIDN is highly expressed in solid tumors and promotes tumorigenesis, whereas its downregulation or loss in hematologic malignancies results in oncogenic protein accumulation, indicating a tissue-dependent dual role. It is also implicated in diverse pathological processes, including Parkinson's disease, non-alcoholic fatty liver disease, and viral infections, mainly by modulating the stability of key transcriptional or metabolic regulators. These findings establish MIDN as a central regulator in cellular homeostasis and disease. However, several issues remain unresolved: its identified substrates are largely restricted to nuclear transcription factors; the universal applicability of β-sheet precursor recognition by the CUHC domain needs validation; and the regulatory and stability mechanisms of MIDN are still unclear. This review focus on the multifunctional roles of MIDN in development and disease, and proposes key future directions: dissecting tissue-specific regulation, molecular functional switching, and disease-specific substrates identification. These efforts will expand our understanding of the pathway and unlock its therapeutic potential, especially for developing therapeutic tools capable of accessing and modulating intranuclear targets to treat disease.