UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis.

Abstract

K63-linked ubiquitination (K63) is closely associated with the interaction, intracellular trafficking or activity of tagged proteins. However, its role during metabolic dysfunction-associated steatohepatitis (MASH) is largely unknown. Here we show that UBE2N, a ubiquitin-conjugating enzyme that specializes in creating K63, is downregulated by THAP11 in human and mouse hepatocytes with MASH. While hepatocyte-specific Ube2n deficiency exacerbates western diet-induced MASH and fibrosis via PANoptosis and impaired mitophagy, its overexpression reverses these pathological phenotypes and restores hepatic homeostasis. Mechanistically, UBE2N increases PARKIN-mediated K63-p62 at lysine 420, promoting K63-p62 translocation into damaged mitochondria for mitophagic clearance. Ube2n deficiency, conversely, induces cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis. Additional Sqstm1 deletion mitigates Ube2n deletion-induced pathologies, highlighting the importance of p62 accumulation for MASH progression. Thus, our results demonstrate that hepatocyte UBE2N is essential for regulation of metabolic stress-mediated mitophagy and PANoptosis, and that p62 is a proof-of-concept target for treating MASH and fibrosis.

Key Findings

• UBE2N is downregulated in hepatocytes with MASH and its deficiency exacerbates disease via PANoptosis and impaired mitophagy.
• UBE2N promotes PARKIN-mediated K63-p62 ubiquitination, facilitating mitophagic clearance of damaged mitochondria.
• UBE2N deficiency leads to cytoplasmic p62 accumulation and NRF2 hyperactivation, driving PANoptosis and MASH progression.

Clinical Significance

Citation

Wang Feng, Lee Jin, Park Jeong-Suet al.. UBE2N deficiency contributes to MASH development via p62-regulated mitophagy and PANoptosis. Nature metabolism. 2026-Sep-04.