Cell Commun Signal. 2026 Jan 21. doi: 10.1186/s12964-026-02668-8. Online ahead of print.
ABSTRACT
BACKGROUND AND AIMS: Metabolic associated fatty liver disease (MAFLD) is closely associated with metabolic disorders, including central obesity, dyslipidaemia, hypertension, hyperglycaemia and persistent abnormalities of liver function tests. Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of MAFLD, characterized by chronic inflammation and accumulation of fat in liver tissue. Currently, no pharmacological interventions specifically tailored for MASH are approved. Signal transducer and activator of transcription 1 (STAT1) is the key transcription factor of the JAK-STAT signaling pathway, participating in physiological and pathological processes such as immune regulation, inflammatory response, antiviral defense, cell proliferation and apoptosis, and plays an important regulatory role in the occurrence and development of MASH. However, the post-translational modification of STAT1 in MASH is unclarified.
METHODS AND RESULTS: We identified that STAT1 was increased in MASH due to the inhibition of ubiquitination levels. Mechanistically, we showed that TRIM21 directly binds to STAT1 and promotes STAT1 degradation by accelerating lysine residue at 48 site-linked ubiquitination. Through gain- and loss-of-function studies in Trim21 knockout mice and adenovirus-treated models (in vivo and in vitro), we further demonstrated TRIM21's protective role in MASH. Collectively, our investigations have revealed that TRIM21 suppresses hepatocyte steatosis relying on regulating STAT1.
CONCLUSION: The ubiquitination of STAT1 in MASH is regulated by TRIM21 which is a key suppressor of MASH. TRIM21 acts as a negative regulator in hepatic steatosis and offers potential therapeutic opportunities for MASH.
PMID:41559695 | DOI:10.1186/s12964-026-02668-8