SMYD2-mediated methylation of STAT1 protects against hepatic ischaemia/reperfusion injury by blocking JAK-STAT1 signalling pathways.

ABSTRACT:

Background

The JAK/STAT pathway plays a pivotal role in hepatic ischaemia/reperfusion (I/R) injury, a serious perioperative complication. Although signal transducers and activators of transcription 1 (STAT1) activation is known to drive I/R-induced injury, the specific post-translational modifications (PTMs) governing its activity in hepatic I/R remain poorly understood.

Objective

This study identifies SMYD2, SET and MYND domain Containing 2 (SMYD2) as a critical regulator of STAT1 and investigates the mechanistic basis of SMYD2-mediated PTMs in modulating STAT1 function during hepatic I/R.

Design

Using an integrated transcriptomic-proteomic approach and functional screening, we identified SMYD2 as a critical regulator of STAT1 activation in hepatic I/R injury. Clinical correlations linked SMYD2 expression to postoperative liver function, while loss-of-function and gain-of-function studies in vitro and in vivo validated its mechanistic role.

Results

Our findings demonstrate that SMYD2 modulates hepatic I/R injury through the JAK-STAT1 pathway. Clinically, elevated SMYD2 expression correlated with improved liver function and better surgical outcomes following hepatectomy. Mechanistic studies revealed that SMYD2 physically interacts with STAT1 and mediates its methylation at lysine 175 (K175), thereby inhibiting STAT1 phosphorylation and nuclear translocation. Both in vitro and in vivo studies demonstrated that SMYD2 overexpression alleviated hepatic I/R injury, whereas its genetic depletion or pharmacological inhibition exacerbated the damage.

Conclusion

This study establishes SMYD2 as a novel negative regulator of STAT1 activity through K175 methylation, providing new insights into the epigenetic control of STAT1 during hepatic I/R injury. Our findings reveal a previously unrecognised mechanism for fine-tuning STAT1 signalling in hepatic I/R injury, and targeting the SMYD2-STAT1 axis may present a promising therapeutic strategy for mitigating I/R-associated liver damage.

SUBMITTER: Yang Z 

PROVIDER: S-EPMC12911573 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature