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SMYD2-mediated methylation of STAT1 protects against hepatic ischaemia/reperfusion injury by blocking JAK-STAT1
Zhiyong Yang1, Yufeng Hu1, Chunyong Yang1
1Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China.
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.
Insights
SET and MYND domain Containing 2 (SMYD2) negatively regulates signal transducers and activators of transcription 1 (STAT1) via methylation in hepatic ischemia/reperfusion (I/R) injury. Targeting this SMYD2-STAT1 axis may offer new therapeutic strategies for liver damage.
Area of Science:
- Hepatology
- Molecular Biology
- Epigenetics
Background:
- Hepatic ischemia/reperfusion (I/R) injury is a significant perioperative complication.
- Signal transducers and activators of transcription 1 (STAT1) activation exacerbates I/R injury.
- The specific post-translational modifications (PTMs) of STAT1 in hepatic I/R are not well understood.
Purpose of the Study:
- Identify novel regulators of STAT1 in hepatic I/R injury.
- Investigate the role of SET and MYND domain Containing 2 (SMYD2) in STAT1 modulation during hepatic I/R.
- Elucidate the mechanistic basis of SMYD2-mediated PTMs on STAT1.
Main Methods:
- Integrated transcriptomic-proteomic analysis and functional screening identified SMYD2.
- Clinical correlation of SMYD2 expression with postoperative liver function.
- In vitro and in vivo loss-of-function and gain-of-function studies validated SMYD2's role.
Main Results:
- SMYD2 regulates hepatic I/R injury via the JAK-STAT1 pathway.
- Elevated SMYD2 expression correlated with improved liver function and surgical outcomes.
- SMYD2 methylates STAT1 at K175, inhibiting its phosphorylation and nuclear translocation, thereby alleviating I/R injury.
Conclusions:
- SMYD2 acts as a novel negative regulator of STAT1 through K175 methylation.
- This study reveals an epigenetic mechanism controlling STAT1 signaling in hepatic I/R.
- Targeting the SMYD2-STAT1 axis presents a potential therapeutic strategy for I/R-associated liver damage.
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