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NSUN2 relies on ALYREF to regulate Nrf2-mediated oxidative stress and alleviate Dox-induced liver injury
Yingying Huang1, Xiao Li1, Lin Wei1
1Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China.
Background:
Doxorubicin (Dox) is associated with various liver injuries, limiting its clinical utility. This study investigates whether NSUN2 participates in Dox-induced liver injury and the associated molecular mechanism.
Methods:
In vivo and in vitro liver cell injury models were constructed based on Dox therapy. The protein levels of NSUN2 and oxidative stress indicators Nrf2, HO-1, and NQO1 were evaluated by Western blot. The RNA binding potential was detected by RNA methylation immunoprecipitation (RIP). Additionally, the effect of NSUN2 on Nrf2 mRNA synthesis and localization was evaluated using an RNA fluorescence probe.
Results:
NSUN2 was downregulated, and liver tissue suffered significant pathological damage in the Dox group. The levels of ALT and AST significantly increased. NSUN2 interference exacerbated Dox-induced liver cell damage, which was reversed by NSUN2 overexpression. RIP demonstrated that NSUN2 recognized and bound to Nrf2 mRNA. Western blot analysis showed the protein level of Nrf2 in the NSUN2-WT group was significantly higher than that of the control group, whereas there was no significant change in Nrf2 level in the mutant NSUN2 group. Luciferase analysis demonstrated that NSUN2 could recognize and activate the Nrf2 5'UTR region of LO2 cells. In addition, RIP analysis revealed that ALYREF could recognize and bind to Nrf2 mRNA and that ALYREF controls the regulatory effect of NSUN2 on Nrf2.
Conclusion:
NSUN2 regulates Dox-induced liver cell damage by increasing Nrf2 mRNA m5C methylation to inhibit inhibiting antioxidant stress. The regulatory effect of NSUN2 on Nrf2 depends on ALYREF.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) protects against doxorubicin (Dox)-induced liver injury by increasing antioxidant stress. NSUN2 regulates Nrf2 mRNA methylation, impacting liver cell damage.
Area of Science:
- Hepatology
- Molecular Biology
- Pharmacology
Background:
- Doxorubicin (Dox) chemotherapy can cause significant liver injury, limiting its use.
- The role of NSUN2 in Dox-induced hepatotoxicity remains unclear.
Purpose of the Study:
- To investigate the involvement of NSUN2 in Dox-induced liver injury.
- To elucidate the molecular mechanism underlying NSUN2's role in this process.
Main Methods:
- Established in vivo and in vitro models of Dox-induced liver injury.
- Assessed protein levels of NSUN2 and oxidative stress markers (Nrf2, HO-1, NQO1) via Western blot.
- Utilized RNA immunoprecipitation (RIP) and RNA fluorescence probes to evaluate NSUN2-Nrf2 mRNA interactions and regulation.
Main Results:
- Doxorubicin treatment downregulated NSUN2 and caused liver damage, evidenced by elevated ALT/AST levels.
- NSUN2 knockdown worsened Dox-induced liver injury, while NSUN2 overexpression protected against it.
- NSUN2 directly binds to Nrf2 mRNA, enhancing Nrf2 protein levels and activating the Nrf2 5'UTR region, a process dependent on ALYREF.
Conclusions:
- NSUN2 protects against Dox-induced liver injury by methylating Nrf2 mRNA (m5C), thereby enhancing antioxidant stress responses.
- The regulatory function of NSUN2 on Nrf2 is mediated through its interaction with ALYREF.
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