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MicroRNA-29a-3p Prevents Drug-Induced Acute Liver Failure through Inflammation-Related Pyroptosis Inhibition
Dan-Dan Xiang1, Jing-Tao Liu2, Zi-Biao Zhong3
1Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Objective:
Little is known about the role of microRNA-29a-3p (miR-29a-3p) in inflammation-related pyroptosis, especially in drug-induced acute liver failure (DIALF). This study aimed to identify the relationship between miR-29a-3p and inflammation-related pyroptosis in DIALF and confirm its underlying mechanisms.
Methods:
Thioacetamide (TAA)- and acetaminophen (APAP)-induced ALF mouse models were established, and human samples were collected. The expression levels of miR-29a-3p and inflammation and pyroptosis markers were measured by quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting, or immunochemical staining in miR-29a-3p knock-in transgenic mouse (MIR29A(KI/KI)) DIALF models. In addition, RNA sequencing was conducted to explore the mechanisms.
Results:
MiR-29a-3p levels were decreased in TAA- and APAP-induced DIALF models. MiR-29a-3p prevented DIALF caused by TAA and APAP. RNA sequencing and further experiments showed that the protective effect of miR-29a-3p on DIALF was mainly achieved through inhibition of inflammation-related pyroptosis, and the inhibition was dependent on activation of the PI3K/AKT pathway. In addition, miR-29a-3p levels were reduced, and pyroptosis was activated in both peripheral blood mononuclear cells and liver tissues of DIALF patients.
Conclusion:
The study supports the idea that miR-29a-3p inhibits pyroptosis by activating the PI3K/AKT pathway to prevent DIALF. MiR-29a-3p may be a promising therapeutic target for DIALF.
Insights
MicroRNA-29a-3p (miR-29a-3p) protects against drug-induced acute liver failure (DIALF) by inhibiting inflammation-related pyroptosis via the PI3K/AKT pathway. Lower miR-29a-3p levels are observed in DIALF patients, suggesting its therapeutic potential.
Area of Science:
- Molecular Biology
- Hepatology
- Immunology
Background:
- Drug-induced acute liver failure (DIALF) pathogenesis involves inflammation and pyroptosis.
- The role of microRNA-29a-3p (miR-29a-3p) in DIALF and pyroptosis remains largely unknown.
Purpose of the Study:
- To investigate the relationship between miR-29a-3p and inflammation-related pyroptosis in DIALF.
- To elucidate the underlying molecular mechanisms of miR-29a-3p in DIALF.
Main Methods:
- Established thioacetamide (TAA)- and acetaminophen (APAP)-induced DIALF mouse models and utilized human samples.
- Quantified miR-29a-3p, inflammation, and pyroptosis markers using qRT-PCR, Western blotting, and immunochemical staining.
- Employed RNA sequencing in miR-29a-3p knock-in transgenic mice (MIR29A(KI/KI)) to explore mechanisms.
Main Results:
- miR-29a-3p levels were significantly decreased in TAA- and APAP-induced DIALF models.
- Overexpression of miR-29a-3p demonstrated a protective effect against TAA- and APAP-induced DIALF.
- RNA sequencing revealed that miR-29a-3p inhibits inflammation-related pyroptosis by activating the PI3K/AKT pathway.
- Reduced miR-29a-3p and activated pyroptosis were observed in DIALF patients' peripheral blood mononuclear cells and liver tissues.
Conclusions:
- miR-29a-3p exerts a protective role in DIALF by suppressing pyroptosis through PI3K/AKT pathway activation.
- miR-29a-3p represents a potential therapeutic target for managing DIALF.
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