Journal
THERANOSTICS
Volume 12, Issue 4, Pages 1570-1588Publisher
IVYSPRING INT PUBL
DOI: 10.7150/thno.67722
Keywords
G alpha(12); acetaminophen-induced liver injury; miR-15a; ALOX12; GPX4
Categories
Funding
- National Research Foundation of Korea (NRF) - Korean government (MSIP) [NRF-2021R1A2B5 B03086265]
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This study demonstrates that ER stress-induced overexpression of G alpha(12) in hepatocytes promotes ferroptosis through dysregulation of ALOX12 mediated by ROCK1, as well as decreased miR-15a. Inhibition of G alpha(12) overexpression and/or the ROCK1 axis may be a promising therapeutic strategy for acute liver injury.
Rationale: Liver injury must be further characterized to identify novel therapeutic approaches. Endoplasmic reticulum (ER) stress may cause hepatocyte death. G alpha(12) affects cell viability and its expression varies depending on physiological conditions. This study investigated whether hepatocyte-specific G alpha(12) overexpression affects acute liver injury, and if so, what the underlying mechanisms and treatment strategies are. Methods: All experiments were performed using human liver, hepatocytes, and toxicant injury models with Gna12 KO and/or hepatocyte-specific G alpha(12) overexpression. RNA-sequencing, immunoblotting, immunohistochemistry, reporter assays, and mutation assays were conducted. Results: Hepatic G alpha(12) was overexpressed in mice challenged with acetaminophen or other ER stress inducers or in patients with acute liver injury or fibrosis/cirrhosis. Several G alpha(12) and ER-associated pathways were identified using transcriptomic analysis. Acetaminophen intoxication was characterized by lipid peroxide-induced ferroptosis and was less severe in G alpha(12)-deficient animals and cells. Conversely, G alpha(12) overexpression in wild-type or Gna12 KO hepatocytes increased hepatotoxicity, promoting lipid peroxidation, inflammation, and ferroptosis. IRE1 alpha-dependent Xbp1 transactivated Gna12. Moreover, G alpha(12) overexpression enhanced the ability of acetaminophen to induce ALOX12, while downregulating GPX4. The level of miR-15a, herein identified as an ALOX12 inhibitor, was decreased. siRNA knockdown or pharmacological inhibition of ROCK1 prevented dysregulation of ALOX12 and GPX4, rescuing animals from toxicant-induced ferroptosis. These changes or correlations among the targets were confirmed in human liver specimens and datasets of livers exposed to other injurious medications. Conclusions: G alpha(12) overexpression by ER stress facilitates hepatocyte ferroptosis through ROCK1-mediated dysregulation of ALOX12, and miR-15a, supporting the concept that inhibition of G alpha(12) overexpression and/or ROCK1 axis may constitute a promising strategy for acute liver injury.
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