TY - JOUR
T1 - Activation of APE1 modulates Nrf2 protected against acute liver injury by inhibit hepatocyte ferroptosis and promote hepatocyte autophagy
AU - Diao, Jianxin
AU - Fan, Huijie
AU - Zhang, Jia
AU - Fu, Xiuqiong
AU - Liao, Rongxin
AU - Zhao, Peng
AU - Huang, Wei
AU - Huang, Shiying
AU - Liao, Huajun
AU - Yu, Jieying
AU - Pan, Dongmei
AU - Wang, Ming
AU - Xiao, Wei
AU - Wen, Xiaomin
N1 - This work was supported by the National Natural Science Foundation of China (No. 82074257, 82174323 and 82004103), the Natural Science Foundation of Guangdong Province (2019A1515011034, 2023A1515011200 and 2022A1515011668), the Project of Administration of Traditional Chinese Medicine of Guangdong Province (20232068) and the Scientific Research Fund of People's Hospital of Yangjiang (No. G2020001).
Publisher Copyright:
© 2024 The Author(s)
PY - 2024/2/20
Y1 - 2024/2/20
N2 - Background: Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) plays a crucial role in DNA base excision repair, cell apoptosis, cell signaling, and the regulation of transcription factors through redox modulation and the control of reactive oxygen species (ROS). However, the connection between APE1 and acute liver injury (ALI) remains enigmatic. This study aims to unravel the molecular mechanisms underlying ALI and shed light on the role of APE1 in this context. Method: We induced acute liver injury (ALI) in mice by lipopolysaccharide/D-galactosamine (LPS/GalN) and intervened with the APE1 inhibitor E3330. We examined the expression of APE1 in ALI mice and ALI patient tissues after E3330 intervention, Additionally, we measured hepatic oxidative stress, ferroptosis, and autophagy marker proteins and genes. In establishing an AML-12 liver cell injury model, we utilized the Nrf2 activator tert-butylhydroquinone (TBHQ) as an intervention and examined APE1, Nrf2, ferroptosis-related proteins, and autophagy marker proteins and mRNA. Results: Both ALI patients and ALI mice exhibited reduced APE1 expression levels. After E3330 intervention, there was a significant exacerbation of liver injury, oxidative stress, and a reduction in the expression of proteins, including GPX4, X-CT, ATG3, ATG5, and LC3 (LC3I/II). Consistent results were also observed in AML-12 cells. With TBHQ intervention, Nrf2 expression increased, along with the expression of proteins associated with iron death and autophagy. Mechanistically, APE1 activation regulates Nrf2 to inhibit ferroptosis and promote autophagy in hepatocytes. Conclusion: The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury.
AB - Background: Apurinic/apyrimidinic endonuclease 1/redox effector factor 1 (APE1/Ref-1) plays a crucial role in DNA base excision repair, cell apoptosis, cell signaling, and the regulation of transcription factors through redox modulation and the control of reactive oxygen species (ROS). However, the connection between APE1 and acute liver injury (ALI) remains enigmatic. This study aims to unravel the molecular mechanisms underlying ALI and shed light on the role of APE1 in this context. Method: We induced acute liver injury (ALI) in mice by lipopolysaccharide/D-galactosamine (LPS/GalN) and intervened with the APE1 inhibitor E3330. We examined the expression of APE1 in ALI mice and ALI patient tissues after E3330 intervention, Additionally, we measured hepatic oxidative stress, ferroptosis, and autophagy marker proteins and genes. In establishing an AML-12 liver cell injury model, we utilized the Nrf2 activator tert-butylhydroquinone (TBHQ) as an intervention and examined APE1, Nrf2, ferroptosis-related proteins, and autophagy marker proteins and mRNA. Results: Both ALI patients and ALI mice exhibited reduced APE1 expression levels. After E3330 intervention, there was a significant exacerbation of liver injury, oxidative stress, and a reduction in the expression of proteins, including GPX4, X-CT, ATG3, ATG5, and LC3 (LC3I/II). Consistent results were also observed in AML-12 cells. With TBHQ intervention, Nrf2 expression increased, along with the expression of proteins associated with iron death and autophagy. Mechanistically, APE1 activation regulates Nrf2 to inhibit ferroptosis and promote autophagy in hepatocytes. Conclusion: The data suggest that APE1 is a pivotal player in ALI, closely linked to its regulation of Nrf2. Strategies involving APE1 activation to modulate Nrf2, thereby inhibiting hepatocyte ferroptosis and promoting autophagy, may represent innovative therapeutic approaches for ALI. Additionally, tert-butylhydroquinone (TBHQ) holds significant promise in the treatment of acute liver injury.
KW - Acute liver injury
KW - Apurinic/apyrimidinic endonuclease 1/redox effector factor 1
KW - Autophagy
KW - Ferroptosis
KW - Nuclear erythroid factor 2 like 2
UR - http://www.scopus.com/inward/record.url?scp=85183559247&partnerID=8YFLogxK
U2 - 10.1016/j.intimp.2024.111529
DO - 10.1016/j.intimp.2024.111529
M3 - Journal article
C2 - 38244516
AN - SCOPUS:85183559247
SN - 1567-5769
VL - 128
JO - International Immunopharmacology
JF - International Immunopharmacology
M1 - 111529
ER -