HnRNPK suppresses macrophage-driven inflammation in autoimmune myocarditis by restraining NCF1-dependent oxidized phospholipid signaling and ferroptosis-related changes.
- 1Department of Cardiology, Institute of Cardiovascular Diseases, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China.
- 2Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Abstract
NADPH oxidase-dependent ROS production, oxidized phospholipid (OxPL) signaling, and macrophage ferroptosis are emerging drivers of inflammatory cardiac injury, yet the upstream regulatory mechanisms governing these processes remain poorly understood. Here, we identify heterogeneous nuclear ribonucleoprotein K (HnRNPK), a multifunctional RNA-binding protein, as a post-transcriptional regulator of macrophage oxidative stress and ferroptosis-related changes in experimental autoimmune myocarditis (EAM). HnRNPK was significantly downregulated in EAM cardiac tissues and inflammatory macrophages, whereas AAV-HnRNPK administration attenuated myocardial inflammatory infiltration, fibrosis, and cardiac dysfunction and reduced macrophage pro-inflammatory activation. Mechanistically, HnRNPK regulated the balance between NR_104383 and coding Ncf1 transcripts, while NR_104383 knockdown and NCF1 add-back partially reversed its anti-inflammatory effects in BMDMs. NCF1 promoted ROS generation, lipid peroxidation, E06-reactive OxPL signals, mitochondria-associated ER membrane (MAM) remodeling, ER stress, and macrophage ferroptosis-related phenotypes. E06 treatment attenuated NCF1-associated MAM remodeling and partially restored GPX4 expression, whereas oxPAPC increased ER-mitochondria contacts and related molecular changes that were attenuated by E06. Together, these findings establish a functional HnRNPK/NR_104383/NCF1 axis linking alternative transcript regulation to NCF1-dependent redox injury, OxPL-associated MAM remodeling, and ferroptosis-related changes in inflammatory macrophages.
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BibTeX
@article{li2026hnrnpk,
title = {{HnRNPK suppresses macrophage-driven inflammation in autoimmune myocarditis by restraining NCF1-dependent oxidized phospholipid signaling and ferroptosis-related changes.}},
author = {Han Li and Wenhu Liu and Jing Hu and Jingjie Xiong and Xuehua Wang and Jiaxi Lv and Ni Xiong and Yanling Huang and Qianyi Liu and Lihui Yin and Yan Wang and Ya Wang and Zhaohui Wang},
journal = {Redox biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104429},
url = {https://europepmc.org/article/MED/42874131},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - HnRNPK suppresses macrophage-driven inflammation in autoimmune myocarditis by restraining NCF1-dependent oxidized phospholipid signaling and ferroptosis-related changes.
AU - Han Li
AU - Wenhu Liu
AU - Jing Hu
AU - Jingjie Xiong
AU - Xuehua Wang
AU - Jiaxi Lv
AU - Ni Xiong
AU - Yanling Huang
AU - Qianyi Liu
AU - Lihui Yin
AU - Yan Wang
AU - Ya Wang
AU - Zhaohui Wang
PY - 2026
DA - 2026/10/08
JO - Redox biology
DO - 10.1016/j.redox.2026.104429
UR - https://europepmc.org/article/MED/42874131
AB - NADPH oxidase-dependent ROS production, oxidized phospholipid (OxPL) signaling, and macrophage ferroptosis are emerging drivers of inflammatory cardiac injury, yet the upstream regulatory mechanisms governing these processes remain poorly understood. Here, we identify heterogeneous nuclear ribonucleoprotein K (HnRNPK), a multifunctional RNA-binding protein, as a post-transcriptional regulator of macrophage oxidative stress and ferroptosis-related changes in experimental autoimmune myocarditis (EAM). HnRNPK was significantly downregulated in EAM cardiac tissues and inflammatory macrophages, whereas AAV-HnRNPK administration attenuated myocardial inflammatory infiltration, fibrosis, and cardiac dysfunction and reduced macrophage pro-inflammatory activation. Mechanistically, HnRNPK regulated the balance between NR_104383 and coding Ncf1 transcripts, while NR_104383 knockdown and NCF1 add-back partially reversed its anti-inflammatory effects in BMDMs. NCF1 promoted ROS generation, lipid peroxidation, E06-reactive OxPL signals, mitochondria-associated ER membrane (MAM) remodeling, ER stress, and macrophage ferroptosis-related phenotypes. E06 treatment attenuated NCF1-associated MAM remodeling and partially restored GPX4 expression, whereas oxPAPC increased ER-mitochondria contacts and related molecular changes that were attenuated by E06. Together, these findings establish a functional HnRNPK/NR_104383/NCF1 axis linking alternative transcript regulation to NCF1-dependent redox injury, OxPL-associated MAM remodeling, and ferroptosis-related changes in inflammatory macrophages.
SN - 2213-2317
ER -