HnRNPK suppresses macrophage-driven inflammation in autoimmune myocarditis by restraining NCF1-dependent oxidized phospholipid signaling and ferroptosis-related changes

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.