Plasma exosomal miR-25-3p alleviates acute pancreatitis-associated lung injury by inhibiting ferroptosis of type II alveolar epithelial cells via NOX4/NCOA4-mediated ferritinophagy
Zixin Wang, Zijian Huang, Jiafu Wang, Liang Zhang, Long Cheng, Meng He, Xuchen Hu, Junpeng Wu, Yusen Feng, Liang Ji, Yan Jin, Gang WangAbstract
Background and Objectives
Acute pancreatitis-associated lung injury (AP-LI) is a severe complication with limited therapeutic options. This study investigated the role of plasma exosomes in AP-LI and the underlying molecular mechanism.
Methods
A murine AP-LI model and primary alveolar type II epithelial (AT2) cells were used. Small RNA sequencing, bioinformatic and enrichment analyses, functional assays, and in vivo and in vitro rescue experiments were performed to identify key exosomal miRNAs and define their downstream signaling pathways.
Results
Plasma exosomes aggravated AP-LI. Small RNA sequencing revealed marked alterations in exosomal miRNA profiles, with miR-25–3p identified as a key candidate associated with oxidative stress and ferroptosis. NADPH oxidase 4 (NOX4) was predicted and validated as a direct target of miR-25–3p. miR-25–3p suppressed NOX4 expression and attenuated ferroptosis in AT2 cells. Nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy acted downstream of NOX4, promoted iron dysregulation, and reinforced ferroptotic injury. Rescue experiments confirmed the protective role of the miR-25–3p/NOX4/NCOA4 axis.
Conclusions
Plasma exosomal miR-25–3p alleviates AP-LI by repressing NOX4 and limiting NCOA4-mediated ferritinophagy and ferroptosis, suggesting a potential therapeutic target for pulmonary complications of acute pancreatitis.