TNFRSF17 Knockdown Alleviates Mitochondrial Dysfunction and Inflammation in COPD Through Suppression of the JAK2/STAT3 Pathway

ABSTRACT Mitochondrial dysfunction is a hallmark of chronic obstructive pulmonary disease (COPD). Nevertheless, the precise molecular mechanisms of COPD have yet to be fully elucidated. Protein−protein interaction (PPI) network construction and weighted gene co‐expression network analysis (WGCNA) were conducted to identify hub genes related to mitochondrial homeostasis. A TNF receptor superfamily member 17 (TNFRSF17)‐knockdown model was established in human bronchial epithelial (HBE) cells treated with cigarette smoke extract (CSE), and in mice exposed to CS and lipopolysaccharide (LPS). Cell counting kit‐8, enzyme‐linked immunosorbent assay, flow cytometry, JC‐1 staining, senescence‐associated β‐galactosidase staining, western blot analysis, and hematoxylin−eosin staining were used to evaluate cellular function, inflammation, and pathology. The involvement of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway was investigated using colivelin analog 1 (C‐A1). CD19, POU2AF1, FCRLA, and TNFRSF17 were identified as mitochondrial homeostasis‐related hub genes, all of which were upregulated in COPD. Following TNFRSF17 knockdown, COPD mice exhibited reduced alveolar destruction, inflammatory cell infiltration, and collagen deposition. TNFRSF17 knockdown alleviated CS‐induced mitochondrial membrane depolarization, calcium overload, reactive oxygen species (ROS) accumulation, ATP depletion, IL‐6 and TNF‐α secretion, and cellular senescence both in vitro and in vivo. TNFRSF17 knockdown suppressed the phosphorylation of JAK2 and STAT3. The protective effects mediated by TNFRSF17 knockdown were significantly abrogated by the C‐A1 treatment. TNFRSF17 knockdown inhibits mitochondrial dysfunction, inflammation, and senescence in COPD by obstructing the JAK2/STAT3 pathway, offering a promising therapeutic strategy for COPD.