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

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.