The role of miR-186-5p in promoting PANoptosis and regulating chronic obstructive pulmonary disease_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZHANG Yu , WANG Liping , MA Jiajia , MAYINER·YIBULAYIN , WANG Enguang ,  WANG Haixu

The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P. R. China;

Corresponding?author：

WANG Haixu, Email: 1556040978@qq.com

Keywords：

Chronic obstructive pulmonary disease; miR-186-5p; PANoptosis; reactive oxygen species

DOI：

10.7507/1671-6205.202504073

Video：

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Objective To investigate the activation of PANoptosis in chronic obstructive pulmonary disease (COPD) and explore the potential regulatory role and molecular mechanism of miR-186-5p in PANoptosis. Methods Gene expression datasets related to COPD (GSE20257, GSE30063, GSE64614) were obtained, and Gene Set Variation Analysis (GSVA) was applied to assess the activation status of PANoptosis in COPD tissues. Differentially expressed PANoptosis-related genes were identified through differential expression analysis. The potential target genes of miR-186-5p were predicted using the TargetScan and ENCORI databases, and potential PANoptosis-regulating genes were identified. In cellular experiments, 16HBE cells were treated with cigarette smoke extract (CSE) to establish a COPD cell model. Cells were transfected with miR-186-5p mimic or inhibitor and divided into six groups: 16HBE, model, model + mimic-NC, model + miR-186-5p mimic, model + inhibitor-NC, and model + miR-186-5p inhibitor. RT-qPCR was used to detect the mRNA expression levels of miR-186-5p, the target gene HMGB1, and PANoptosis-related genes (RIPK1, RIPK3, Caspase-8, ZBP1, and NLRP3). Western blotting was used to measure the expression levels of HMGB1 and related proteins. ELISA was performed to detect inflammatory cytokines (IL-1β, IL-6, IL-18). Reactive oxygen species (ROS) levels were detected using fluorescent probes, and cell apoptosis was assessed by TUNEL staining. Results GSVA analysis showed that PANoptosis was significantly activated in COPD tissues (P<0.05). A total of 1361 differentially expressed genes were identified, among which eight PANoptosis-related genes were predicted to be targeted by miR-186-5p. miR-186-5p was significantly upregulated in COPD tissues, while its target gene HMGB1 was downregulated across all three datasets, suggesting a potential negative regulatory relationship. In the COPD cell model, the expression of miR-186-5p and PANoptosis-related genes (RIPK1, RIPK3, Caspase-8, ZBP1, NLRP3) was significantly increased, while HMGB1 expression was significantly decreased compared with the control group (P<0.05). Inhibition of miR-186-5p significantly downregulated the expression of PANoptosis-related genes and upregulated HMGB1 expression (P<0.05). Furthermore, compared with the model group, inhibition of miR-186-5p resulted in significant reductions in inflammatory cytokines (IL-1β, IL-6, IL-18), ROS levels, and cell apoptosis rate (P<0.05). Conclusion PANoptosis is significantly activated in COPD. miR-186-5p may exacerbate inflammation and cell apoptosis by promoting the expression of PANoptosis-related genes through targeted suppression of HMGB1.

Citation： ZHANG Yu, WANG Liping, MA Jiajia, MAYINER·YIBULAYIN, WANG Enguang, WANG Haixu. The role of miR-186-5p in promoting PANoptosis and regulating chronic obstructive pulmonary disease. Chinese Journal of Respiratory and Critical Care Medicine, 2025, 24(11): 775-784. doi: 10.7507/1671-6205.202504073 Copy

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11.	Dong L, Geng Z, Liu Z, et al. IGF2BP2 knockdown suppresses thyroid cancer progression by reducing the expression of long non-coding RNA HAGLR. Pathol Res Pract, 2021, 225: 153550.
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14.	Lamberti MJ, Montico B, Ravo M, et al. Integration of miRNA: mRNA co-expression revealed crucial mechanisms modulated in immunogenic cancer cell death. Biomedicines, 2022, 10(8): 1896.
15.	Tang Y, Zhang X, Wang S, et al. Up-regulation of lncRNA WT1-AS ameliorates Abeta-stimulated neuronal injury through modulation of miR-186-5p/CCND2 axis in Alzheimer's disease. Cell Mol Biol (Noisy-le-grand), 2024, 70(1): 200-206.
16.	Tamkini M, Nourbakhsh M, Movahedi M, et al. Unveiling the role of miR-186 in SIRT1 regulation in adipocytes: implications for adipogenesis and inflammation in obesity. J Diabetes Metab Disord, 2025, 24(1): 42.
17.	Fu Y, Zhao J, Chen J, et al. miR-186-5p regulates the inflammatory response of chronic obstructive pulmonary disorder by targeting HIF-1alpha. Mol Med Rep, 2024, 29(2): 34.
18.	Shi R, Liang R, Wang F, et al. Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD. Apoptosis, 2024, 29(11-12): 2091-2107.
19.	Wang S, Zhang Y. HMGB1 in inflammation and cancer. J Hematol Oncol, 2020, 13(1): 116.
20.	Lin L, Li J, Song Q, et al. The role of HMGB1/RAGE/TLR4 signaling pathways in cigarette smoke-induced inflammation in chronic obstructive pulmonary disease. Immun Inflamm Dis, 2022, 10(11): e711.
21.	Matarazzo L, Hernandez Santana YE, Walsh PT, et al. The IL-1 cytokine family as custodians of barrier immunity. Cytokine, 2022, 154: 155890.
22.	Panek I, Liczek M, Gabryelska A, et al. Inflammasome signalling pathway in the regulation of inflammation - its involvement in the development and exacerbation of asthma and chronic obstructive pulmonary disease. Postepy Dermatol Alergol, 2023, 40(4): 487-495.
23.	Cheung EC, Vousden KH. The role of ROS in tumour development and progression. Nat Rev Cancer, 2022, 22(5): 280-297.
24.	Fan X, Dong T, Yan K, et al. PM2. 5 increases susceptibility to acute exacerbation of COPD via NOX4/Nrf2 redox imbalance-mediated mitophagy. Redox Biol, 2023, 59: 102587.
25.	Wang Y, Wang W, Zhou S, et al. Poldip2 knockdown protects against lipopolysaccharide-induced acute lung injury via Nox4/Nrf2/NF-kappaB signaling pathway. Front Pharmacol, 2022, 13: 958916.
26.	Chang TM, Chi MC, Chiang YC, et al. Promotion of ROS-mediated apoptosis, G2/M arrest, and autophagy by naringenin in non-small cell lung cancer. Int J Biol Sci, 2024, 20(3): 1093-1109.
27.	Huang J, Zhou X, Xu Y, et al. Shen Qi Wan regulates OPN/CD44/PI3K pathway to improve airway inflammation in COPD: Network pharmacology, bioinformatics, and experimental validation. Int Immunopharmacol, 2025, 144: 113624.

1. Christenson SA, Smith B M, Bafadhel M, et al. Chronic obstructive pulmonary disease. Lancet, 2022, 399(10342): 2227-2242.
2. Chen X, Zhou CW, Fu YY, et al. Global, regional, and national burden of chronic respiratory diseases and associated risk factors, 1990-2019: Results from the Global Burden of Disease Study 2019. Front Med (Lausanne), 2023, 10: 1066804.
3. Vogelmeier CF, Roman-Rodriguez M, Singh D, et al. Goals of COPD treatment: Focus on symptoms and exacerbations. Respir Med, 2020, 166: 105938.
4. Ritchie AI, Wedzicha JA. Definition, Causes, Pathogenesis, and consequences of chronic obstructive pulmonary disease exacerbations. Clin Chest Med, 2020, 41(3): 421-438.
5. Sun X, Yang Y, Meng X, et al. PANoptosis: Mechanisms, biology, and role in disease. Immunol Rev, 2024, 321(1): 246-262.
6. Zheng M, Kanneganti TD. The regulation of the ZBP1-NLRP3 inflammasome and its implications in pyroptosis, apoptosis, and necroptosis (PANoptosis). Immunol Rev, 2020, 297(1): 26-38.
7. Shi C, Cao P, Wang Y, et al. PANoptosis: A cell death characterized by pyroptosis, apoptosis, and necroptosis. J Inflamm Res, 2023, 16: 1523-1532.
8. Wei L, Wang X, Zhou H. Interaction among inflammasome, PANoptosise, and innate immune cells in infection of influenza virus: Updated review. Immun Inflamm Dis, 2023, 11(9): e997.
9. Pandeya A, Kanneganti TD. Therapeutic potential of PANoptosis: innate sensors, inflammasomes, and RIPKs in PANoptosomes. Trends Mol Med, 2024, 30(1): 74-88.
10. Van Eeckhoutte HP, Donovan C, Kim R Y, et al. RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD. Eur Respir J, 2023, 61(4): 2201506.
11. Dong L, Geng Z, Liu Z, et al. IGF2BP2 knockdown suppresses thyroid cancer progression by reducing the expression of long non-coding RNA HAGLR. Pathol Res Pract, 2021, 225: 153550.
12. Song YD, Bai XM, Ma J. The association of systemic immune-inflammation index with lung function, risk of COPD and COPD severity: a population-based study. PLoS One, 2024, 19(6): e0303286.
13. Barnes PJ. Targeting cellular senescence as a new approach to chronic obstructive pulmonary disease therapy. Curr Opin Pharmacol, 2021, 56: 68-73.
14. Lamberti MJ, Montico B, Ravo M, et al. Integration of miRNA: mRNA co-expression revealed crucial mechanisms modulated in immunogenic cancer cell death. Biomedicines, 2022, 10(8): 1896.
15. Tang Y, Zhang X, Wang S, et al. Up-regulation of lncRNA WT1-AS ameliorates Abeta-stimulated neuronal injury through modulation of miR-186-5p/CCND2 axis in Alzheimer's disease. Cell Mol Biol (Noisy-le-grand), 2024, 70(1): 200-206.
16. Tamkini M, Nourbakhsh M, Movahedi M, et al. Unveiling the role of miR-186 in SIRT1 regulation in adipocytes: implications for adipogenesis and inflammation in obesity. J Diabetes Metab Disord, 2025, 24(1): 42.
17. Fu Y, Zhao J, Chen J, et al. miR-186-5p regulates the inflammatory response of chronic obstructive pulmonary disorder by targeting HIF-1alpha. Mol Med Rep, 2024, 29(2): 34.
18. Shi R, Liang R, Wang F, et al. Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD. Apoptosis, 2024, 29(11-12): 2091-2107.
19. Wang S, Zhang Y. HMGB1 in inflammation and cancer. J Hematol Oncol, 2020, 13(1): 116.
20. Lin L, Li J, Song Q, et al. The role of HMGB1/RAGE/TLR4 signaling pathways in cigarette smoke-induced inflammation in chronic obstructive pulmonary disease. Immun Inflamm Dis, 2022, 10(11): e711.
21. Matarazzo L, Hernandez Santana YE, Walsh PT, et al. The IL-1 cytokine family as custodians of barrier immunity. Cytokine, 2022, 154: 155890.
22. Panek I, Liczek M, Gabryelska A, et al. Inflammasome signalling pathway in the regulation of inflammation - its involvement in the development and exacerbation of asthma and chronic obstructive pulmonary disease. Postepy Dermatol Alergol, 2023, 40(4): 487-495.
23. Cheung EC, Vousden KH. The role of ROS in tumour development and progression. Nat Rev Cancer, 2022, 22(5): 280-297.
24. Fan X, Dong T, Yan K, et al. PM2. 5 increases susceptibility to acute exacerbation of COPD via NOX4/Nrf2 redox imbalance-mediated mitophagy. Redox Biol, 2023, 59: 102587.
25. Wang Y, Wang W, Zhou S, et al. Poldip2 knockdown protects against lipopolysaccharide-induced acute lung injury via Nox4/Nrf2/NF-kappaB signaling pathway. Front Pharmacol, 2022, 13: 958916.
26. Chang TM, Chi MC, Chiang YC, et al. Promotion of ROS-mediated apoptosis, G2/M arrest, and autophagy by naringenin in non-small cell lung cancer. Int J Biol Sci, 2024, 20(3): 1093-1109.
27. Huang J, Zhou X, Xu Y, et al. Shen Qi Wan regulates OPN/CD44/PI3K pathway to improve airway inflammation in COPD: Network pharmacology, bioinformatics, and experimental validation. Int Immunopharmacol, 2025, 144: 113624.

Chinese Journal of Respiratory and Critical Care Medicine

The role of miR-186-5p in promoting PANoptosis and regulating chronic obstructive pulmonary disease

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