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J Adv Res
. 2025 May 9:S2090-1232(25)00299-1.
doi: 10.1016/j.jare.2025.05.005. Online ahead of print. Palmitoylated COX-2Cys555 reprogramed mitochondrial metabolism in pyroptotic inflammatory injury in patients with post-acute COVID-19 syndrome
Jia-Shen Wu 1 , Chi-Yu Xu 2 , Su-Min Mo 3 , Xin-Mou Wu 4 , Ze-Bang Du 5 , Lin Che 6 , Yi-Ling Zhang 7 , Kai-Li Yang 8 , Ting-Dong Li 9 , Sheng-Xiang Ge 10 , Tian-Ying Zhang 11 , Zhong-Ning Lin 12 , Yu-Chun Lin 13
Affiliations
Introduction: The complex interplay between protein palmitoylation, mitochondrial dynamics, and inflammatory responses plays a pivotal role in respiratory diseases. One significant features of post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) is the occurrence of a storm of inflammatory cytokines related to the NOD-like receptor protein 3 (NLRP3). However, the specific mechanisms via which palmitoylation affects mitochondrial function and its impact on the NLRP3 inflammasome under pathological respiratory conditions remain to be elucidated.
Objective: This study aimed to investigate how protein palmitoylation influences the inflammatory responses and mitochondrial dynamics in respiratory diseases, such as those induced by the SARS-CoV-2 spike S protein in PACS, thereby providing a therapeutic target for inflammatory lung injury.
Methods: In vivo experiments were conducted using AdV5-pADM-CMV-COVID-19-S (AdV5-S) nasal drip-treated C57BL/6 mice to assess NLRP3 inflammasome activation and inflammatory response. In vitro experiments were performed using pCMV-S-transfected human lung epithelial BEAS-2B cells to analyze the effects of DHHC5-mediated palmitoylation of cyclooxygenase-2 (COX-2) at cysteine 555 (COX-2Cys555) on mitochondrial metabolism and NLRP3 inflammasome activation.
Results: Palmitoylation of COX-2Cys555 enhanced its interaction with hexokinase 2 (HK2) to regulate mitochondrial metabolic reprogramming, leading to NLRP3 inflammasome activation and pyroptosis. Pharmacological and genetic suppression of palmitoylation diminished the mitochondrial localization of palmitoylated COX-2 and its interaction with HK2, thereby reducing mitochondrial metabolic reprogramming. Furthermore, genetic intervention targeting DHHC5 (shDhhc5) alleviated NLRP3 activation and pyroptosis, mitigating the chronic inflammatory damage associated with PACS.
Conclusion: This study highlights the regulatory role of COX-2Cys555 palmitoylation in mitochondrial metabolism and lung inflammatory injury, and suggests potential therapeutic targets to combat respiratory pathogenesis linked to palmitoylated COX-2.
Keywords: COX-2 palmitoylation; Lung inflammatory injury; Mitochondrial metabolic reprogramming; NLRP3 inflammasome activation; Post-acute COVID-19 syndrome (PACS); SARS-CoV-2 spike protein.
. 2025 May 9:S2090-1232(25)00299-1.
doi: 10.1016/j.jare.2025.05.005. Online ahead of print. Palmitoylated COX-2Cys555 reprogramed mitochondrial metabolism in pyroptotic inflammatory injury in patients with post-acute COVID-19 syndrome
Jia-Shen Wu 1 , Chi-Yu Xu 2 , Su-Min Mo 3 , Xin-Mou Wu 4 , Ze-Bang Du 5 , Lin Che 6 , Yi-Ling Zhang 7 , Kai-Li Yang 8 , Ting-Dong Li 9 , Sheng-Xiang Ge 10 , Tian-Ying Zhang 11 , Zhong-Ning Lin 12 , Yu-Chun Lin 13
Affiliations
- PMID: 40349960
- DOI: 10.1016/j.jare.2025.05.005
Introduction: The complex interplay between protein palmitoylation, mitochondrial dynamics, and inflammatory responses plays a pivotal role in respiratory diseases. One significant features of post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) is the occurrence of a storm of inflammatory cytokines related to the NOD-like receptor protein 3 (NLRP3). However, the specific mechanisms via which palmitoylation affects mitochondrial function and its impact on the NLRP3 inflammasome under pathological respiratory conditions remain to be elucidated.
Objective: This study aimed to investigate how protein palmitoylation influences the inflammatory responses and mitochondrial dynamics in respiratory diseases, such as those induced by the SARS-CoV-2 spike S protein in PACS, thereby providing a therapeutic target for inflammatory lung injury.
Methods: In vivo experiments were conducted using AdV5-pADM-CMV-COVID-19-S (AdV5-S) nasal drip-treated C57BL/6 mice to assess NLRP3 inflammasome activation and inflammatory response. In vitro experiments were performed using pCMV-S-transfected human lung epithelial BEAS-2B cells to analyze the effects of DHHC5-mediated palmitoylation of cyclooxygenase-2 (COX-2) at cysteine 555 (COX-2Cys555) on mitochondrial metabolism and NLRP3 inflammasome activation.
Results: Palmitoylation of COX-2Cys555 enhanced its interaction with hexokinase 2 (HK2) to regulate mitochondrial metabolic reprogramming, leading to NLRP3 inflammasome activation and pyroptosis. Pharmacological and genetic suppression of palmitoylation diminished the mitochondrial localization of palmitoylated COX-2 and its interaction with HK2, thereby reducing mitochondrial metabolic reprogramming. Furthermore, genetic intervention targeting DHHC5 (shDhhc5) alleviated NLRP3 activation and pyroptosis, mitigating the chronic inflammatory damage associated with PACS.
Conclusion: This study highlights the regulatory role of COX-2Cys555 palmitoylation in mitochondrial metabolism and lung inflammatory injury, and suggests potential therapeutic targets to combat respiratory pathogenesis linked to palmitoylated COX-2.
Keywords: COX-2 palmitoylation; Lung inflammatory injury; Mitochondrial metabolic reprogramming; NLRP3 inflammasome activation; Post-acute COVID-19 syndrome (PACS); SARS-CoV-2 spike protein.