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  3. Palmitoylated COX-2Cys555 reprogrammed mitochondrial metabolism in pyroptotic inflammatory injury in patients with post-acute COVID-19 syndrome

Palmitoylated COX-2Cys555 reprogrammed mitochondrial metabolism in pyroptotic inflammatory injury in patients with post-acute COVID-19 syndrome

  • J Adv Res. 2025 May 9:S2090-1232(25)00299-1. doi: 10.1016/j.jare.2025.05.005.
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

Affiliations

  • 1 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: 326202056090@stu.xmu.edu.cn.
  • 2 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: nlrp3cy09@63.com.
  • 3 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: 326202250857@stu.xmu.edu.cn.
  • 4 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: 32620190153928@stu.xmu.edu.cn.
  • 5 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: 32620191150574@stu.xmu.edu.cn.
  • 6 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: chelin@sysucc.org.cn.
  • 7 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: 32620231150891@stu.xmu.edu.cn.
  • 8 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: 32620231150884@stu.xmu.edu.cn.
  • 9 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: litingdong@xmu.edu.cn.
  • 10 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: sxge@xmu.edu.cn.
  • 11 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: zhangtianying@xmu.edu.cn.
  • 12 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: linzhn@xmu.edu.cn.
  • 13 State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiang'an Hospital of Xiamen University, National Innovation Platform for Industry-Education Integration in Vaccine Research, School of Public Health, Xiamen University, Xiamen 361102, China. Electronic address: linych@xmu.edu.cn.
PMID: 40349960 DOI: 10.1016/j.jare.2025.05.005
Abstract

Introduction: The complex interplay between protein palmitoylation, mitochondrial dynamics, and inflammatory responses plays a pivotal role in respiratory diseases. One significant feature 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 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.

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