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

作者：Jia‐Shen Wu, Chi-Yu Xu, Su-Min Mo, Xin-Mou Wu, Ze‐Bang Du, Lin Che, Yi-Ling Zhang, Kaili Yang, Tingdong Li, Shengxiang Ge, Tianying Zhang, Zhong‐Ning Lin, Yu-Chun Lin · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.05.005 · 被引用次数：7 · 研究领域：Inflammasome and immune disorders、interferon and immune responses、Respiratory Support and Mechanisms

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-2 Cys555 ) on mitochondrial metabolism and NLRP3 inflammasome activation. Results Palmitoylation of COX-2 Cys555 enhanced its interaction with hexokinase 2 (HK2) to regulate mitochondrial metabolic reprogramming, leading to NLRP3 inflammasome activation and pyropt...