Updated publication reference for PubMed record(s): 31723016. We previously reported that tumor-cell inflammasomes play a key role in tumor control and act as favorable prognostic markers in nasopharyngeal carcinoma (NPC). Activated inflammasomes frequently form distinguishable ASC specks and govern the cellular secretion of IL-1. However, we know little about the biological and biochemical differences between cells with and without ASC speck formation. In this study, we used proteomic iTRAQ analysis to analyze the proteomes of NPC cells that differ in their apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC) speck formation upon cisplatin treatment. We identified proteins that were differentially over-expressed in cells with specks, and found that they fell into two Gene ontology (GO) pathways: mitochondrial oxidative phosphorylation (OxPhos) and ubiquinone metabolism. We observed up-regulation of various components of the OxPhos machinery (including NDUFB3, NDUFB8 and ATP5B), and subsequently found that these changes lead to mitochondrial ROS (mtROS) production, which promotes the formation and activation of NLRP3 inflammasomes and subsequent pyroptosis. In NPC patients with [Define this term?] high-NLRP3 tumors, better recurrence-free survival was significantly associated with high-level expression of NDUFB8 (P=0.037) and ATP5B (P=0.029), as examined using immunohistochemistry. Together, our results demonstrate that upregulated mitochondrial OxPhos components are strongly associated with NLRP3 inflammasome activation in NPC. Our findings further suggest that high-level expression of OxPhos components could be prognostic markers and/or promising therapeutic targets in patients with NPC.