PPARα suppresses growth of hepatocellular carcinoma in a high-fat diet context by reducing neutrophil extracellular trap release

Background & Aims: The role of infiltrating neutrophils in hepatocellular carcinoma (HCC) is modulated by cellular metabolism, specifically lipid homeostasis. Throughout the progression of HCC, alterations in lipid metabolism are intricately linked with regulation of neutrophil function and the release of neutrophil extracellular traps (NETs). However, how much the protumor effect of a high-fat diet (HFD) depends on NETs and the potential interplay between NETs and other leukocytes in HCC remains uncertain. Methods: In this study, the molecular mechanism of NET release and the potential beneficial effects of PPARa agonists on the HCC microenvironment were explored through proteomics, metabolomics, tissue microarray, immunofluorescence, flow cytometry, western blot, and dual-luciferase reporter gene assays (n = 6 per group). Results: Our study demonstrated a notable inhibition of PPARa signaling in HCC. Furthermore, the disruption of PPARa-mediated lipid metabolism was responsible for the release of NETs. The presence of a HFD was observed to induce mitochondrial impairment in neutrophils, leading to the activation of cGAS-STING by oxidized mitochondrial DNA (Ox-mtDNA). Consequently, this activation triggered the release of NETs containing Ox-mtDNA through the enhancement of NLRP3-GSDMD-N in a NF-KB- dependent manner. Moreover, the release of NETs within HCC tissues effectively isolated cytotoxic leukocytes in the outer regions of HCC. Conclusions: Our study not only provides insight into the relationship between lipid metabolism disorders and NETs' tumor- promoting function, but also provides an important strategic reference for multi-target or combined immunotherapy of HCC. (c) 2024 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver (EASL). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).