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

Abstract

Listen

Translate article

Background & AimsThe 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 various signaling that regulate neutrophil function and the release of neutrophil extracellular traps (NETs). However, the dependence of high-fat diet (HFD) on NETs for regulating the development of HCC and the potential interplay between NETs and other leukocytes remains uncertain. MethodsIn this study, the molecular mechanism of NETs release and the potential improvement of the HCC microenvironment by PPARα agonists were explored through proteomics, metabolomics, tissue microarray, immunofluorescence, flow cytometry, Western blot, and dual-luciferase reporter gene assay (n = 6 per group). ResultsOur study demonstrated a notable inhibition of PPARα signaling in HCC. Furthermore, the disruption of PPARα-mediated lipid metabolism was responsible for the release of NETs. The presence of 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-κB-dependent manner. Moreover, the release of NETs within HCC tissues effectively isolated cytotoxic leukocytes in the outer regions of HCC cells. ConclusionsOur study not only enriched the relationship between lipid metabolism disorders and NETs’ tumor-promoting function, but also provided an important strategic reference for multi-target or combined immunotherapy of HCC. Impact and implicationsWe have identified PPARα and its agonists as therapeutic targets for controlling the neutrophil extracellular traps associated with high lipid metabolism. Results from preclinical models suggest that PPARα can limit mitochondrial oxidative stress, inhibit cGAS-STING-NF-κB signaling, and limit the release of neutrophil extracellular traps, thereby increasing the contact of anti-tumor leukocytes and hepatocellular cancer cells, thereby limiting tumor growth.