Identification of a novel prognostic signature related to PANoptosis and its regulatory mechanism as well as targeted treatment of active ingredients and traditional Chinese medicine in lung adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) with a poor prognosis is the most common type of lung cancer, and one of the most aggressive and rapidly fatal tumor types. PANoptosis is a newly identified pro-inflammatory programmed cell death pathway controlled by the recently discovered cytoplasmic polymeric protein complex is called a PANoptosome. PANoptosome Components are linked to a variety of human diseases, including autoinflammatory diseases, cancer, etc. However, the specific effect of PANoptosis regulatory factors in regulating the prognosis and potential mechanism in lung adenocarcinoma is unclear. Here, we ultimately identified 14 differentially expressed PANoptosis related regulators by comparing unpaired and paired lung adenocarcinoma samples and summarized the genetic mutations and molecular correlations of PANoptosis regulators in LUAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that these PANoptosis factors were mainly involved in the NOD-like receptor signaling pathway, necroptosis, TNF signaling pathway, apoptosis, and IL-17 signaling pathway. PANoptosis related prognostic signature based on three genes (FADD, MAP3K7, and NLRP3) has a good performance in prognostic prediction models of LUAD patients. The validation results showed that the expression trend of the FADD gene and protein was in agreement with the previous analysis results of the Cancer Genome Atlas (TCGA) database. In addition, we found that the expression of FADD was involved in most immune infiltrating cell types. We also found the regulatory axis of lncRNA TUG1/ miR-128–3p /FADD in the progression of LUAD. Besides, we found that resveratrol, quercetin, capsaicin, as well as Silybum marianum (L.) Gaertn. (Shui Fei Ji), Schisandra chinensis (Turcz.) Baill. (Wu Wei Zi), Mangifera indica L. (Mang Guo), Panax ginseng C.A.Mey. (Ren Shen) are potential therapeutic drugs targeting PANoptosis prognostic signature FADD. In a word, we analyzed and identified a novel PANoptosis related prognostic signature FADD as a potential biomarker for LUAD, and revealed its role in regulating immune microenvironment, as well as found its potential lncRNA TUG1/ miR-128–3p/FADD regulatory axis and targeted therapy traditional Chinese medicine (TCM) and active ingredients, which provides a basis for the development of new targeted immunotherapy drugs.