Targeting FCRLA to Induce Necrosis in Lung Adenocarcinoma: A Novel Strategy for Prognosis and Therapy via MPT-Driven Pathways

Xiaoli Sun¹Bowen Cai²Shusen Zhang³Xiaowei Cao¹Zhen Wang¹Zhigang Cai^2*

• ¹Shijiazhuang People’s Hospital, Shijiazhuang, Hebei Province, China
• ²Second Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
• ³Xingtai City People's Hospital, Xingtai, Hubei Province, China

The induction of mitochondrial permeability transition-driven necrosis (MPTDN) is therapeutically relevant in various cancers. However, few studies have explored the role of MPTDNrelated genes (MPTDNRGs) in lung adenocarcinoma (LUAD). Therefore, this study investigated the regulatory mechanisms of MPTDNRGs in LUAD. Methods: This study was based on The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD), GSE31210, and MPTDNRGs. First, the genes obtained from TCGA-LUAD were intersected through differential expression analysis and weighted gene co-expression network analysis (WGCNA) to obtain the candidate FCRLA gene. An FCRLA knockdown cell model was constructed in vitro using LUAD cells, and cell-related phenotypic experiments, including proliferation and apoptosis, were performed. The integrity of the mitochondrial structure was observed using electron microscopy, and the mitochondrial membrane potential was detected using a JC-1 probe. Results: A total of 82 candidate genes were identified by intersecting 3,231 differentially expressed genes with 566 key module genes. Subsequently, three prognostic genes (RASGRP2, CD79A, and FCRLA) were further screened. CD79A and FCRLA were significantly expressed in the LUAD group, whereas the opposite was true for RASGRP2. In vitro studies indicated that FCRLA knockdown significantly inhibited the proliferation of LUAD cells and induced necrosis in these cells. Electron microscopy found that the mitochondrial structure was disrupted after FCRLA knockdown. The JC-1 probe indicated that the mitochondrial membrane potential in the FCRLA-knockdown group was significantly reduced, suggesting impaired mitochondrial function. Discussion: RASGRP2, CD79A, and FCRLA have been identified as being associated with MPTDN in LUAD cells. FCRLA knockdown may suppress mitochondrial permeability transition through specific pathways, thereby driving LUAD cell necrosis and providing potential targets for subsequent LUAD treatment.