MARCH1 promotes malignant progression in lung adenocarcinoma by regulating PLPP3 ubiquitination.
BACKGROUND Lung adenocarcinoma (LUAD) is a malignant tumor characterized by high invasiveness and poor prognosis. Although phospholipid phosphatase 3 (PLPP3) is downregulated in LUAD, its functional mechanisms in this cancer remain poorly understood. METHODS The expression levels of PLPP3 and membrane-associated RING-CH-1 (MARCH1) in LUAD tissues and cells were evaluated using the Gene Expression Profile Interactive Analysis (GEPIA) database, Gene Expression Omnibus (GEO), quantitative real-time polymerase chain reaction (qRT-PCR), and Western blot techniques. The roles of MARCH1 and PLPP3 in LUAD were investigated through functional assays (colony formation, flow cytometry, wound healing assay, Transwell assay, nude mouse xenograft model, immunohistochemistry (IHC), Fe²⁺ detection, malondialdehyde (MDA) detection, glutathione (GSH) detection, lipid reactive oxygen species (ROS) detection, and cell counting kit-8 (CCK-8) assay). Mechanistic studies, including co-immunoprecipitation (Co-IP), ubiquitination assay, and cycloheximide (CHX) chase experiments, were conducted to elucidate their potential regulatory mechanisms. RESULTS PLPP3 was downregulated in LUAD. PLPP3 suppressed cell proliferation, promoted apoptosis, inhibited migration and invasion in LUAD cells, and impaired tumor growth in vivo. In addition, PLPP3 downregulated glutathione peroxidase 4 (GPX4) and upregulated acyl-coA synthetase long chain family member 4 (ACSL4), elevated Fe²+ and MDA levels, reduced GSH levels, and increased lipid ROS levels. These effects could be reversed by ferroptosis inhibitor Ferrostatin‑1 (Fer‑1) and Liproxstatin-1 (Lip-1). Furthermore, MARCH1 promoted the K48- and K63-linked polyubiquitination of PLPP3, thereby leading to the rapid proteasomal degradation of PLPP3. Rescue experiments demonstrated that MARCH1 enhanced the malignant phenotypes of LUAD cells, inhibited ferroptosis, and promoted tumor progression by suppressing PLPP3 expression. CONCLUSION MARCH1 promotes the malignant progression of LUAD by regulating the ubiquitination of PLPP3, highlighting its potential as a therapeutic target.