Targeting piRNA‐137463 Inhibits Tumor Progression and Boosts Sensitivity to Immune Checkpoint Blockade via De Novo Cholesterol Biosynthesis in Lung Adenocarcinoma

Abstract

The important role of PIWI‐interacting RNAs (piRNAs) in tumors has garnered increasing attention. However, research on their role in lung adenocarcinoma (LUAD) remains limited. Elevated levels of piRNA‐137463 have been linked to poor prognosis in LUAD patients. Inhibition of piRNA‐137463 curbed the proliferation, migration, and invasion of LUAD cells, enhanced T cell cytotoxicity through increased IFN‐γ secretion, disrupted cholesterol metabolism, and reduced intracellular cholesterol, lipid raft content, and PD‐L1 expression in LUAD cells. Bioinformatic prediction identified a potential interaction between piRNA‐137463 and lncRNA LOC100128494. Inhibiting piRNA‐137463 increased the stability and expression of LOC100128494, which further modulated insulin‐induced gene 1 protein (INSIG1) levels via a competitive endogenous RNA network involving LOC100128494 and miR‐24‐3p. Notably, the effect of piRNA‐137463 in LUAD cells is dependent on the expression of LOC100128494 and INSIG1. Inhibiting the expression of piRNA‐137463 with AntagopiRNA‐137463 suppressed tumor growth and metastasis via LOC100128494 in nude mice and enhanced the response of LUAD to anti‐PD‐1 therapy in immune‐competent mice. In summary, this study elucidates the role of piRNA‐137463 in the reprogramming of cholesterol metabolism, which drives the progression of LUAD, thereby identifying a new target for the comprehensive clinical management of LUAD.