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

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.